BOOK OF
ABSTRACTS
IMPRESSUM
ORGANIZER Croatian Chemical Society, Zagreb, Croatia Section of Medicinal/Pharmaceutical Chemistry www.hkd.hr
PUBLISHED BY Croatian Chemical Society, Zagreb, Croatia
EDITORS Nikola Basarić, Danijel Namjesnik, Ivana Perković, Višnja Stepanić
DESIGN Danijel Namjesnik
TEXT PREPARED BY Authors, who are fully responsible for the abstracts
CONFERENCE VENUE Sheraton Dubrovnik Riviera Hotel Šetalište dr. F. Tuđmana 17 - 20207, Srebreno, Mlini, Croatia www.sheratondubrovnikriviera.com Tel: +385 (0)20 601 500
ISBN 978-953- 55232-8- 4 CIP zapis je dostupan u računalnome katalogu Nacionalne i sveučilišne knjižnice u Zagrebu pod brojem 000000000.
Zagreb, 2017
ORGANIZER
Section of Medicinal/Pharmaceutical Chemistry of the Croatian Chemical Society Zagreb, Croatia
SILVER PARTNER
SUPPORTED BY
SPONSORS
SPONSORS
MEDIA PARTNERS
The 10th Joint Meeting on Medicinal Chemistry 2017
Dear Participants,
The 10th JMMC follows the tradition created by several European national medicinal chemistry societies to organize these joint scientific events in the years between the biennial International Symposia on Medicinal Chemistry (EFMC/ISMC). Various European cities have hosted the JMMC since the first one 1999 in Taormina: Budapest (2001 and 2009), Krakow (2003), Vienna (2005), Portorož (2007), Catania (2011), Lublin (2013) and the most recent one in Athens (2015). The JMMCs is an important scientific event in the field of medicinal chemistry which gives the opportunity for networking of the participants coming mainly from the nine middle European countries: Austria, Croatia, Czech Republic, Greece, Hungary, Italy, Poland, Slovakia and Slovenia. This leads us to the principal aims of the Meeting: dissemination of research results, training of young researchers and enhancement of transnational collaborations between scientists from academia as well as industry. The 10th JMMC will continue the tradition and will cover drug discovery advances in the major therapeutic areas, including anti-infectives, neurodegenerative diseases and oncology. JMMC 2017 will present various topics which will cover advances in approaches for hit findings and accelerating lead optimization process, exploration of new chemical entities from nature, discovery of small molecule chemical probes, optimization of drug delivery and computational medicinal chemistry. Our intention is to get together scientists from different countries, disciplines and sectors, and in a relaxed atmosphere discuss and rationalize results and challenges associated with new drug discovery. As you know, Dubrovnik is one of the most visited spots on the Croatian coastline, where Mediterranean grace, rich history and culture fusion in a unique beauty and harmony. Looking forward to seeing You in Dubrovnik, the Pearl of the Adriatic!
Vesna Gabelica Marković Head of the Section of Medicinal/Pharmaceutical Chemistry of the Croatian Chemical Society
6 The 10th Joint Meeting on Medicinal Chemistry 2017
NATIONAL ORGANIZING COMMITTEE
Vesna Gabelica Marković (Chair) Croatian Chemical Society, Zagreb Nikola Basarić Ruđer Bošković Institute, Zagreb Ivanka Jerić Ruđer Bošković Institute, Zagreb Sanja Koštrun Fidelta Ltd., Zagreb Danijel Namjesnik Faculty of Science, University of Zagreb Ivana Perković Faculty of Pharmacy and Biochemistry, University of Zagreb Silvana Raić-Malić Faculty of Chemical Engineering and Technology, University of Zagreb Rosana Ribić Faculty of Science, University of Zagreb Višnja Stepanić Ruđer Bošković Institute, Zagreb Ines Vujasinović Fidelta Ltd., Zagreb
7 The 10th Joint Meeting on Medicinal Chemistry 2017
INTERNATIONAL ORGANIZING COMMITTEE
Vesna Gabelica Marković (Chair) Croatian Chemical Society, Zagreb, Croatia Schnürch Michael Vienna University of Technology, Vienna, Austria Jarmila Vinšová Charles University in Prague, Prague, Czech Republic Emmanuel Mikros National and Kapodistrian University of Athens, Athens, Greece János Wölfling University of Szeged, Szeged, Hungary Girolamo Cirrincione University of Palermo, Palermo, Italy Katarzyna Kieć-Kononowicz Jagiellonian University Medical College, Kraków, Poland Andrej Boháč Comenius University in Bratislava, Bratislava, Slovakia Marko Anderluh University of Ljubljana, Ljubljana, Slovenia
8 The 10th Joint Meeting on Medicinal Chemistry 2017
INTERNATIONAL SCIENTIFIC COMMITTEE
Marko Mihovilovic Vienna University of Technology, Vienna, Austria Višnja Stepanić Ruđer Bošković Institute, Zagreb, Croatia Jarmila Vinšová Charles University in Prague, Prague, Czech Republic Anna Tsantili National and Kapodistrian University of Athens, Athens, Greece Péter Mátyus Semmelweis University, Budapest, Hungary Gabriele Costantino University of Parma, Parma, Italy Dariusz Matosiuk Medical University of Lublin, Poland Milan Remko Comenius University in Bratislava, Bratislava, Slovakia Danijel Kikelj University of Ljubljana, Ljubljana, Slovenia
9 The 10th Joint Meeting on Medicinal Chemistry 2017
PLENARY LECTURERS
Nenad Ban (ETH Zürich, CH) Beyond the Prokaryotic Ribosome: Structural and Functional Insights Into Eukaryotic and Mitochondrial Ribosomes
Gerhard Klebe (University of Marburg, DE) What Thermodynamics Can Help to Understand Protein-Ligand Binding in Medicinal Chemistry
Paul Brennan (University of Oxford, UK) Chemical Probes in Target Discovery
Margot Ernst (Medical University Vienna, AT)
GABAA Receptor Subtypes: A Structure Guided Path to Selective Compounds
Ivo Piantanida (Ruđer Bošković Institute, HR) Design of Small Molecular Probes for Proteins and DNA / RNA
Martin Krátký (Charles University, CZ) Oligotuftsin-based Carriers for Novel Antimycobacterial Active Agents and Their Conjugates
10 The 10th Joint Meeting on Medicinal Chemistry 2017
PLENARY LECTURERS
Grigoris Zoidis (National and Kapodistrian University of Athens, GR) Metal Chelating Agents Against Viruses and Parasites
János Wölfling (University of Szeged, HU) Old Scaffolds in New Role: Steroids as Antiproliferative Agents
Girolamo Cirrincione (University of Palermo, IT) Marine Environment Inspires Kinases Inhibitors
Jadwiga Turlo (Medical University of Warsaw, PL) Polysaccharides as Biological Response Modifiers: Structure-Activity Relationship
Stanislav Gobec (University of Ljubljana, SI) New Hits and Leads for Neurodegenerative Disorders
11 The 10th Joint Meeting on Medicinal Chemistry 2017
KEYNOTE LECTURERS
Hannes Mikula (Technical University Vienna, AT) Pretargeted Prodrug Activation Through Bioorthogonal Elimination
Vesna Eraković Haber (Fidelta Ltd., HR) Patient Derived Testing Systems – Reaching Beyond Targed Based Drug Discovery
Robert Vianello (Ruđer Bošković Institute, HR) Computational Insight into the Catalytic Activity of Monoamine Oxidase Enzyme for Targeting Neurological Diseases
Marta Kučerová-Chlupáčová (Charles University, CZ) Antimicrobial Potential of 1,2,4-Oxadiazoles and Their Synthesis
Radim Nencka (Czech Academy of Sciences, CZ) Rational Design of PI4KB Inhibitors as Potential Broad-spectrum Antiviral Agents
Nektarios Aligiannis (National and Kapodistrian University of Athens, GR) Can Multivariate Statistics Aid to the Reveal of Bioactive Compounds? An NMR and HPTLC Approach
Vasiliki Sarli (Aristotle University of Thessaloniki, GR) New Drug Conjugates Based on Azasteroids or Peptides for Targeted Drug Delivery in Cancer Therapy
Marco Macchia (University of Pisa, IT) Endocannabinoid System Modulation: Therapeutic Implications and Future Perspectives
12 The 10th Joint Meeting on Medicinal Chemistry 2017
KEYNOTE LECTURERS
Gianluca Sbardella (University of Salerno, IT) A "Library-on-Library" Screening Approach to Identify Small-Molecule Ligands of Methyl-Lysine Reader Proteins
Krzysztof Kaminski (Jagiellonian University, PL) Hybrid Compounds in the Search for the New Highly Effective Anticonvulsants
Maciej Dawidowski (Medical University of Warsaw, PL) Disrupting the PEX14-PEX5 Interaction by Small Molecules Provides a Novel Strategy for Treatment of Trypanosoma Infections
Magdaléna Májeková (Slovak Academy of Sciences, SK) Ligand-based Drug Design of Novel Aldose Reductase Inhibitors from Databases of Indole-1-Acetic Acids
Pavol Jakubec (Slovak University of Technology, SK; Harward University, USA) A Platform for the Discovery of New Macrolide Antibiotics
Matej Sova (University of Ljubljana, SI) Design and Synthesis of Novel Modulators of Toll-like Receptors and Inhibitors of Indoleamine 2,3-Dioxygenase (IDO1)
Nace Zidar (University of Ljubljana, SI) Discovery of N-phenylpyrrolamides as ATPase Inhibitors of DNA Gyrase and Topoisomerase IV
13 The 10th Joint Meeting on Medicinal Chemistry 2017
KEYNOTE LECTURERS
SUNDAY, JUNE 25
14:00-17:00 Registration 17:00-17:30 Opening of the Meeting A WAY FORWARD TO NEW ANTI-INFECTIVES Moderator: Gabriele Costantino (Italy) Nenad Ban (ETH Zürich, CH) 17:30-18:15 PL-1 Beyond the Prokaryotic Ribosome: Structural and Functional Insights Into Eukaryotic and Mitochondrial Ribosomes Pavol Jakubec (Slovak University of Technology, SK; Harward University, USA) 18:15-18:45 KL-1 A Platform for the Discovery of New Macrolide Antibiotics Martin Krátký (Charles University, CZ) 18:45-19:25 PL-2 Oligotuftsin-based Carriers for Novel Antimycobacterial Active Agents and Their Conjugates 19:30 Welcome party MONDAY, JUNE 26 RATIONAL APPROACH TO THE DESIGN OF NOVEL DRUGS Moderator: Margot Ernst (Austria) Gerhard Klebe (University of Marburg, DE) 9:00-9:45 PL-3 What Thermodynamics Can Help to Understand Protein-Ligand Binding in Medicinal Chemistry Nace Zidar (University of Ljubljana, SI) 9:45-10:15 KL-2 Discovery of N-phenylpyrrolamides as ATPase Inhibitors of DNA Gyrase and Topoisomerase IV 10:15-10:45 Coffee break ANTI-INFECTIVE CASE STUDIES Moderator: Marko Anderluh (Slovenia) Grigoris Zoidis (National and Kapodistrian University of Athens, GR) 10:45-11:25 PL-4 Metal Chelating Agents Against Viruses and Parasites Marta Kučerová-Chlupáčová (Charles University, CZ) 11:25-11:55 KL-3 Antimicrobial Potential of 1,2,4-Oxadiazoles and Their Synthesis Radim Nencka (Czech Academy of Sciences, CZ) 11:55-12:25 KL-4 Rational Design of PI4KB Inhibitors as Potential Broad-spectrum Antiviral Agents 12:25-15:00 Lunch – POSTER SESSION I FILLING THE GAP IN THE DISCOVERY OF NEW ANTI-CANCER DRUGS Moderator: Ivo Piantanida (Croatia) Girolamo Cirrincione (University of Palermo, IT) 15:00-15:40 PL-5 Marine Environment Inspires Kinases Inhibitors Matej Sova (University of Ljubljana, SI) 15:40-16:10 KL-5 Design and Synthesis of Novel Modulators of Toll-like Receptors and Inhibitors of Indoleamine 2,3-Dioxygenase (IDO1) 16:10-16:30 Coffee break János Wölfling (University of Szeged, HU) 16:30-17:10 PL-6 Old Scaffolds in New Role: Steroids as Antiproliferative Agents Vasiliki Sarli (Aristotle University of Thessaloniki, GR) 17:10-17:40 KL-6 New Drug Conjugates Based on Azasteroids or Peptides for Targeted Drug Delivery in Cancer Therapy 18:30 Trip to Dubrovnik
14 The 10th Joint Meeting on Medicinal Chemistry 2017
TUESDAY, JUNE 27 LOOKING AT THE EPIGENETIC LEVEL Moderator: János Wölfling (Hungary) Paul Brennan (University of Oxford, UK) 9:00-9:45 PL-7 Chemical Probes in Target Discovery Gianluca Sbardella (University of Salerno, IT) 9:45-10:15 KL-7 A "Library-on-Library" Screening Approach to Identify Small-Molecule Ligands of Methyl-Lysine Reader Proteins 10:15-10:35 Coffee break IN SEARCH FOR NOVEL BIOLOGICALLY ACTIVE MOLECULES Moderator: Jadwiga Turlo (Poland) Margot Ernst (Medical University Vienna, AT) 10:35-11:15 PL-8 GABAA Receptor Subtypes: A Structure Guided Path to Selective Compounds Maciej Dawidowski (Medical University of Warsaw, PL) 11:15-11:45 KL-8 Disrupting the PEX14-PEX5 Interaction by Small Molecules Provides a Novel Strategy for Treatment of Trypanosoma Infections Krzysztof Kaminski (Jagiellonian University, PL) 11:45-12:15 KL-9 Hybrid Compounds in the Search for the New Highly Effective Anticonvulsants Nektarios Aligiannis (National and Kapodistrian University of Athens, GR) 12:15-12:45 KL-10 Can Multivariate Statistics Aid to the Reveal of Bioactive Compounds? An NMR and HPTLC Approach 12:45-14:00 Lunch TARGETING NEURODEGENERATIVE DISORDERS Moderator: Vesna Eraković Haber (Croatia) Stanislav Gobec (University of Ljubljana, SI) 14:00-14:40 PL-9 New Hits and Leads for Neurodegenerative Disorders Marco Macchia (University of Pisa, IT) 14:40-15:10 KL-11 Endocannabinoid System Modulation: Therapeutic Implications and Future Perspectives Robert Vianello (Ruđer Bošković Institute, HR) 15:10-15:40 KL-12 Computational Insight into the Catalytic Activity of Monoamine Oxidase Enzyme for Targeting Neurological Diseases 15:40-17:00 Coffee break – POSTER SESSION II ORAL PRESENTATIONS – section I Moderator: Magdaléna Májeková (Slovak Republic) Manabu Kawada (Institute of Microbial Chemistry - BIKAKEN, JP) 17:00-17:15 OP-1 Anti-Helicobacter Pylori Activity of a Novel Derivative of Intervenolin Nela Malatesti (University of Rijeka, HR) 17:15-17:30 OP-2 In vitro Photodynamic Activity of a New Tri-Cationic Amphiphilic Porphyrin Against Herpes Simplex Virus 1, Bacteria And Cancer Cells Giannamaria Annunziato (University of Parma, IT) 17:30-17:45 OP-3 Discovery of New, Potential Anti-Infective Compounds Based on Carbonic Anhydrase Inhibitors by Rational Target-Focus Repurposing Approach Michaela Barančoková (University of Ljubljana, SI) 17:45-18:00 OP-4 Discovery of Novel Gyrase B Inhibitors and Gyrase B/Topoisomerase IV (ParE) Dual Inhibitors with In Vitro Antibacterial Activity Tommaso Felicetti (University of Perugia, IT) 18:00-18:15 OP-5 Fighting Antimicrobial Resistance by Breaking Resistance Mechanisms Dmitry Tsvelikhovsky (The Hebrew University of Jerusalem, IL) 18:15-18:30 OP-6 α-Enaminones: New Building Blocks for Direct Synthesis of Biologically Active Alkaloids Marcin J. Cieślak (Polish Academy of Sciences, PL) 18:30-18:45 OP-7 Novel Benzo[b]furan Derivatives – Biological Activity and Protein Target Identification in Leukemic Cells Moran Shubely (Bar-Ilan University, IL) 18:45-19:00 OP-8 Development of Novel Drug Candidate Against Prostate Cancer
15 The 10th Joint Meeting on Medicinal Chemistry 2017
ORAL PRESENTATIONS – section II Moderator: Jarmila Vinšová (Czech Republic) Rafał Kurczab (Polish Academy of Sciences, PL) 17:00-17:15 OP-9 Evaluation of Halogen Bonding Hot Spots by Virtual Screening of Commercial Databases – a Case Study of 5-HT7R Jaroslaw Polanski (University of Silesia, PL) 17:15-17:30 OP-10 Big Data: Avogadro Stoichiometry Explains Hyperbolic Ligand Efficiency Trend Vassilios Myrianthopoulos (University of Athens, GR) 17:30-17:45 OP-11 From Public Domain Compound Collections to Cell-Active Epigenetic Modulators. The Case of the NCI Repository Thavendran Govender (University of KwaZulu Natal, ZA) 17:45-18:00 OP-12 Mass Spectrometric Imaging as a Preclinical Tool for Medicinal Chemists David Chan Bodin Siebert (Technical University Vienna, AT) 18:00-18:15 OP-13 Pyrazoloquinolinones, Revisited GABAA Receptor Tool Compounds Svetlana Maklakova (Lomonosov Moscow State University, RU) 18:15-18:30 OP-14 Synthesis of Tissue-Specific Conjugates for Targeted Drug Delivery Into Hepatic Cells Rosana Leiva (Universitat de Barcelona, ES) 18:30-18:45 OP-15 Novel Polycyclic N-acylpyrrolidines as 11β-HSD1 Inhibitors Maria Majellaro (University of Santiago de Compostela, ES) 18:45-19:00 OP-16 Enantiospecific Modulation Of A2B Adenosine Receptor 20:00 Gala Dinner WEDNESDAY, JUNE 28 LIGAND-BASED APPROACH Moderator: Gianluca Sbardella (Italy) Jadwiga Turlo (Medical University of Warsaw, PL) 9:00-9:40 PL-10 Polysaccharides as Biological Response Modifiers: Structure-Activity Relationship Magdaléna Májeková (Slovak Academy of Sciences, SK) 9:40-10:10 KL-13 Ligand-based Drug Design of Novel Aldose Reductase Inhibitors from Databases of Indole-1-Acetic Acids Hannes Mikula (Technical University Vienna, AT) 10:10-10:40 KL-14 Pretargeted Prodrug Activation Through Bioorthogonal Elimination 10:40-11:00 Coffee break FROM MOLECULAR PROBES TO CLINICS Moderator: Hannes Mikula (Austria) Ivo Piantanida (Ruđer Bošković Institute, HR) 11:00-11:40 PL-11 Design of Small Molecular Probes for Proteins and DNA / RNA Vesna Eraković Haber (Fidelta Ltd., HR) 11:40-12:10 KL-15 Patient Derived Testing Systems – Reaching Beyond Targed Based Drug Discovery
12:15-12:45 WINNING POSTERS FLASH PRESENTATIONS
12:45-13:00 CLOSING
16 The 10th Joint Meeting on Medicinal Chemistry 2017
CONTENTS
PLENARY LECTURES
PL-1 BEYOND THE PROKARYOTIC RIBOSOME: STRUCTURAL AND FUNCTIONAL INSIGHTS INTO EUKARYOTIC AND MITOCHONDRIAL RIBOSOMES Nenad Ban ...... 31 PL-2 OLIGOTUFTSIN-BASED CARRIERS FOR NOVEL ANTIMYCOBACTERIAL ACTIVE AGENTS AND THEIR CONJUGATES Martin Krátký, Zsuzsa Baranyai, Szilvia Bősze, Nóra Szabó and Jarmila Vinšová...... 32 PL-3 WHAT THERMODYNAMICS CAN HELP TO UNDERSTAND PROTEIN-LIGAND BINDING IN MEDICINAL CHEMISTRY Gerhard Klebe ...... 33 PL-4 METAL CHELATING AGENTS AGAINST VIRUSES AND PARASITES Grigoris Zoidis ...... 34 PL-5 MARINE ENVIRONMENT INSPIRES KINASES INHIBITORS Girolamo Cirrincione...... 35 PL-6 OLD SCAFFOLDS IN NEW ROLE: STEROIDS AS ANTIPROLIFERATIVE AGENTS János Wölfling, Éva Frank, Erzsébet Mernyák, Gyula Schneider, Mihály Szécsi and István Zupkó ...... 36 PL-7 CHEMICAL PROBES IN TARGET DISCOVERY Paul Brennan ...... 37
PL-8 GABAA RECEPTOR SUBTYPES: A STRUCTURE GUIDED PATH TO SELECTIVE COMPOUNDS Konstantina Bampali, David Siebert, Marko D. Mihovilovic, Michael Schnürch, and Margot Ernst ...... 38 PL-9 NEW HITS AND LEADS FOR NEURODEGENERATIVE DISORDERS Urban Košak, Damijan Knez, Boris Brus, Stanislav Gobec ...... 39 PL-10 POLYSACCHARIDES AS BIOLOGICAL RESPONSE MODIFIERS: STRUCTURE-ACTIVITY RELATIONSHIP Jadwiga Turlo ...... 40 PL-11 DESIGN OF SMALL MOLECULAR PROBES FOR PROTEINS AND DNA / RNA Ivo Piantanida ...... 41 PL-12 FROM EXCEPTIONAL KINASE CONFORMATION TO DUAL KINASE INHIBITORS - CHEMISTRY OF 2-AMINOOXAZOLES Andrej Boháč, Peter Šramel, Juraj Dobiaš, Miroslav Murár, Matúš Hlaváč, Maroš Smolíček and Gilles Hanquet ...... 42
KEYNOTE LECTURES
KL-1 A PLATFORM FOR THE DISCOVERY OF NEW MACROLIDE ANTIBIOTICS Ian B. Seiple, Ziyang Zhang, Pavol Jakubec, Peter M. Wright, Audrey Langlois-Mercier, Daniel T. Hog, Kazuo Yabu, Senkara Rao Allu, Takehiro Fukuzaki, Peter N. Carlsen, Yoshiaki Kitamura, Xiang Zhou, Matthew L. Condakes, Filip Szczpinski, William D. Green and Andrew G. Myers ...... 44 KL-2 DISCOVERY OF N-PHENYLPYRROLAMIDES AS ATPASE INHIBITORS OF DNA GYRASE AND TOPOISOMERASE IV Nace Zidar ...... 45 KL-3 ANTIMICROBIAL POTENTIAL OF 1,2,4-OXADIAZOLES AND THEIR SYNTHESIS Marta Kučerová-Chlupáčová, Anastasia Katirtzi, Pavlina Dzamova, Lucie Kolcarkova, Klara Konecna, Ondrej Jandourek and Veronika Opletalova ...... 46
17 The 10th Joint Meeting on Medicinal Chemistry 2017
KL-4 RATIONAL DESIGN OF PI4KB INHIBITORS AS POTENTIAL BROAD-SPECTRUM ANTIVIRAL AGENTS Radim Nencka, Ivana Mejdrová, Dominika Chalupská, Pavla Plačková, Christin Müller, Michal Šála, Eliška Procházková, Adriana Baumlová, Milan Dejmek, Dmytro Strunin, Jan Weber, Gary Lee, Helena Mertlíková- Kaiserová, John Ziebuhr, Gabriel Birkus and Evzen Boura...... 47 KL-5 DESIGN AND SYNTHESIS OF NOVEL MODULATORS OF TOLL-LIKE RECEPTORS AND INHIBITORS OF INDOLEAMINE 2,3-DIOXYGENASE (IDO1) Matej Sova, Urban Švajger, Kaja Rožman, Damijan Knez, Samo Lešnik, Janez Konc and Stanislav Gobec ...... 48 KL-6 NEW DRUG CONJUGATES BASED ON AZASTEROIDS OR PEPTIDES FOR TARGETED DRUG DELIVERY IN CANCER THERAPY Vasiliki Sarli ...... 49 KL-7 A "LIBRARY-ON-LIBRARY" SCREENING APPROACH TO IDENTIFY SMALL-MOLECULE LIGANDS OF METHYL-LYSINE READER PROTEINS Gianluca Sbardella ...... 50 KL-8 APPLICATION OF UGI MULTICOMPONENT REACTION IN SYNTHESIS OF NOVEL 2,6-DIKETOPIPERAZINE DERIVATIVES WITH HIGH AND BROAD ACTIVITY IN ANIMAL MODELS OF EPILEPSY Maciej Dawidowski ...... 51 KL-9 HYBRID COMPOUNDS IN THE SEARCH FOR THE NEW HIGHLY EFFECTIVE ANTICONVULSANTS Krzysztof Kaminski ...... 52 KL-10 CAN MULTIVARIATE STATISTICS AID TO THE REVEAL OF BIOACTIVE COMPOUNDS? AN NMR AND HPTLC APPROACH V. I. Boka, K. Stathopoulou, D. Benaki, E. Gikas, E. Mikros and N. Aligiannis ...... 53 KL-11 ENDOCANNABINOID SYSTEM MODULATION: THERAPEUTIC IMPLICATIONS AND FUTURE PERSPECTIVES Marco Macchia ...... 54 KL-12 COMPUTATIONAL INSIGHT INTO THE CATALYTIC ACTIVITY OF MONOAMINE OXIDASE ENZYME FOR TARGETING NEUROLOGICAL DISEASES Robert Vianello ...... 55 KL-13 LIGAND-BASED DRUG DESIGN OF NOVEL ALDOSE REDUCTASE INHIBITORS FROM DATABASES OF INDOLE-1-ACETIC ACIDS Magdaléna Májeková, Jana Ballekova, Marta Soltesova Prnova and Milan Stefek ...... 56 KL-14 PRETARGETED PRODRUG ACTIVATION THROUGH BIOORTHOGONAL ELIMINATION Hannes Mikula ...... 57 KL-15 PATIENT DERIVED TESTING SYSTEMS – REACHING BEYOND TARGED BASED DRUG DISCOVERY Vesna Eraković Haber ...... 58
ORAL PRESENTATIONS
OP-1 ANTI-HELICOBACTER PYLORI ACTIVITY OF A NOVEL DERIVATIVE OF INTERVENOLIN Manabu Kawada, Tomokazu Ohishi, Hikaru Abe, Chigusa Hayashi, Chiharu Sakashita, Shun-ichi Ohba, Hiroyuki Inoue, Masayuki Igarashi, Takumi Watanabe and Masakatsu Shibasaki ...... 60 OP-2 IN VITRO PHOTODYNAMIC ACTIVITY OF A NEW TRI-CATIONIC AMPHIPHILIC PORPHYRIN AGAINST HERPES SIMPLEX VIRUS 1, BACTERIA AND CANCER CELLS Nela Malatesti, Maja Cokarić Brdovčak, Lara Djaković, Igor Jurak, Anđelo Šuvak, Ivana Gobin, Anja Harej and Sandra Kraljević Pavelić ...... 61 OP-3 DISCOVERY OF NEW, POTENTIAL ANTI-INFECTIVE COMPOUNDS BASED ON CARBONIC ANHYDRASE INHIBITORS BY RATIONAL TARGET-FOCUS REPURPOSING APPROACH G. Annunziato, A. Angeli, F. D’Alba, A. Bruno, M. Pieroni, D. Vullo, V. De Luca, C. Capasso, C. T. Supuran and G. Costantino ...... 62 OP-4 DISCOVERY OF NOVEL GYRASE B INHIBITORS AND GYRASE B/TOPOISOMERASE IV (PARE) DUAL INHIBITORS WITH IN VITRO ANTIBACTERIAL ACTIVITY Michaela Barančoková, Janez Ilaš, Tihomir Tomašič, Nace Zidar, Andraž Lamut, Davide Benedetto Tiz, Päivi Tammela, Antonio Felici, Vanesa Garrido and Danijel Kikelj ...... 63
18 The 10th Joint Meeting on Medicinal Chemistry 2017
OP-5 FIGHTING ANTIMICROBIAL RESISTANCE BY BREAKING RESISTANCE MECHANISMS Tommaso Felicetti, Rolando Cannalire, Giuseppe Manfroni, Maria Letizia Barreca, Sabatini Stefano, and Violetta Cecchetti ...... 64 OP-6 Α-ENAMINONES: NEW BUILDING BLOCKS FOR DIRECT SYNTHESIS OF BIOLOGICALLY ACTIVE ALKALOIDS David Lankri, Ghassan Albarghouti and Dmitry Tsvelikhovsky ...... 65 OP-7 NOVEL BENZO[B]FURAN DERIVATIVES – BIOLOGICAL ACTIVITY AND PROTEIN TARGET IDENTIFICATION IN LEUKEMIC CELLS Marcin J. Cieślak, Karolina Królewska, Julia Kaźmierczak-Barańska, Milena Sobczak, Bożena Kuran, Mariola Napiórkowska, Jerzy Kossakowski, Iwona Wybrańska and Barbara Nawrot ...... 66 OP-8 DEVELOPMENT OF NOVEL DRUG CANDIDATE AGAINST PROSTATE CANCER Moran Shubely, Dhanoop Manikoth Ayyathan, Michael Shokhen, Michael Blank and Arie Gruzman ...... 67 OP-9 EVALUATION OF HALOGEN BONDING HOT SPOTS BY VIRTUAL SCREENING OF COMMERCIAL DATABASES – A CASE STUDY OF 5-HT7R Rafał Kurczab, Grzegorz Satała and Andrzej J. Bojarski ...... 68 OP-10 BIG DATA: AVOGADRO STOICHIOMETRY EXPLAINS HYPERBOLIC LIGAND EFFICIENCY TREND Jaroslaw Polanski, Urszula Kucia, Aleksandra Tkocz, Roksana Duszkiewicz and Anna Pedrys ...... 69 OP-11 FROM PUBLIC DOMAIN COMPOUND COLLECTIONS TO CELL-ACTIVE EPIGENETIC MODULATORS. THE CASE OF THE NCI REPOSITORY Vassilios Myrianthopoulos, Nadine Martinet, Christian Bronner, Jessica Ann Downs, Susanne Müller, Stefan Knapp and Emmanuel Mikros ...... 70 OP-12 MASS SPECTROMETRIC IMAGING AS A PRECLINICAL TOOL FOR MEDICINAL CHEMISTS Thavendran Govender ...... 71
OP-13 PYRAZOLOQUINOLINONES, REVISITED GABAA RECEPTOR TOOL COMPOUNDS David Chan Bodin Siebert, Xenia Simeone, Konstantina Bampali, Marko Mihovilovic, Michael Schnürch and Margot Ernst ...... 72 OP-14 SYNTHESIS OF TISSUE-SPECIFIC CONJUGATES FOR TARGETED DRUG DELIVERY INTO HEPATIC CELLS S. Yu. Maklakova, V. V. Hapko, R. A. Petrov, T. S. Zatsepin, T. O. Abakumova, O. V. Sergeeva, E. K. Beloglazkina, N. V. Zyk, V. E. Koteliansky and A. G. Majouga ...... 73 OP-15 NOVEL POLYCYCLIC N-ACYLPYRROLIDINES AS 11Β-HSD1 INHIBITORS Rosana Leiva, Constantí Seira, Andrew McBride, Margaret Binnie, Axel Bidon-Chanal, F. Javier Luque, Scott P. Webster and Santiago Vázquez ...... 74
OP-16 ENANTIOSPECIFIC MODULATION OF A2B ADENOSINE RECEPTOR Maria Majellaro, Jhonny Azuaje, Carlos Carbajales, Abel Crespo, Angela Stefanachi, Cosimo Altomare, Saverio Cellamare, María I. Loza, José Brea, María I. Cadavid, Hugo Gutiérrez de Terán and Eddy Sotelo...... 75
POSTERS
P-1 FREE RADICAL SCAVENGING POTENCY OF DIHYDROCAFFEIC ACID: THERMODYNAMICS OF 2H+/2e– PROCESSES Ana Amić, Zoran Marković, Jasmina Dimitrić Marković, Bono Lučić and Dragan Amić ...... 77 P-2 RADICAL SCAVENGING AND COX-2 INHIBITION BY COLON METABOLITES OF POLYPHENOLS: A THEORETICAL APPROACH Ana Amić, Zoran Marković, Jasmina M. Dimitrić Marković, Svetlana Jeremić, Bono Lučić and Dragan Amić ...... 78 P-3 CYTOTOXICITY OF A KOJIC ACID DERIVATIVE ON A375 HUMAN MALIGNANT MELANOMA AND HGF1 FIBROBLAST CELLS M. D. Aytemir, G. Karakaya, A. Ercan and S. Öncül ...... 79 P-4 DESIGN AND SYNTHESIS OF NOVEL TARGETED CHEMICAL CHAPERONES AS A BASIS FOR AMYOTROPHIC LATERAL SCLEROSIS (ALS) TREATMENT Salome Azoulay-Ginsburg, Tamar Getter, Edward Korshin and Arie Gruzman ...... 80
19 The 10th Joint Meeting on Medicinal Chemistry 2017
P-5 MULTICOMPONENT SYNTHESIS OF NOVEL ANDROSTANO-PYRIMIDINES AND THEIR PHARMACOLOGICAL EVALUATION IN VITRO Ádám Baji, Éva Frank and Mónika Kiricsi ...... 81 P-6 A COMPARATIVE MOLECULAR MODELLING STUDY OF MAO-A, MAO-B AND SSAO INHIBITORS Balázs Balogh, Michela Contu, Elias Maccioni and Péter Mátyus ...... 82 P-7 IDENTIFICATION OF NEW KDM4 INHIBITORS THROUGH A HTS AND HIT REFINEMENT STRATEGY A. L. Balzano, F. Sarno, C. Milite, G. Franci, I. Forné, L. Altucci, A. Ihmof, S. Castellano and G. Sbardella ...... 83 P-8 SYNTHESIS AND ANTIOXIDATIVE ACTIVITY OF SOME QUATERNARY 3-HYDROXYQUINUCLIDINIUM SALTS DETERMINED BY DPPH METHOD Linda Bazina, Matilda Šprung, Barbara Soldo and Renata Odžak ...... 84 P-9 PHYTOCHEMICAL COMPOSITION AND BIOLOGICAL ACTIVITY OF THE EXTRACTS OF SATUREJA SUBSPICATA VIS. GROWING IN BOSNIA AND HERZEGOVINA Mejra Bektašević, Ivana Carev, Marin Roje, Mladenka Jurin and Olivera Politeo ...... 85 P-10 NOVEL ANTICANCER DRUGS DISPIRO-OXINDOLE SERIES BASED ON VARIOUS TYPES OF HETEROCYCLES: SYNTHESIS AND BIOLOGICAL TESTING A. A. Beloglazkina, A. A.Barashkin, G. A. Kotovskii, M. A. Kunin, N. A. Karpov, M. E. Kukushkin, E. K. Beloglazkina, N. V. Zyk D. A. Skvortsov, N. A. Vorobyeva and A. G. Majouga ...... 86 P-11 OSTEOBLASTIC CELL BEHAVIOUR ON DIFFERENT TITANIUM - SURFACE ANALYSIS M. Lukaszewska-Kuska, R. Majchrowski and B. Dorocka-Bockowska ...... 87 P-12 A NOVEL CLASS OF HIGHLY POTENT SMALL MOLECULE INHIBITORS OF RHINOVIRUS REPLICATION: 6-{[2-(METHYLCARBAMOYL)PYRIDIN-4-YL]OXY}BENZO[B]THIOPHENE-2-CARBOXYLIC ESTER DERIVATIVES S. B. Han, J. W. Kim, U.-K. Jung, J. Y. Lee, C. Kim and Y.-S. Jung ...... 88 P-13 SYNTHESIS, DOCKING AND ANTI-CANDIDA ACTIVITY OF SOME NEW 1,4-PHENYLENE-BISTHIAZOLES AS INHIBITORS OF LANOSTEROL 14α-DEMETHYLASE Anca-Maria Borcea, Ilioara Oniga, Gabriel Marc, Dan C Vodnar, Adrian Pîrnău, Laurian Vlase, Andreea Pricopie, Brîndușa Tiperciuc and Ovidiu Oniga ...... 89 P-14 SCREENING OF BIOLOGICAL ACTIVITY OF CENTAUREA SPECIES AQUEOUS EXTRACTS Ivana Carev, Anja Golemac, Sanda Raić, Jelena Žarković, Ana Kelavić, Maria Šarić, François-Xavier Pellay and Olivera Politeo ...... 90 P-15 ANTIOXIDANT ACTIVITY AND LIPOPHILICITY EVALUATION OF SOME NEW THIAZOLYL-TRIAZOLE SCHIFF BASES Cezar Login, Daniela Benedec, Ioana Ionuţ, Cristina Nastasă, Anca Stana, Ovidiu Oniga and Brîndușa Tiperciuc ...... 91 P-16 NOVEL 2,4-DIAMINOPYRIMIDINE BEARING FUSED TRICYCLIC RING MOIETY FOR ANAPLASTIC LYMPHOMA KINASE (ALK) INHIBITOR Chang-Soo Yun, Chong Ock Lee, Hyoung Rae Kim, Chi Hoon Park, Pilho Kim and Jong Yeon Hwang ...... 92 P-17 TARGETED DELIVERY OF CYTOTOXIC AGENTS VIA cRGD PEPTIDE IN CANCER THERAPY AND THERANOSTICS Theodora Chatzisideri, Savvas Thysiadis, Sotirios Katsamakas, Theodore Lazarides and Vasiliki Sarli ...... 93 P-18 METHODS OF SYNTHESIS OF BIOLOGICALLY ACTIVE ANALOGUES AND HOMOLOGUES AMINOPHOSPHONATES AND AMINOBISHOSPHONATES Ewa Chmielewska, Joanna Wietrzyk and Paweł Kafarski ...... 94 P-19 MOLECULAR MODELING AND DYNAMICS STUDIES OF LIGAND-DEPENDENT CONFORMATIONAL MACROSTATES OF A2A ADENOSINE RECEPTOR Yoonji Lee, Changbong Hyeon and Sun Choi...... 95 P-20 NEW DICARBOXIMIDE DERIVATIVES – ANTICANCER ACTIVITY AND MECHANISM OF ACTION Julia Kaźmierczak-Barańska, Karolina Królewska, Marcin J Cieślak, Milena Sobczak, Bożena Kuran, Mariola Napiórkowska, Jerzy Kossakowski and Barbara Nawrot ...... 96 P-21 ANTIPROLIFERATIVE ACTIVITY OF QUINONE METHIDES WITH BODIPY CHROMOPHORE Matej Cindrić, Nikola Basarić, Irena Martin Kleiner, Lidija Uzelac and Marijeta Kralj ...... 97 P-22 MEPHEDRONE METABOLITES AND DERIVATIVES Daniela Cintulova, Laurin Wimmer, Harald H. Sitte and Marko D. Mihovilovic ...... 98
20 The 10th Joint Meeting on Medicinal Chemistry 2017
P-23 NOVEL SOLUBLE EPOXIDE HYDROLASE INHIBITORS FEATURING A 2-OXAADAMANTANE MOIETY I: PIPERIDINE DERIVATIVES Sandra Codony, Javier Pizarro, Elena Valverde, Eugènia Pujol, M. Isabel Loza, J. Manuel Brea, Elena Sáez, Julen Oyarzábal, Belén Pérez, Rosana Leiva, Manuel Vázquez-Carrera and Santiago Vázquez ...... 99 P-24 NOVEL SOLUBLE EPOXIDE HYDROLASE INHIBITORS FEATURING A 2-OXAADAMANTANE MOIETY II: AROMATIC DERIVATIVES Eugènia Pujol, Javier Pizarro, Elena Valverde, Sandra Codony, Tiziana Ginex, M. Isabel Loza, J. Manuel Brea, Belén Pérez, Elena Sáez, Julen Oyarzábal, F. Javier Luque, Rosana Leiva, Manuel Vázquez-Carrera, Santiago Vázquez ...... 100 P-25 BIOLOGICAL ACTIVITIES OF EXTRACTS FROM THYME (THYMUS VULGARIS) LEAVES Biljana Damjanović-Vratnica, Slađana Krivokapić, Snežana Pantović and Svetlana Perović ...... 101 P-26 SYNTHESIS, ANTICANCER ACTIVITY AND DOCKING STUDIES OF NEW PHENYLAMINOPYRIMIDINE DERIVATIVES Aslı Demirci, İrem Durmaz, Rengül Çetin Atalay, and İlkay Küçükgüzel ...... 102 P-27 RADIOLABELED 1,2,4,5-TETRAZINES AS BIOORTHOGONAL IMAGING TOOLS Christoph Denk, Martin Wilkovitsch, Thomas Wanek, Claudia Kuntner Hannes, Dennis Svatunek and Hannes Mikula 103 P-28 IDENTIFICATION OF EXPANDED CAG REPEATS LIGANDS TO COUNTERACT HUNTINGTON’S DISEASE Jenny Desantis, Kenji Schorp, Serena Massari, Anna Bochicchio, Frank Matthes, Judith Schilling, Stephanie Weber, Nina Offermann, Paolo Carloni, Kamyar Hadian, Giulia Rossetti, Oriana Tabarrini and Sybille Krauss . 104 P-29 SYNTHESIS OF SOME NEW BENZOTHIAZOLONE DERIVATIVES AND INVESTIGATION OF THEIR CHOLINESTERASE INHIBITOR ACTIVITIES Deniz S. Doğruer, Merve Erdoğan and Burcu Kılıç ...... 105 P-30 LONG-CHAIN DERIVATIVES OF (TRIFLUOROMETHYLPHENYL)PIPERAZINES – SYNTHESIS AND EVALUATION OF THE ACTIVITY TOWARDS 5-HT RECEPTORS Anna Drabczyk, Jolanta Jaśkowska, Damian Kułaga, Grzegorz Satała and Magdalena Malinowska ...... 106 P-31 SYNTHESIS AND EVALUATION OF THE ACTIVITY TOWARDS 5-HT RECEPTORS OF NEW LIGANDS FROM THE LCAPS GROUP Anna Drabczyk, Jolanta Jaśkowska, Damian Kułaga, Grzegorz Satała and Magdalena Malinowska ...... 107 P-32 SYNTHESIS OF PHOTOSWITCHABLE INHIBITORS FOR CNS APPLICATIONS D. Dreier, M. Holy, K. Jäntsch, H. H. Sitte and M. D. Mihovilovic ...... 108 P-33 AER METHOD: A GOOD WAY TO OBTAIN APIs AS IONIC LIQUIDS E. Alcalde, I. Fallon, F. Roig, J. Esquena, M. J. García-Celma and I. Dinarès...... 109 P-34 SYNTHESIS OF SOME NEW BENZOXAZOLONE DERIVATIVES AND EVALUATION OF THEIR CHOLINESTERASE INHIBITOR ACTIVITIES Merve Erdoğan, Burcu Kılıç and Deniz S. Doğruer ...... 110 P-35 DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NEW SERIES OF DIHYDROXYLATED 2,6-DIPHENYL-4-CHLOROPHENYLPYRIDINES: DNA NON-INTERCALATIVE CATALYTIC TOPOISOMERASE I & IIα DUAL INHIBITOR Eung-Seok Lee, Ganesh Bist, Til Bahadur Thapa Magar, Aarajana Shrestha, Pramila Katila and Youngjoo Kwon ...... 111 P-36 SYNTHESIS OF RING A-FUSED PYRAZOLE REGIOISOMERS IN THE ANDROSTANE SERIES AND AN EVALUATION OF THEIR CELL-GROWTH INHIBITORY EFFECTS IN VITRO Éva Frank, Ádám Baji, Gergő Mótyán and István Zupkó ...... 112 P-37 SYNTHESIS, CYTOSTATIC AND ANTIBACTERIAL EVALUATIONS OF N-4-BENZOYLCYTOSINE–1,2,3-TRIAZOLE AND 7-DEAZAPURINE–1,2,3-TRIAZOLE HYBRIDES Maja Stipković Babić, Mande Miošić, Moris Mihovilović, Marijana Jukić, Ljubica Glavaš-Obrovac, Domagoj Drenjančević, Silvana Raić-Malić and Tatjana Gazivoda Kraljević ...... 113 P-38 STERANE-FUSED PYRAZOLES: AN EFFICIENT MICROWAVE-ASSISTED SYTHESIS ON RING A Gergő Mótyán, Réka Kiss-Faludy, János Wölfilng and Éva Frank ...... 114 P-39 BROADLY EFFECTIVE METAL CHELATORS, AS INFLUENZA PA ENDONUCLEASE AND HEPATITIS C VIRUS INHIBITORS Erofili Giannakopoulou, Annelies Stevaert, Efseveia Frakolaki, Vassilios Myrianthopoulos, Emmanuel Mikros, Ralf Bartenschlager, Niki Vassilaki, Lieve Naesens and Grigoris Zoidis ...... 115
21 The 10th Joint Meeting on Medicinal Chemistry 2017
P-40 ORGANOCATALYSIS MEETS BETA LACTAMS Thavendran Govender, Tricia Naicker, Hendrik G. Kruger and Per I. Arvidsson ...... 116
P-41 SEARCH FOR 5-HT6 RECEPTOR AGENTS AMONG TRIAZINE DERIVATIVES OF HYDANTOIN Jadwiga Handzlik, Rafał Kurczab, Dorota Łażewska, Małgorzata Więcek, Angelika Nowakowska, Grzegorz Satała, Andrzej J. Bojarski and Katarzyna Kieć-Kononowicz ...... 117 P-42 NOVEL SYNTHESIS OF (+)-DIENOMYCIN C AND ANALOGOUS COMPOUNDS WITH ANTIBACTERIAL ACTIVITY Hajime Yokoyama, Yuko Hayashi, Hiromi Ejiri, Masahiro Miyazawa and Yoshiro Hirai ...... 118 P-43 NOVEL para SUBSTITUTED N-ARYL 3-HYDROXYPYRIDIN-4-ONE MANNOSIDES: SYNTHESIS, HEMAGGLUTINATION INHIBITORY PROPERTIES AND MOLECULAR MODELING V. Petrović Peroković, Ž. Car, K. Meglić, R. Ribić, T. Tandarić, R. Vianello and S. Tomić ...... 119 P-44 ANTIBACTERIAL AND ANTIPROLIFERATIVE ACTIVITY OF NOVEL 2-BENZIMIDAZOLYL AND 2- BENZOTHIAZOLYL SUBSTITUED BENZOTHIENO-2-CARBOXAMIDES Maja Cindrić, Mihaela Perić, Marijeta Kralj, Irena Martin Kleiner, Hana Čipčić Paljetak, Mario Matijašić, Donatella Verbanac, Grace Karminski-Zamola and Marijana Hranjec ...... 120 P-45 SYNTHESIS OF DIPEPTIDES CONTAINING PHOTOCHEMICALLY REACTIVE MODIFIYED TYROSINE AND EVALUATION OF THEIR DNA BINDING Antonija Husak, Josipa Matić, Ivo Piantanida and Nikola Basarić ...... 121 P-46 TARGETED DEGRADATION OF ANAPLASTIC LYMPHOMA KINASE (ALK) BY APPLYING THE PROTEOLYSIS TARGETING CHIMERAS (PROTAC) Jong Yeon Hwang, Chi-Hoon Park, Dong Ho Lee, Chung Hyo Kang, Chong Ock Lee and Jae Du Ha ...... 122 P-47 LIPOPHILICITY EVALUATION AND IN SILICO ADME-TOX STUDIES OF SOME NOVEL THIOSEMICARBAZONE AND 1,3,4-THIADIAZOLINE DERIVATIVES Ioana Ionuț, Gabriel Marc, Ovidiu Oniga and Brîndușa Tiperciuc ...... 123
P-48 SYNTHESIS OF NOVEL RING STRUCTURES AS GABAA RECEPTOR LIGANDS WITH FUNCTIONAL SELECTIVITY Maria Teresa Iorio, Laurin Wimmer, Konstantina Bampali, Margot Ernst and Marko Mihovilovic ...... 124 P-49 SYNTHESIS AND BIOLOGICAL EVALUATION OF CHALCONE DERIVATIVES AS NEUROPROTECTIVE AGENTS FOR PARKINSON’S DISEASE Bo Ko Jang, Ji Won Choi, Jong-Hyun Park, Seul Ki Yeon, Si Won Kim, Yerim Lee, Su Jeong Shin, Hyeon Jeong Kim, Hyeon Ji Kim, Yong Gu Kang, Ae Nim Pae and Ki Duk Park ...... 125 P-50 SYNTHESIS, STRUCTURE-ACTIVITY RELATIONSHIPS, AND MOLECULAR MODELING STUDIES OF NEW LONG- CHAIN CHLOROARYLPIPERAZINES DERIVATIVES AS 5-HT7 AND 5-HT1A RECEPTOR LIGANDS Jolanta Jaśkowska, Paweł Śliwa, Zbigniew Majka, Anna K. Drabczyk, Damian Kułaga, Magdalena Malinowska and Grzegorz Satała ...... 126 P-51 NEW METHODS FOR SYNTHESIS OF THE TRAZODONE ANTIDEPRESSANT Przemysław Zaręba, Jolanta Jaśkowska and Zbigniew Majka...... 127 P-52 PHENYLSULFONYL HYDRAZIDE DERIVATIVES AS NOVEL POTENT ANTI-INFLAMMATORY AGENTS Hui Rak Jeong, Sun Yeung Kim and Jae Yeol Lee ...... 128 P-53 DESIGN, SYNTHESIS AND EVALUATION OF INDOLE DERIVATIVES AS MULTIFUNCTIONAL AGENTS AGAINST ALZHEIMER’S DISEASE Jacques Joubert, Ireen Denya and Sarel F. Malan...... 129 P-54 3,4-DIHYDROQUINAZOLINE DERIVATIVES AS NOVEL AND SELECTIVE BUTYRYLCHOLINESTERASE INHIBITORS Da Woon Jung, Jin Han Kim, Hong Bin Yoon and Jae Yeol Lee ...... 130 P-55 HIGH THROUGHPUT SCREENING FOR DIPEPTIDYL PEPTIDASE III INTERACTING PROTEINS Snježana Jurić, Katarzyna Kliza, Koraljka Husnjak and Mihaela Matovina ...... 131 P-56 IN VITRO, IN VIVO AND MOLECULAR MODELING STUDIES OF N-(3-{4-[3-(TRIFLUOROMETHYL)PHENYL]- PIPERAZIN-1-YL}PROPYL)-1H-INDAZOLE-3-CARBOXAMIDE (D2AAK3) AS A POTENTIAL ANTIPSYCHOTIC Agnieszka A. Kaczor, Katarzyna M. Targowska-Duda, Marta Kruk-Słomka, Andrea G. Silva, Peter Kolb, Antti Poso, Grażyna Biała and Marian Castro...... 132
22 The 10th Joint Meeting on Medicinal Chemistry 2017
P-57 DIRECT PHOSPHONYLATION OF HETEROAROMATIC COMPOUNDS AS A MEAN TO SYNTHESIZE CYTOTOXIC AGENTS Ewa Chmielewska, Monika Prokopowicz, Natalia Wojtowicz, Joanna Wietrzyk, Piotr Młynarz and Paweł Kafarski ...... 133 P-58 EVALUATION OF ANTIMYCOBACTERIAL ACTIVITY FOR A RANGE OF POLYCYCLIC AMANTADINE AND PENTACYCLOUNDECANE DERIVATIVES Erika Kapp, Jacques Joubert, Samantha L. Sampson, Margaretha de Vos and Sarel F. Malan ...... 134 P-59 DEVELOPMENT OF A DISINFECTANT PRODUCT CONTAINING THE ESSENTIAL OIL EXTRACTED FROM ROSMARINUS OFFICINALIS L. Fetta Kessal, Amina Dahmoune, Amina Azzam, Boumrar Silia and Boualem Samia...... 135 P-60 DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF D-RING OPENED 17-β ESTRADIOL ANALOGUES AS ESTROGEN RECEPTOR SUBTYPE-SELECTIVE LIGANDS Sun Young Lee, Yun Seon Song, Minsun Chang and Hee-Doo Kim ...... 136 P-61 SYNERGISTIC ANTICANCER EFFECT OF T-TYPE CALCIUM CHANNEL BLOCKER AND CHEMOTHERAPEUTIC AGENTS IN HUMAN LUNG CANCER Jin Han Kim, Hong Bin Yoon, Da Woon Jung and Jae yeol Lee ...... 137 P-62 DISCOVERY OF PHENYLSULFONYL HYDRAZIDE DERIVATIVES AS NOVEL AND SELECTIVE mPGES-1 INHIBITORS Sun Young Kim, Hui Rak Jeong and Jae yeol Lee ...... 138 P-63 RUTHENIUM-BASED CATALYSTS FOR ASYMMETRIC TRANSFER HYDROGENATION Andrea Kišić, Michel Stephan, Barbara Mohar, Andrej Emanuel Cotman, and Dominique Cahard ...... 139 P-64 THE PREPARATION OF THE FOUR STEREOISOMERS OF 16-HYDROXYMETHYL-13-EPI-ESTRA- 1,3,5(10)-TRIEN-17-OL-3-METHYL-, AND 3-BENZYLETHERS Anita Kiss, János Wölfling and Gyula Schneider ...... 140 P-65 DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF CXCR3 AND CXCR4 MODULATORS WITH PYRAZOLOPYRIDINE SCAFFOLD Anja Kolarič, Urban Švajger, Tihomir Tomašič, Nikola Minovski, Nuška Tschammer and Marko Anderluh ...... 141 P-66 CHEMICAL PROTEOMICS IN THE EVALUATION OF THE EGFRI LAPATINIB PHARMACOLOGY Tatjana Kovačević, Krunoslav Nujić and Milan Mesić ...... 142 P-67 MEDICAL CHEMICAL DEFENCE AGAINST CHEMICAL NERVE AGENT THREATS Zrinka Kovarik, Nikolina Maček-Hrvat and Tamara Zorbaz...... 143 P-68 ANTITUMOR ACTIVITY OF ANTHROLS THAT PHOTOCHEMICALLY GENERATE QUINONE METHIDES OR REACTIVE OXYGEN SPECIES AND THEIR SELECTIVITY TOWARDS CANCER STEM CELLS Lidija Uzelac, Đani Škalamera, Kata Mlinarić-Majerski, Nikola Basarić and Marijeta Kralj ...... 144 P-69 SURFACE INTERACTIONS BETWEEN OLIGOPEPTIDE DERIVATIVES OF SALICYLIC ACID AND CALCITE AS A MODEL OF AN INORGANIC DRUG DELIVERY SYSTEM Marko Ukrainczyk, Lara Štajner, Zlatko Brkljača, Robert Stepić, David Smith, Ana Sunčana Smith, Matija Gredičak, Ivanka Jerić, Andreja Jakas and Damir Kralj ...... 145 P-70 OLIGOTUFTSIN-BASED CARRIERS FOR NOVEL ANTIMYCO-BACTERIAL ACTIVE AGENTS AND THEIR CONJUGATES Krátký Martin, Baranyai Zsuzsa, Szilvia Bősze, Szabó Nóra, Vinšová Jarmila ...... 146 P-71 NOVEL 1,2,3-TRIAZOLYL-7-SUBSTITUTED COUMARINS AND BIS(COUMARIN-TRIAZOLYL)BENZENES: SYNTHESIS, PHOTOPHYSICAL PROPERTIES AND CYTOSTATIC EVALUATION Kristina Bobanović, Ema Horak, Lidija Furač, Marijeta Kralj, Lidija Uzelac, Ivana Murković Steinberg and Svjetlana Krištafor ...... 147 P-72 DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL POTENT MDM2/P53 SMALL MOLECULE INHIBITORS M. E. Kukushkin, V. K. Novotortsev, V. E. Filatov, A. A. Beloglazkina, N. A. Vorobyeva, D. A. Skvortsov, E. K. Beloglazkina, N. V. Zyk and A. G. Majouga ...... 148 P-73 SYNTHESIS AND BIOLOGICAL ACTIVITY OF NOVEL LONG CHAIN ARYLOPIPERAZINES (LACPs) WITH PYRIDYL MOIETY AS LIGANDS FOR SEROTONIN RECEPTORS Damian Kułaga, Jolanta Jaśkowska, Anna Drabczyk, Grzegorz Satała and Magdalena Malinowska ...... 149
23 The 10th Joint Meeting on Medicinal Chemistry 2017
P-74 DIFFERENT ROLES OF HALOGEN SUBSTITUENTS IN LIGAND-RECEPTOR INTERACTIONS – A CLASS A GPCRS CASE STUDY Rafał Kurczab...... 150 P-75 SYNTHESIS AND BIOLOGICAL POTENTIAL OF SERIES A AND B MODIFIED STEROIDAL D-LACTONES Ivana Kuzminac, Marina Savić, Dimitar Jakimov, Olivera Klisuric, Andrea Nikolić and Marija Sakač ...... 151 P-76 IN SILICO & IN VITRO EVALUATION OF NOVEL INHIBITORS OF MITOCHONDRIAL F1F0-ATPASE Dimitrios Karagiannis, Panagiotis Efentakis, George Lambrinidis, Ioanna Andreadou and Emmanuel Mikros .. 152 P-77 3-AROYL-1,4-DIARYLPYRROLES INHIBIT CHRONIC MYELOID LEUKEMIA CELL GROWTH THROUGH AN INTERACTION WITH TUBULIN Giuseppe La Regina, Valentina Naccarato, Antonio Coluccia, Addolorata Maria Luce Coluccia, Ernest Hamel and Romano Silvestri ...... 153 P-78 INHIBITION OF DENGUE VIRUS BY NOVEL INHIBITORS OF RNA-DEPENDENT RNA POLYMERASE AND PROTEASE ACTIVITIES Giuseppe La Regina, Valeria Famiglini, Domiziana Masci, Antonio Coluccia, Jin-Ching Lee, John Hiscott and Romano Silvestri ...... 154 P-79 PHENOXYMETHYL DERIVATIVES OF 1,3,5-TRIAZINE AS NOVEL CLASS OF 5-HT6 RECEPTOR LIGANDS Dorota Łażewska, Małgorzata Więcek, Michał Stelmasiński, Grzegorz Satała, Rafał Kurczab, Andrzej J. Bojarski, Katarzyna Kieć-Kononowicz and Jadwiga Handzlik ...... 155 P-80 BLOCKADE OF RAS ACTIVITY BY INHIBITORS OF THE ENZYME ISOPRENYLCYSTEINE CARBOXYL METHYLTRANSFERASE (ICMT) S. Ortega-Gutiérrez, M. Martín-Fontecha, N. Marín-Ramos, F.J. Ortega, A. Gil, M. Balabasquer, I. Cushman, I.R. Torrecillas, L. Pardo, P.J. Casey, M.R. Philips and M.L. López-Rodríguez ...... 156 P-81 STUDY FOR THE DEVELOPMENT OF NEW PURINE ANALOGUES AS HIGHLY SPECIFIC LIGANDS AGAINST FUNGAL NUCLEOBASE TRANSPORTERS Efthymios-Spyridon Gavriil, Spyridon Dimitrakis, Nikolaos Lougiakis, George Lambrinidis, Emmanuel Mikros, Panagiotis Marakos, Nicole Pouli and George Diallinas...... 157 P-82 SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL SMALL-MOLECULE PSMA-TARGETED PACLITAXEL CONJUGATES A. E. Machulkin, A. P. Ber, I. V. Saltykova, E. K. Beloglazkina, N. V. Zyk, V. E Koteliansky and A. G. Majouga .... 158 P-83 DESIGN, SYNTHESIS AND IN VITRO EVALUATION OF MODULATORS OF PFKFB3 AUTOREGULATORY DOMAIN H.Macut, X.Hu, D.Tarantino, S.Pellegrino and M.L.Gelmi ...... 159 P-84 ISOXAZOLE DERIVATIVES AS IMMUNOMODULATORS Marcin Mączyński, Angelika Drynda, Stanisław Ryng and Bożena Obmińska-Mrukowicz ...... 160 P-85 PYRROLYL NON-DKA DERIVATIVES AS NOVEL INHIBITORS OF HIV-1 REVERSE TRANSCRIPTASE-ASSOCIATED RIBONUCLEASE H FUNCTION V. N. Madia, F. Saccoliti, G. Pupo, V.Tudino, F. Esposito, A. Corona, N. Grandi, E. Tramontano, R. Costi and R.Di Santo ...... 161 P-86 NOVEL ANTIMALARIALS FROM NATURE: EVOLUTIONARY GENERATED VIRTUAL COMPOUND LIBRARIES FROM NATURAL PRODUCTS WITH ANTIPLASMODIAL ACTIVITIES Samuel Egieyeh, James Syce, Alan Christoffels and Sarel F. Malan ...... 162 P-87 THE SYNTHESIS OF NEW ARYLPIPERAZINES FOR CNS DISORDERS Magdalena Malinowska, Jolanta Jaśkowska, Anna Drabczyk and Damian Kułaga ...... 163 P-88 BIOLOGICAL EVALUATIONS OF AMIDINE AND AMIDOXIME SUBSTITUTED HETEROCYCLES WITH 1,2,3-TRIAZOLYL SPACER Silvija Maračić, Petra Grbčić, Mirela Sedić, Sandra Kraljević Pavelić and Silvana Raić-Malić ...... 164
P-89 DESIGN, SYNTHESIS AND CYTOTOXIC ACTIVITY EVALUATION OF NEW AMINOSUBSTITUTED PYRAZOLOPYRIDINES Nikolaos Lougiakis, Vasiliki Giannouli, Ioannis K. Kostakis, Panagiotis Marakos, Nicole Pouli, Orestis Argyros and Constantin Tamvakopoulos ...... 165
24 The 10th Joint Meeting on Medicinal Chemistry 2017
P-90 IN VITRO CITOTOXITY AND ANTI-TUMOR INVESTIGATION OF PHENYLBORONIC ACID Maja Marasović, Mladen Miloš, Siniša Ivanković and Ranko Stojković ...... 166 P-91 MICROWAVE ASSISTED SYNTHESIS OF SOME NEW THIAZOLIDINE-2,4-DIONE DERIVATIVES AS POTENTIAL ANTIMICROBIAL AGENTS Gabriel Marc, Ioana Ionuț, Dan Vodnar, Adrian Pîrnău, Brîndușa Tiperciuc and Ovidiu Oniga ...... 167 P-92 WEB-4D-QSAR OF 17β-HYDROXYSTEROID DEHYDROGENASE TYPE 3 INHIBITORS Eduardo B. de Melo, Tuanny P. Schmidt and João Paulo A. Martins ...... 168 P-93 WEB-4D-QSAR OF URACIL DERIVATIVES DESCRIBED AS THYMIDINE PHOSPHORYLASE INHIBITORS João Paulo A. Martins and Eduardo B. de Melo ...... 169 P-94 SYNTHESIS AND DETERMINATION OF PHYSICOCHEMICAL PROPERTIES OF NEW POTENTIAL ANTIMYCOBACTERIAL DRUGS Pavlína Marvanová, Tereza Padrtová, Klára Odehnalová, Otakar Humpa and Petr Mokrý ...... 170 P-95 EXPLORATION OF NEW ANTICANCER CHEMOTHERAPEUTIC AGENTS BASED ON ANTITUMOR NATURAL PRODUCT ANDRASTINS Shuqiang Yin, Quan Li, Aki Kohyama, Kenji Sugimoto and Yuji Matsuya ...... 171 P-96 DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL PYRROLE-BASED AS EZH2 INHIBITORS R. Mazzone, C. Zwergel, M. Tafani, A. Nebbioso, L. Altucci, A. Mai and S. Alente ...... 172 P-97 SYNTHESIS OF NOVEL 13α-ESTRONE DERIVATIVES AS POTENTIAL 17β-HSD1 INHIBITORS Ildikó Bacsa, Rebeka Jójárt, János Wölfling, Gyula Schneider, Bianka Edina Herman, Mihály Szécsi and Erzsébet Mernyák ...... 173 P-98 ANTITUMORAL AND ANTIVIRAL ACTIVITIES OF NOVEL 1,2,3-TRIAZOLYL APPENDED L-ASCORBIC ACID DERIVATIVES Andrijana Meščić, Anja Harej, Višnja Stepanić, Sandra Kraljević Pavelić, Dominique Schols and Silvana Raić-Malić ...... 174 P-99 IDENTIFICATION OF NEW INHIBITORS OF PRMTs BY A MULTI-SUBSTRATE-ADDUCT APPROACH C. Milite, D. Rescigno, A. Feoli, S. Castellano and G. Sbardella ...... 175 P-100 SYNTHESIS AND EVALUATION OF NEW N-ACYLETHANOLAMINES PPAR-α LIGANDS PLANNED FROM CARDANOL Camila de Oliveira Miranda, Carolyn Cummins and Luiz A Soares Romeiro ...... 176 P-101 DEVELOPMENT OF NOVEL REAGENTS FOR GENERATING ISLETS Β-CELLS AND ENHANCING THEIR FUNCTION BASED ON CLUSTERED NANOFORMULATION OF NEUROLIGIN-2 MIMETICS Munder Anna, Shtriker Efrat, Viskind Olga, Korshin Edward, Chessler Steven, and Gruzman Arie ...... 177 P-102 TARGETING PLASMODIUM FALCIPARUM GLUCOSE-6-PHOSPHATE DEHYDROGENASE IN THE PURSUIT OF NOVEL ANTIMALARIAL AGENTS Diego Muñoz-Torrero, Nelson Alencar, Irene Sola, María Linares, Caterina Pont, Luca Di Palma, Carla Barbaraci, Cristina Sampedro, Jordi Juárez-Jiménez, Paloma Abad, Susana Pérez-Benavente, Jerónimo Lameira, José M. Bautista and F. Javier Luque ...... 178 P-103 A SYNTHESIS OF “DUAL WARHEAD” β ARYL ETHENESULFONYL FLUORIDES AND ONE-POT REACTION TO β SULTAMS Praveen K. Chinthakindi, Kimberleigh B. Govender, A. Sanjeeva Kumar, Hendrik G. Kruger, Thavendran Govender, Tricia Naicker and Per I. Arvidsson ...... 179 P-104 SYNTHESIS AND CYTOTOXIC PROPERTIES OF NEW DERIVATIVES OF BENZOFURANS M. Napiórkowska, M. Cieślak, K. Królewska, J. Kaźmierczak-Barańska and B. Nawrot ...... 180 P-105 INVESTIGATION OF THE ANTIPROLIFERATIVE AND ANTIHYPERGLYCEMIC ACTIVITIES OF NEW THIAZOLIDINEDIONE DERIVATIVES Cristina Nastasă, Daniel Scherman, Alina Pârvu, Ovidiu Oniga and Brîndușa Tiperciuc ...... 181 P-106 ANTICARCINOGENIC POTENTIAL OF PLUM (Prunus domestica L.) KERNEL EXTRACTS OBTAINED BY SUBCRITICAL WATER Nataša Nastić, Slavica Ražić, Ana Damjanović, Aleksandra Cvetanović, Višnja Gaurina Srček, Igor Slivac, Kristina Radošević and Jaroslava Švarc-Gajić ...... 182
25 The 10th Joint Meeting on Medicinal Chemistry 2017
P-107 IN VITRO SCREENING OF ANTICARCINOGENIC PROPERTIES OF CHERRY STEM EXTRACTS OBTAINED BY SUBCRITICAL WATER Nataša Nastić, Višnja Gaurina Srček, Kristina Radošević, Igor Slivac, Aleksandra Cvetanović, Vesna Novakov and Jaroslava Švarc-Gajić ...... 183 P-108 DESIGN, SYNTHESIS AND ANTICONVULSANT ACTIVITY OF NEW PIPERAZINAMIDES DERIVED FROM 3-ISOBUTYL-2,5-DIOXOPYRROLIDIN-1-YL-ACETIC ACID Jolanta Obniska, Małgorzata Góra, Sabina Rybka, Krzysztof Kamiński and Anna Rapacz ...... 184 P-109 IDENTIFICATION OF 3-[3, 4-BIS-(TERT-BUTYL-DIMETHYL-SILANYLOXY)-PHENYL]-PROPIONIC ACID AS AN ADIPONECTIN EXPRESSION ENHANCER Tsutomu Oikawa, Motomu Inoue, Yurie Ueno, Atsuko Motojima, Nobuyasu Matsuura, Tomio Saito and Hiroyuki Osada ...... 185 P-110 SYNTHESIS AND BIOLOGICAL ACTIVITY OF 3-AMINOTHYMOQUINONE Una Glamočlija, Subhash Padhye, Selma Špirtović-Halilović, Amar Osmanović, Elma Veljović, Sunčica Roca, Irena Novaković, Sandra Kraljević Pavelić, Anja Harej and Davorka Završnik ...... 186 P-111 SYNTHESIS AND ANTICONVULSANT ACTIVITY OF NEW PHENOXYACETHAMIDE DERIVATIVES OF AMINES, AMINOALKANOLS OR AMINO ACIDS Katarzyna Pańczyk, Anna Waszkielewicz, Dorota Żelaszczyk, Ewa Żesławska, Karolina Słoczyńska, Paulina Koczurkiewicz, Elżbieta Pękala and Henryk Marona ...... 187 P-112 THEORETICAL PREDICTION OF LIPOPHILICITY OF THIOSEMICARBAZIDE DERIVATIVES Agata Paneth, Tomasz Plech, Dominika Janowska, Szymon Kosiek, Nazar Trotsko, and Monika Wujec ...... 188 P-113 NOVEL SPIRO CARBOCYCLIC HYDANTOIN-DERIVATIVES WITH POTENT ANTITRYPANOSOMAL ACTIVITY Vasiliki Pardali, Martin C. Taylor, John M. Kelly and Grigoris Zoidis ...... 189 P-114 SYNTHESIS AND BIOLOGICAL EVALUATION OF HYDROXAMATE COMPOUNDS AS HDAC6 INHIBITORS Hui Yeon Mok, Han Pyo Son, Seung Yeop Baek, Hyun-Ju Park and Young Hoon Jung ...... 190 P-115 DRUG DESIGN AND SYNTHESIS OF NEW INDOLYLARYLSULFONES AS HIV-1 NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS S. Passacantilli, V. Famiglini, G. La Regina, A. Coluccia, D.Masci, J. A. Estè, G. Maga and R. Silvestri ...... 191 P-116 NEW (AMINOMETHYLENE)BISPHOSPHONATES OBTAINED FROM HETEROCYCLIC AMINES AND THEIR BIOLOGICAL ACTIVITY Patrycja Miszczyk, Ewa Chmielewska, Błażej Dziuk, Joanna Wietrzyk and Paweł Kafarski ...... 192 P-117 Abstract retracted for technical reasons ...... 193 P-118 Abstract retracted for technical reasons ...... 194 P-119 SYNTHESIS, ANTIBACTERIAL ACTIVITY AND SAR STUDY OF NOVEL AMIDINO 2-SUBSTITUTED BENZIMIDAZOLE DERIVATIVES Nataša Perin, Marijana Hranjec, Mihaela Perić, Hana Čipčić Paljetak, Mario Matijašić, Višnja Stepanić, Donatella Verbanac, Grace Karminski-Zamola and Kristina Starčević ...... 195 P-120 CHEMICAL COMPOSITION AND BIOACTIVE EFFECTS OF LAVENDER ESSENTIAL OIL FROM MONTENEGRO Svetlana Perović, Snežana Pantović, Valentina Šćepanović, Andrej Perović and Biljana Damjanović-Vratnica ...... 196 P-121 NOVEL СONJUGATES OF DOXORUBICIN WITH ASGP-RECEPTOR LIGANDS FOR TARGETED DELIVERY R. A. Petrov, S. A. Petrov, E. E. Ondar, S. Yu. Maklakova, I. V. Saltykova, E. K. Beloglazkina, A. G. Majouga and V. E. Koteliansky ...... 197 P-122 SYNTHESIS, CHARACTERIZATION AND CYTOTOXICITY OF PHENOLIC COPPER(II) COMPLEXES Vladimir P. Petrović, Dušica Simijonović, Zorica D. Petrović, Marko N. Živanović and Snežana D. Marković..... 198 P-123 THIOSEMICARBAZIDE DERIVATIVES WITH 4-NITROPHENYL GROUP AS MULTI-TARGET DRUGS Monika Pitucha, Małgorzata Miazga-Karska, Agnieszka A. Kaczor, Katarzyna Klimek, Zbigniew Karczmarzyk, Maciej Woś, Waldemar Wysocki, Grazyna Ginalska, Zofia Urbanczyk-Lipkowska and Maja Morawiak...... 199 P-124 DESIGN AND SYNTHESIS OF NEW SUBSTITUTED NUCLEOSIDES AS POTENTIAL ANTI-HCMV AGENTS Maria Gerasi, Georgios Papadakis, Nikolaos Lougiakis, Panagiotis Marakos and Nicole Pouli ...... 200
26 The 10th Joint Meeting on Medicinal Chemistry 2017
P-125 SCREENING PHYSIOLOGICALLY RELEVANT SUBSTRATES OF ALDOSE REDUCTASE: ENZYME ACTIVITIES AND DIFFERENTIAL INHIBITION Marta Soltesova Prnova, Jana Ballekova, Yoel Rodriguez, Magdaléna Májeková and Milan Stefek...... 201 P-126 POST HEROIN DOSE TISSUE DISTRIBUTION OF 6-MONOACETYLMORPHINE (6-MAM) WITH MALDI IMAGING Belin G. Teklezgi, Annapurna Pamreddy, Sooraj Baijnath, Nirmala D. Gopal, Tricia Naicker, Hendrik G. Kruger and Thavendran Govender ...... 202 P-127 RATIONAL DESIGN OF NEW POTENT NON-NUCLEOSIDE INHIBITORS OF TERMINAL DEOXYNUCLEOTIDYL TRANSFERASE ACTIVE IN LEUKEMIC CELLS G. Pupo, A. Coluccia, A. Messore, V. N. Madia, F.Saccoliti, L. Pescatori, R. Costi, G. Maga, E. Crespan and R. Di Santo .. 203 P-128 SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL 2-(HETERO)ARYL-6-(2-IMIDAZOLINYL)BENZO- THIAZOLES AS ANTICANCER AGENTS Livio Racané, Lucija Ptiček, Mirela Sedić, Petra Grbčić, Sandra Kraljević Pavelić, Irena Sović, Grace Karminski-Zamola ...... 204 P-129 NEW PRIMAQUINE AMIDES WITH HYDROXYPHENYL AND HALOGENPHENYL SUBSTITUENTS Zrinka Rajić Džolić, Maja Beus and Branka Zorc ...... 205 P-130 SYNTHESIS AND EVALUATION OF MULTI-TARGET LIGANDS PLANNED FROM CARDANOL FOR THE TREATMENT OF ALZHEIMER'S DISEASE Giselle de Andrade Ramos, Luiz A. Soares Romeiro, Manuela Bartolini, Paul E. Fraser and Ling Wu ...... 206 P-131 DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL G9A INHIBITORS FROM A SCAFFOLD HOPPING APPROACH D. Rescigno, C. Milite, M. Viviano, S. Castellano and G. Sbardella ...... 207 P-132 SYNTHESIS OF MULTIANTENNARY MANNOSE DERIVED DESMURAMYL PEPTIDES Rosana Ribić, Marija Paurević, Nora Tir and Srđanka Tomić ...... 208 P-133 MOLECULAR MODELING AND SYNTHESIS OF PYRUVATE DEHYDROGENASE KINASE INHIBITORS AS A POTENTIAL ANTICANCER TARGETS Agata Rosińska, Urszula Kijkowska-Murak and Dariusz Matosiuk ...... 209 P-134 DISCOVERY OF NOVEL DIARYL SULFIDE DERIVATIVES AS INHIBITORS OF TRYPANOTHIONE REDUCTASE ENZYME F. Saccoliti, V. N. Madia, G. Pupo, V. Tudino, G. Colotti, G. Angiulli, A. Fiorillo, P. Baiocco, T. Di Muccio, M. Gramiccia, L. Scipione, R. Costi, A. Ilari and R. Di Santo...... 210 P-135 PSORALENE DERIVATIVES INHIBITORS OF THE β5i SUBUNIT OF THE IMMUNOPROTEASOME Eva Shannon Schiffrer, Izidor Sosič, Martina Gobec, Irena Mlinarič-Raščan and Stanislav Gobec ...... 211 P-136 THE APPLICATION OF FMO-EDA CALCULATION TO STUDY THE SELECTIVITY OF 2-CHLOROPHENYL- PIPERAZIN DERIVATIVE TO SEROTONIN AND DOPAMINE RECEPTORS Paweł Śliwa, Jolanta Jaśkowska and Rafał Kurczab ...... 212 P-137 AN ASPARTATE-AMINE SALT BRIDGE – THE ETS-NOCV STUDY Paweł Śliwa, Rafał Kurczab and Andrzej J. Bojarski ...... 213 P-138 STEROID RECEPTOR BINDING AFFINITIES OF SELECTED MODIFIED STEROIDS- A SCREENING TOOL FOR IDENTIFICATION OF POTENTIAL THERAPEUTICS Sofija S. Bekić, Marija N. Sakač, Suzana S. Jovanović-Šanta, Edward T. Petri and Andjelka S. Ćelić ...... 214 P-139 DEVELOPMENT OF BIOORTHOGONAL 2-NITROIMIDAZOLE BASED HYPOXIA SENSITIVE PROBES Barbara Sohr, Christoph Denk, Thomas Wanek and Hannes Mikula ...... 215 P-140 NEUROPROTECTIVE POTENTIAL OF LINEZOLID: A QUANTITATIVE AND DISTRIBUTION STUDY VIA MASS SPECTROMETRY Sooraj Baijnath, Chivonne Moodley, Bongani Ngcobo, Sanil D. Singh, Gert Kruger, Per I. Arvidsson, Tricia Naicker, Alexander Pym and Thavendran Govender ...... 216 P-141 SYNTHESIS, ANTITUMOR AND ANTIOXIDATIVE ACTIVITY OF NITRO AND AMINO SUBSTITUTED BENZIMIDAZOLE AND BENZOTHIAZOLE 2-CARBOXAMIDES Irena Sović, Ida Boček, Petra Roškarić, Marijeta Kralj, Irena Martin Kleiner, Kristina Starčević and Marijana Hranjec ...... 217
27 The 10th Joint Meeting on Medicinal Chemistry 2017
P-142 ESTIMATION OF BINDING AFFINITY FOR SOME SYNTHESIZED COUMARIN DERIVATIVES WITH RECEPTORS IMPORTANT FOR BACTERIAL GROWTH AND DEVELOPMENT Selma Špirtović-Halilović, Elma Veljović, Mirsada Salihović, Aida Šapčanin, Amar Osmanović, Nihada Škrijelj and Davorka Završnik ...... 218 P-143 ANTIBACTERIAL THIAZOLIN-4-ONES AS POTENTIAL DNA GYRASE AND TOPOISOMERASE IV INHIBITORS Anca Stana, Radu Tamaian, Dan C. Vodnar, Ovidiu Oniga and Brîndușa Tiperciuc ...... 219 P-144 DESIGN, SYNTHESIS, X-RAY STUDIES AND BIOLOGICAL EVALUATION OF NOVEL CHALCONE DERIVATIVES – POTENTIAL MICROTUBULE TARGETING AGENTS Tomasz Stefanski, Rafał Kurczab, Artur Korzanski, Katarzyna Skonieczka, Barbara Grolik, Emilia Kania, Barbara Bojko, Zbigniew Dutkiewicz, Agnieszka Gielara-Korzańska, Renata Mikstacka, Adam Hogendorf and Maciej Kubicki ...... 220 P-145 OPIOID RECEPTOR ACTIVITY AND ANALGESIC POTENCY OF DPDPE PEPTIDE ANALOGUES CONTAINING A XYLENE BRIDGE Azzurra Stefanucci, Giorgia Macedonio, Ettore Novellino, Sako Mirzaie, Stefano Pieretti, Paola Minosi, Edina Szúcs, Anna I. Erdei, Ferenc Zador, Sandor Benyhe and Adriano Mollica ...... 221 P-146 IDENTIFICATION OF NOVEL STAT3 INHIBITORS AND SYNTHESIS-ASSISTED ELUCIDATION OF MOLECULAR MECHANISM Seungbeom Lee, Changjin Lim, Joonseong Hur and Young-Ger Suh ...... 222 P-147 HIGHLY REACTIVE DIENOPHILES FOR BIOORTHOGONAL TETRAZINE LIGATIONS Dennis Svatunek, Maximilian Haider and Hannes Mikula ...... 223 P-148 SYNTHESIS AND CYTOTOXIC ACTIVITY OF NEW DERIVATIVE OF ISOTHIAZOLOPYRIDINE Piotr Świątek, Agnieszka Matera-Witkiewicz, Karolina Królewska-Golińska, Julia Kaźmierczak-Barańska, Marcin Cieślak and Barbara Nawrot ...... 224 P-149 STUDIES ON ARYL-SUBSTITUTED PHENYLALANINES: SYNTHESIS, ACTIVITY AND DIFFERENT BINDING MODES AT AMPA RECEPTORS Ewa Szymańska, Birgitte Nielsen, Darryl S. Pickering and Tommy N. Johansen...... 225 P-150 NOVEL AND EFFICIENT BICYCLIC GUANIDINE CATALYST FOR THE CYCLOTRIMERIZATION OF ISOCYANATES. A QUANTUM CHEMICAL STUDY. Tana Tandarić and Robert Vianello ...... 226 P-151 DESIGN AND SYNTHESIS OF DUAL G9A METHYLTRANSFERASE/LSD1 DEMETHYLASE OR SELECTIVE LSD1 INHIBITORS BY STRUCTURAL MANIPULATION OF THE QUINAZOLINE SCAFFOLD Daniela Tomaselli, Alessia Lucidi, Mariantonietta Forgione, Gebremedhin Solomon Hailu, Valentina Speranzini, Biagina Marrocco, Simona Pilotto, Andrea Mattevi, Dante Rotili and Antonello Mai ...... 227 P-152 HOMOLOGY MODELLING, STRUCTURE- AND LIGAND-BASED DRUG DESIGN OF NOVEL CALCIUM CHANNEL BLOCKERS WITH LEISHMANICIDAL ACTIVITIES Carlos Henrique Tomich de Paula da Silva, Leonardo Bruno Federico, Laura M. Alcântara, Carolina B. Moraes, Lucio H. Freitas-Júnior and Joaquín M. Campos Rosa ...... 228 P-153 NOVEL D- GLUCOSAMINE N- PEPTIDYL DERIVATIVES ENDOWED WITH SELECTIVE ACTIVITY TOWARDS IKK ALPHA V. Tudino, V. N. Madia, F. Saccoliti, G. Pupo, R. Cocchiola, A. Scotto D’Abusco, R. Scandurra, R. Costi and R. Di Santo . 229 P-154 MEMANTINE ANALOGUES WITH ACTIVITY AS GLUTAMATE N-METHYL D-ASPARTATE RECEPTOR ANTAGONISTS Andreea L.Turcu, Daina Martínez-Falguera, Francesc X. Sureda and Santiago Vázquez ...... 230 P-155 NOVEL THIAZOLES AS TRYPANOCIDAL AGENTS Santiago Vázquez, Rosana Leiva, Jèssica Rubí, Martin C. Taylor, Belén Pérez and John M. Kelly ...... 231 P-156 FLUORINATED PHENYLALANINE DERIVATIVES: VERSATILE BIOLOGICAL ACTIVITY Martin Krátký, Jarmila Vinšová, Šárka Štěpánková, Jiřina Stolaříková ...... 232 P-157 DISCOVERY OF THE FIRST-IN-CLASS CHEMICAL PROBES FOR THE SPINDLIN1 METHYL-LYSINE READER DOMAIN M. Viviano, S. Castellano, M. T. Bedford, H. Li and G. Sbardella ...... 233 P-158 HYDRAZINO PEPTIDOMIMETICS AS MODULATORS OF PROTEIN-PROTEIN INTERACTIONS Kristina Vlahoviček-Kahlina, Luka Kavčič, Marija Marković, Janez Plavec, Ivo Piantanida and Ivanka Jerić...... 234
28 The 10th Joint Meeting on Medicinal Chemistry 2017
P-159 SALICYLANILIDE MUTUAL PRODRUGS: SYNTHESIS AND BIOLOGICAL ACTIVITY R. Vosátka, M. Krátký, J. Vinšová...... 235 P-160 SYNTHESIS AND PHARMACOLOGICAL ACTIVITY IN A GROUP OF PHENOXYALKYL DERIVATIVES OF PIPERAZINE Anna M. Waszkielewicz, Katarzyna Pańczyk, Karolina Pytka, Anna Rapacz, Monika Głuch-Lutwin, Agata Siwek, Adam Bucki, Marcin Kołaczkowski and Henryk Marona ...... 236 P-161 STRUCTURE-ACTIVITY RELATIONSHIP STUDY OF INTERVENOLIN, A NATURAL QUINOLONE WITH ANTI- TUMOR AND ANTI-HELICOBACTER PYLORI ACTIVITIES Takumi Watanabe, Hikaru Abe, Manabu Kawada, Chiharu Sakashita, Shun-ichi Ohba, Hiroyuki Inoue, Tomokazu Ohishi, Tohru Masuda, Chigusa Hayashi, Masayuki Igarashi and Masakatsu Shibasaki ...... 237 P-162 DISCOVERY OF ISOQUINOLINOQUINAZOLINONES AS A NOVEL PPAR GAMMA ANTAGONISTS Yifeng Jin,Younho Han, Daulat B. Khadka, Kwang Youl Lee and Won-Jea Cho ...... 238 P-163 SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF NEW S-TRIAZOLE DERIVATIVES M. Wujec, A. Paneth, Ł. Popiołek, T. Plech, Sz. Kosiek, E. Kędzierska and J. Kotlińska ...... 239 P-164 DEVELOPMENT OF THE METHOD FOR HPLC ASSAY OF THE LIMОNIUM GMЕLINII DRY EXTRACT G.Е. Zhussupova, D.T. Kassymova, A.I. Zhussupova ...... 240 P-165 STRUCTURE-ACTIVITY AND MECHANISTIC STUDY OF INHIBITORY EFFECTS OF POLYSUBSTITUTED PYRIMIDINES ON PROSTAGLANDIN E2 PRODUCTION Zdeněk Zídek, Zlatko Janeba, Petr Jansa, Miloslav Kverka, Eva Kmoníčková, Filip Kalčic and Viktor Kolman...... 241 P-166 DESIGN AND ANTIMYCOBACTERIAL EVALUATION OF COMPOUNDS COMBINING PYRAZINAMIDE AND PARA AMINOBENZOIC ACID Jan Zitko and Martin Doležal ...... 242 P-167 BIOLOGICAL ACTIVITY OF NOVEL PRIMAQUINE-CINNAMIC ACID CONJUGATES OF THE ACYLSEMICARBAZIDE TYPE K. Pavić, K. Ester, M. Kralj, D. Schols, D. Hadjipavlou-Litina, E. Pontiki and B. Zorc ...... 243 P-168 ANTIMYCOBACTERIAL SCREENING OF FOUR SERIES OF PRIMAQUINE DERIVATIVES Josef Jampílek, Sarka Pospíšilová, H. Michnová, Kristina Pavić, Ivana Perković and Branka Zorc ...... 244 P-169 INSIGHTS INTO ANTIOXIDANT AND CYTOSTATIC ACTIVITY OF THE NOVEL PRIMAQUINE UREIDOAMIDES Branka Zorc, Kristina Pavić, Dimitra Hadjipavlou-Litina, Eleni Pontiki, Marijeta Kralj and Katja Ester ...... 245 P-170 NITROGEN BASICITY AFFECTS ALDOSE REDUCTASE INHIBITION IN A SERIES OF 5-CARBOXYMETHYLATED TETRAHYDROPYRIDOINDOLES: STRUCTURE-ACTIVITY RELATIONSHIPS AND MOLECULAR MODELING Jana Ballekova, Marta Soltesova Prnova, Milan Stefek and Magdaléna Májeková ...... 246 P-171 CAN THE BCHE POLYMORPHISM AFFECT THE INHIBITION POTENCY OF CARBAMYLATING AND REVERSIBLE INHIBITORS FROM EVERYDAY LIFE? Anita Bosak and Zrinka Kovarik ...... 247 P-172 ANTIMALARIAL SCREENING OF PRIMAQUINE DERIVATIVES AGAINST ERYTHROCYTIC STAGE OF P. falciparum B. Zorc, K. Pavić, F. Supek, J. Levatić, and M. Kaiser ...... 248
INDEX ...... 249
PARTICIPANTS ...... 257
29 The 10th Joint Meeting on Medicinal Chemistry 2017
PLENARY LECTURES
30 The 10th Joint Meeting on Medicinal Chemistry 2017
PL-1
BEYOND THE PROKARYOTIC RIBOSOME: STRUCTURAL AND FUNCTIONAL INSIGHTS INTO EUKARYOTIC AND MITOCHONDRIAL RIBOSOMES
Nenad Ban
Institute of Molecular Biology and Biophysics, ETH Zürich, Otto-Stern-Weg 5, 8093 Zürich Switzerland [email protected]
We are investigating bacterial and eukaryotic ribosomes and their functional complexes to obtain insights into the process of protein synthesis. Eukaryotic ribosomes are much more complex than their bacterial counterparts, require a large number of assembly and maturation factors during their biogenesis, use numerous initiation factors, and are subjected to extensive regulation. We have investigated the structures of eukaryotic ribosomes and their complexes involved in initiation and maturation and complexes involved in regulation of protein synthesis.[1-4] These results provide insights into the architecture of the eukaryotic ribosome and into various eukaryotic-specific aspects of protein synthesis. Using electron microscopy, we determined the complete molecular structure of the 55S mammalian mitoribosome. The maps that we calculated between 3.4 and 3.6 Å resolution allowed de-novo tracing of a large number of mitochondrial specific ribosomal proteins and visualization of interactions between tRNA and mRNA in the decoding centre, the peptidyl transferase center, and the path of the nascent polypeptide through the idiosyncratic tunnel of the mammalian mitoribosome. Furthermore, the structure suggested a mechanism of how mitochondrial ribosomes, specialized for the synthesis of membrane proteins, are attached to membranes.[5,6]
[1] J. Rabl, M. Leibundgut, F. Sandro, S.F. Ataide, A. Haag, N. Ban, Nature, 2010, 331(6018). 730. [2] S. Klinge, F. Voigts-Hoffmann, M. Leibundgut, S. Arpagaus, N. Ban, Science, 2011, 334, 941. [3] J.P. Erzberger et al., Cell, 2014, 158, 1123. [4] C.H. Aylett et al. Science, 2016, 351(6268), 48. [5] B.J. Greber, D. Boehringer et al., Nature, 2014, 505(7484), 515. [6] B.J. Greber, P. Bieri, et al., Science, 2015, 348(6232), 303.
31 The 10th Joint Meeting on Medicinal Chemistry 2017
PL-2
OLIGOTUFTSIN-BASED CARRIERS FOR NOVEL ANTIMYCO- BACTERIAL ACTIVE AGENTS AND THEIR CONJUGATES
Krátký Martin,[a],* Baranyai Zsuzsa,[b] Szilvia Bősze,[b] Szabó Nóra[c] and Vinšová Jarmila[a]
[a] Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic [b] MTA-ELTE Research Group of Peptide Chemistry, Pázmány Péter Sétány 1/A, Budapest, H-1117, Hungary, P.O. Box 32, 1518 Budapest 112, Hungary [c] Laboratory of Bacteriology, Korányi National Institute for Tuberculosis and Respiratory Medicine, Pihenő út 1, Budapest, H-1122, Hungary * [email protected]
The global tuberculosis epidemic and increasing emergence of drug-resistant Mycobacterium tuberculosis (Mtb.) strains as well as non-tuberculous mycobacteria (NTM) call for intensive research on novel therapeutic interventions. Drug delivery systems (DDS) may help to overcome inconvenient properties of bioactive molecules, e.g., poor solubility, bioavailability or selectivity. Additionally, they are useful in targeted drug delivery.[1] We selected tuftsin-based oligopeptides as potential carriers for small antimycobacterial active molecules. Tuftsin derivatives are non-toxic, non-immunogenic and biodegradable. They also enhance immune response and target macrophages specifically, thus increasing cellular uptake, activity and reducing toxicity.[2,3] A pilot study with isoniazid indicates that this concept is viable.[2] Salicylanilides (2-hydroxy-N-phenylbenzamides) have exhibited interesting antimicrobial properties including drug-resistant Mtb. and NTM (MIC ≥ 0.5 µM), but their potential use is prevented due to limited solubility and comparatively higher toxicity.[4] These obstacles can be overcome, i.a., by employment of DDS. That is why salicylanilides bearing a carbonyl group were selected as model compounds for the evaluation of oligotuftsine carriers. Oligotuftsin-based carriers ([TKPKG]n, n = 1-4) were synthesized by solid-phase synthesis (Fmoc/tBu strategy, rink amide MBHA resin, diisopropylcarbodiimide/HOBt, NMP). N-Terminus and/or side chain lysine ε-amino group(s) were substituted to obtain carriers with various properties. Carboxylic acids (acetic, succinic, palmitic etc.) modify lipophilicity, short peptide spacers (G5, GFLG cleavable by cathepsin B) were used to control the cellular site where the drug is released, whereas fluorescein enables to determine cellular uptake by flow cytometry and fluorescent microscopy. One or more aminooxyacetic acid molecule(s) were coupled with peptides to provide a reactive group for the attachment of active molecules. After these modifications, peptide carriers were cleaved from the resin TFA and purified. Then, carriers were coupled with salicylanilide derivatives to form acid stable oxime bond. Novel conjugates were purified and characterised.[3] Generally, salicylanilide-oligotuftsin conjugates exhibited a significant extracellular antimyco- bacterial activity including against drug-resistant Mtb. Moreover, they are more effective against intracellular mycobacteria than parent salicylanilides. Cellular uptake was enhanced substantially, too, together with decreased cytostatic and cytotoxic effects on mammalian cells. In conclusion, our tuftsine peptides are perspective carriers for antimycobacterial agents.
Acknowledgments: This work was supported by the Czech Science Foundation project No. 17- 27514Y.
[1] G. Tiwari, R. Tiwari, et al., Int. J. Pharm. Invest., 2012, 2, 2. [2] K. Horvati, G. Mezo, et al., J. Pept. Sci., 2009, 15, 385. [3] Z. Baranyai, M. Krátký, et al., Eur. J. Med. Chem., 2017, under revision. [4] Z. Baranyai, M. Krátký, J. Vinšová, et al., Eur. J. Med. Chem., 2015, 101, 692.
32 The 10th Joint Meeting on Medicinal Chemistry 2017
PL-3
WHAT THERMODYNAMICS CAN HELP TO UNDERSTAND PROTEIN-LIGAND BINDING IN MEDICINAL CHEMISTRY
Gerhard Klebe
Institute of Pharmaceutical Chemistry, University of Marburg, Marbacher Weg 6, D35032 Marburg, Germany [email protected]
Small-molecule drug discovery involves the optimization of various physicochemical properties of a ligand, particularly the binding affinity for its target receptor(s). In recent years, there has been growing interest in using thermodynamic profiling of ligand–receptor interactions in order to select and optimize those ligands that look most promising to become a drug candidate with desirable physicochemical properties. The thermodynamics of binding are influenced by multiple factors, including hydrogen bonding and hydrophobic interactions, desolvation, residual mobility, dynamics and the local water structure. How well do we understand these properties on the molecular level? Is it only important that a sufficient number of hydrogen bonds are formed and the shape of the molecules fit perfectly together? How much contributes the burial of hydrophobic surface portion and how important are changes of the degrees of freedom upon complex formation? Both binding partners are conformationally flexible species and will adapt to one another upon complex formation. However, who is going to pay for these adaptations? All biological processes occur in water, thus the ubiquitously present water molecules take an important impact on protein-ligand binding, and even rearrangements of water molecules on the surface of a formed protein-ligand complex modulate the affinity of complex formation. Structural and thermodynamic considerations help to get insight into the driving forces for complex formation. Water takes in manifold ways influence on the structure and energetics of protein-ligand complex formation. The impact of such effects is less apparent in a strong modulation of affinity (ΔG) but, owing to compensatory effects, it strongly shifts the enthalpy/entropy inventory and tunes binding kinetics. Upon ligand binding water molecules are displaced, rearranged or recruited to engage in new contacts between protein and ligand. The newly formed complex is coated by a rearranged water shell. All these processes take influence on the thermodynamic and binding-kinetic signature of the formed complex. Decisive for the characteristics of the involved hydrophobic effect is the state of the water molecules before and after ligand binding. The displacement of ordered and firmly embedded water molecules results in another signature than the displacement of disordered, partly dynamic water molecules. In case binding occurs in empty or partly solvated but structurally stable pockets significantly different energetics are observed compared to transient pockets opened upon binding. The water network created around exposed ligand functional groups in flat solvent- exposed pockets takes strong impact on the thermodynamic signature of the complex and seems to govern binding kinetics. As the parameters affinity and binding kinetics are determinant for the efficacy of binding, they must be optimized individually for each drug in tailored fashion. By closely linking the results of high resolution X-ray and neutron diffraction, microcalorimetry, binding kinetics and computer simulations we want to characterize the determining influence of water on the efficacy of ligand binding.[1]
[1] G. Klebe, Nat. Rev. Drug Discov. 2015, 14(2), 95.
33 The 10th Joint Meeting on Medicinal Chemistry 2017
PL-4
METAL CHELATING AGENTS AGAINST VIRUSES AND PARASITES
Zoidis Grigoris
School of Health Sciences, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimioupoli-Zografou, GR-15771, Athens, Greece [email protected]
Influenza viruses cause considerable morbidity and mortality, whether in the context of annual epidemics, sporadic pandemics, or outbreaks of avian influenza virus. For hepatitis C virus (HCV), an estimated 170 million people are chronically infected worldwide. These individuals are at high risk of developing progressive liver injury or hepatocellular carcinoma. Another major public health problem in many areas of sub-Saharan Africa is sleeping sickness (human African trypanosomiasis), which currently kills ca. 50 000 people each year. Since emerging viral resistance remains high, the cost threaten the efficacy of currently approved antiviral drugs and the attention of pharmaceutical industry concerning neglected and relatively unprofitable parasitic disease is little, new antiviral and antiparasitic drugs are urgently needed. Metalloenzymes are enzyme proteins containing metal ions (metal cofactors), which are directly bound to the protein or to enzyme-bound nonprotein components (prosthetic groups). Approximately one-third of proteins are metalloproteins, which serve to execute a wide array of functions in vivo, including facilitating matrix degradation, modulating DNA transcription, and many others. Given the importance of these functions, metalloenzymes play a significant role in human, virus and parasite physiology. Pathologies for which metalloenzymes are implicated include cancer, heart disease, influenza A and HCV. Given the impact of these diseases on human health, metalloenzyme inhibition offers an appealing approach to disease treatment. Indeed, sales of metalloprotein inhibitors account for billions of dollars in pharmaceutical sales annually. Hydroxamates act as bidentate ligands and are able to form hydrogen bonds; they can act as potent inhibitors of any enzyme that contains metal ion and residues able to act as hydrogen-bond donors or acceptors. Almost all the enzymes that contain M2+ ion are easily coordinated with any hydroxamic acid derivative. In most of the enzyme proteins containing metal ions, hydroxamates bind bidentately to their catalytic M2+ ion to create a distorted trigonal bipyramidal geometry around the M2+ as shown in Figure. Thus, the metal-chelating property and multiple hydrogen-bond formation ability of hydroxamates have made them an intriguing family of compounds with a wide spectrum of biological activities, among them antiviral and antiparasitic.[1]-[3]
Figure: The predicted binding orientation of hydroxamates in the catalytic site of PA influenza endonuclease and HCV polymerase shown in a ribbon representation.
Acknowledgments: Prof. Zoidis would like to thank the National and Kapodistrian University of Athens (ELKE Account) for financial support.
[1] G. Zoidis, E. Giannakopoulou, at al., MedChemComm 2016, 7(3), 447. [2] C. Fytas, G. Zoidis, at al., J. Med. Chem. 2011, 54 (14), 5250. [3] A. Tsatsaroni, G. Zoidis, at al., Tet. Lett. 2013, 54, 3238.
34 The 10th Joint Meeting on Medicinal Chemistry 2017
PL-5
MARINE ENVIRONMENT INSPIRES KINASES INHIBITORS
Girolamo Cirrincione
Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy [email protected]
Marine organisms constitute a very unique source of bioactive molecules belonging to a great variety of different chemical structural classes. Among marine derived bioactive molecules, over 70 novel compounds showed significant inhibitory activity against kinases, important enzymes involved in vital role cell regulation and signal transmission pathways, controlling cell differentiation, proliferation and apoptosis.[1] Several marine derived molecules are in the pharmaceutical pipeline and have successfully reached the market. In particular there are six FDA-approved drugs and many others are under clinical trials.[2] Bis-indole marine alkaloids, have emerged as important lead compounds for the discovery of new biologically active derivatives due to their potent biological activities shown. Among them, nortopsentins A–C having a characteristic 2,4-bis(3’-indolyl)imidazole skeleton, isolated from Spongosorites ruetzleri, exhibited in vitro cytotoxicity against P388 cells (IC50 values: 4.5–20.7 µm) and their synthetic analogs in which the imidazole moiety of nortopsentin was replaced by different 5-membered heterocycles, showed improved biological activity against a wide range of human tumor cell lines with GI50 values reaching sub-micromolar level. In particular, thiazole nortopsentin analogs 1-4, in which one or both indole units of the natural nortopsentins were also manipulated, showed even better activity and inhibition of cyclin-dependent kinase 1 (CDK1).[3] Many derivatives, belonging to this class of compounds, revealed significant biological activity also in STO e MesoII cell lines, derived from human diffuse malignant peritoneal mesothelioma (DMPM), a very aggressive and resistant form of cancer, inducing a caspase-dependent apoptotic response, with a concomitant reduction of the expression of the anti-apoptotic protein survivin. The most active derivatives were also investigated in vivo showing a significant tumor volume inhibition of DMPM xenografts (range, 58%-75%) at well-tolerated doses, and two complete responses in each treatment group.
R N R3 S Y R R 3 N N Z H X W N N N N
H H R1 R2 Nortopsentins Thiazole Nortopsentin Analogs 1 X=Y=Z=CH, W=N; 2 X=W=N, Y=Z=CH; 3 X=N, Y=W=Z=CH; 4 X=Y=W=CH, Z=N;
In order to confirm the therapeutic efficacy of this series of compounds, further studies were performed against cancer stem cells (CSCs) subpopulation freshly isolated from surgical resections of patients with the aim to identify new molecules potentially useful in therapy. Preliminary data showed that the treatment of colorectal CSCs, bearing different mutational background, with thiazole nortopsentin analogs, induced reduction of cells viability at 24 hours, potently induced the exit of CSCs from dormancy state. This phenomenon rendered the highly resistant CSCs sensitive to conventional chemotherapy drugs, oxaliplatin and 5FU. These results supported the use of these compounds as an innovative differentiation therapy that could be used in combination with standard chemotherapy as additive effect.
[1] D. Skropeta et al., Mar. Drugs, 2011, 9, 2131. [2] B. S. Bharate et al., Chem. Rev., 2013, 113, 6761. [3] a) A. Carbone et al., J. Med. Chem., 2013, 56, 7060; b) B. Parrino et al., Mar. Drugs, 2015, 13, 1901; c) A. Carbone et al., Mar. Drugs, 2015, 13, 460.
35 The 10th Joint Meeting on Medicinal Chemistry 2017
PL-6
OLD SCAFFOLDS IN NEW ROLE: STEROIDS AS ANTIPROLIFERATIVE AGENTS
János Wölfling,[a],* Éva Frank,[a] Erzsébet Mernyák,[a] Gyula Schneider,[a] Mihály Szécsi[b] and István Zupkó[c]
[a] Department of Organic Chemistry, University of Szeged, Dóm tér 8. H-6720, Szeged, Hungary [b] 1st Department of Medicine, University of Szeged, Korányi fasor 8-10, H-6720 Szeged, Hungary [c] Department of Pharmacodynamics and Biopharmacy, University of Szeged, Eötvös utca 6. H-6720, Szeged, Hungary * [email protected]
One of the main trends in medicinal chemistry is the structural modification of biologically active natural products with the aim of obtaining drug-like molecules with selective biological action. Steroids can be found widespread in nature; their function in plants, in human and in animal body is mostly well-known. They show high selectivity in some of their actions because they are subject to a special transport system and receptors. The literature reveals several antitumoural steroid derivatives, but elimination of their hormonal activity and improvement of their tumour selectivity are frequently ongoing problems. Structural modifications of natural steroids may lead to hormonally inactive at the same time effective and selective cytostatic derivatives. The whole arsenal of synthetic organic chemistry is disposable for modifying the molecules of steroidal sex hormones. As a result of chemical transformations, we synthesized hundreds of new derivatives, such as homo- or secosteroids, epimeric and/or heteroring-containing compounds. The formation of steroid hybrids with other steroids or non-steroidal natural products may lead to new conjugates exhibiting different biological activities from those of the original constituents. The in vitro antiproliferative activities of the new derivatives were determined on several cancer cells by using MTT assay. Some of our new compounds display remarkable cytostatic effects against ovarian and cervical cell lines. We investigated the antiandrogenic effects of the new compounds by determining their in vitro inhibition of rat testicular C17,20-lyase, Δ5-3β-hydroxysteroid dehydrogenase (Δ5-3β-HSD) and 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) activities.
Acknowledgments: The authors are grateful for financial support from the National Research, Development and Innovation (NKFI) Fund of Hungary (K113150 and K109107).
36 The 10th Joint Meeting on Medicinal Chemistry 2017
PL-7
CHEMICAL PROBES IN TARGET DISCOVERY
Paul Brennan
University of Oxford, UK [email protected]
Epigenetics is the study of heritable changes in phenotype that are not encoded in an organism’s DNA. Epigenetic effects due to persistent changes in gene transcription have been linked to chemical modification of DNA and the proteins that package and regulate DNA in the nucleus, histones. One of the major post-translational modifications of histones is acetylation of lysine residues prevalent in histone tails. The principal readers of histone acetyl lysine marks are bromodomains (BRDs), which are a diverse family of over sixty evolutionary conserved protein-interaction modules. Proteins that contain BRDs have been implicated in the development of a large variety of diseases, including cancer and inflammation. In order to decipher the complex biology of bromodomains and provide evidence linking specific bromodomain targets to disease, we are discovering selective, cell active small molecule inhibitors of bromodomains.
37 The 10th Joint Meeting on Medicinal Chemistry 2017
PL-8
GABAA RECEPTOR SUBTYPES: A STRUCTURE GUIDED PATH TO SELECTIVE COMPOUNDS
Konstantina Bampali,[a] David Siebert,[b] Marko D. Mihovilovic,[b] Michael Schnürch,[b] and Margot Ernst[a],*
[a] Department of Molecular Neurosciences, Medical University of Vienna, Spitalgasse 4, 1090 Wien, Austria [b] TU Wien, Institute of Applied Synthetic Chemistry, Getreidemarkt 9/163-OC, 1060 Vienna * [email protected]
[1] Atomic resolution structures of cys-loop receptors, including one of a GABAA receptor subtype, allow amazing insights into the structural features of these pentameric ligand-gated ion channels. Here we present a comprehensive analysis of more than thirty cys-loop receptor structures that revealed several allosteric binding sites not previously described in GABAA receptors. Four so far undescribed putative ligand binding sites can be identified in each prototypical GABAA receptor subunit based on this structural data.[3] The large fragment of the intracellular domain that is present [2] in the structure of the 5-HT3 receptor can be utilized to generate GABAA receptor models with a corresponding intracellular domain fragment.[3] [3] Schematic view of a hetero-pentameric GABAA receptor model with allosteric binding site localizations indicated by colored regions. Results of mutational and photoaffinity ligand studies in GABAA receptors can be analyzed in the light of the model structures. This leads to an assignment of candidate ligands to proposed novel pockets. Candidate binding sites for several ligands are presented. The structural studies can serve as hypotheses generators, and some previously controversial structural interpretations of biochemical data can be resolved in the light of the presented multi-template approach to comparative modeling. Crystal and cryo- EM microscopic structures of the closest homologues that were solved in different conformational states[4,5] provided important insights into structural rearrangements of binding sites during conformational transitions. The impact of structural variation and conformational motion on the shape of the investigated binding sites can be studied in this way. Structure guided approaches to identify new binding sites along with specific ligands for these are possible, and lead to a new generation of subtype selective allosteric modulators. The structures can also shed light on the molecular basis that underlies the functional diversity among receptor isoforms. A showcase of ligand development will be presented.
[1] P. Miller, A. Aricescu, Nature, 2014, 512, 270. [2] G. Hassaine et al., Nature, 2014, 512, 276. [3] R. Puthenkalam et al., Front. Mol. Neurosci., 2016, 9, 44. [4] T. Althoff et al., Nature, 2014, 512, 333. [5] J. Du et al., Nature, 2015, 526, 224.
38 The 10th Joint Meeting on Medicinal Chemistry 2017
PL-9
NEW HITS AND LEADS FOR NEURODEGENERATIVE DISORDERS
Urban Košak, Damijan Knez, Boris Brus, Stanislav Gobec*
Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia * [email protected]
Alzheimer’s disease (AD) is characterized by severe cholinergic deficit, which results in progressive and chronic deterioration of memory and cognitive functions. Together with acetylcholinesterase, butyrylcholinesterase (BChE) contributes to the termination of cholinergic neurotransmission. Its enzymatic activity increases with disease progression, thus classifying BChE as a viable therapeutic target in advanced AD. In vivo active BChE inhibitors are limited to covalent carbamate inhibitors with potential reactivity-based toxicities. In the first step, we developed a selective and highly potent noncovalent BChE inhibitor.[1] In the next step, this compound was used as a starting point for the synthesis of a comprehensive series of close structural analogues in order to study the structure-activity relationships and to obtain compounds with improved on-target activities. More than 100 compounds were synthesized resulting in improved inhibitors with nano to picomolar inhibition constants. The most promising inhibitor improved memory, cognitive functions, and learning abilities of mice in a model of the cholinergic deficit that characterizes AD, without producing acute cholinergic side effects. This inhibitor therefore provides a promising advanced lead compound for the alleviation of symptoms caused by cholinergic hypofunction in AD.[2] Limited clinical efficacy of current symptomatic treatment and minute effect on the progression of AD has shifted the research focus from targeting single enzyme or receptor towards multi-target-directed ligands (MTDLs). These ligands are able to interact with multiple pathological processes of AD, and have the unmet potential to halt the progression or even to cure the disease. Therefore, our potent BChE inhibitors were used as starting points to develop a new series of multifunctional ligands. The derivatives designed and synthesized displayed balanced BChE inhibition, antioxidant activity and inhibition of amyloid β aggregation. The co-crystal structure of typical inhibitor in complex with BChE explained the molecular basis for its low nanomolar inhibition of the enzyme. The most promising compounds also showed metal chelating properties, inhibited redox activity of chelated Cu2+ ions, were non-cytotoxic, and were not substrates of active efflux transport system as determined in Caco2 cells, thereby providing promising lead multifunctional ligands for AD treatment. A series of dual BChE/monoamine oxidase-B (MAO-B) inhibitors was also developed based on the selective BChE inhibitors.[3] In addition, nanomolar MAO-A and MAO-B inhibitors with piperidine scaffold were derived thereof, and they showed promising neuroprotective activity in 6-hydroxydopamine cell model of Parkinson’s disease.
[1] B. Brus et al., J. Med. Chem., 2014, 57, 8167. [2] U. Košak et al., Sci. Rep., 2016, 6, 39495. [3] U. Košak et al., Bioorg. Med. Chem. Lett., 2017, 25, 633.
39 The 10th Joint Meeting on Medicinal Chemistry 2017
PL-10
POLYSACCHARIDES AS BIOLOGICAL RESPONSE MODIFIERS: STRUCTURE - ACTIVITY RELATIONSHIP
Jadwiga Turło
Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of Warsaw, 1 Banacha St., 02-097 Warsaw, Poland [email protected]
Polysaccharides are among the best known and most potent macromolecules with antitumor and immunomodulatory properties. With respect to the mechanism of the pharmacological activity, they are classified as biological response modifiers (BRMs). Although the relationship between their activity and the chemical composition has been extensively investigated over the past three decades, there are some conflicting reports on this topic.[1] Polysaccharides with strong immunomodulatory activity include neutral and acidic ones; some of them are bound to protein or peptide residues. In addition to the primary structure of polysaccharides, higher structure, such as chain conformation, also plays an important role in their activities.[2] Although structure-activity relationship (SAR) among higher sugars is not clear, it is assumed that determinants of their immunomodulatory activity are: the monosaccharide composition, water solubility, molecular weight, branching degrees (DBs) and triple helical conformation [3]. The next issue to be solved is the mechanism of immunomodulating activity of mushroom polysaccharides. One possible pathway of host-mediated actions from polysaccharide-drug Lentinan is binding of β- glucans to iC3b-receptors (CR3, CD11b/CD18) of phagocytic cells and natural killer (NK) cells and stimulation of phagocytosis and/or cytotoxic degranulation, as suggested by Chihara (1992) [4] and later modified by Wasser (1999).[5] The polysaccharide fractions isolated from the natural sources (bacteria, fungi, plants) or obtained by biotechnological methods are often subjected to structural modifications in order to improve their pharmacological activity and/or pharmacokinetic properties. Uncertainty of the structural data on the atomic level considerably hinders this task. An example of structural modifications of polysaccharides that lead to changes in their biological activity is incorporation of selenium atoms performed in our laboratory by biotechnological methods. We have isolated a Se-containing polysaccharide-protein fraction from selenium-enriched mycelial culture of Lentinula edodes. The results of preliminary tests of immunomodulatory activity of these fractions were surprising: the effect of Se-polysaccharides on the proliferation of human blood lymphocytes demonstrated their selective immunosuppresive activity and a very low toxicity at the same time. This activity is opposite to immunostimulating activity of L. edodes-derived polysaccharides, described in the literature. We speculate that incorporation of selenium into exopolysaccharide molecules changes their spatial structure which affects the biological activity.
Acknowledgements: Investigation of structure-activity relationship in Se-enriched polysaccharides is supported by grant from the Polish National Science Centre DEC-2013/09/B/NZ7/03978
[1] M. Zhang, S.W. Cui, P.C.K. Cheung, Q. Weng, Trends Food Sci Technol., 2007, 18, 4. [2] S.P. Wasser, Appl. Microbiol. Biot., 2002, 10, 13. [3] L. Zhang, X. Li, X. Xu, F. Zeng, Carbohydr Res., 2005, 340, 1515. [4] G. Cihara, Int J Orient Med., 1992,17, 57. [5] S.P. Wasser, A.L. Weiss, Int J Med Mushrooms., 1999,1, 31.
40 The 10th Joint Meeting on Medicinal Chemistry 2017
PL-11
DESIGN OF SMALL MOLECULAR PROBES FOR PROTEINS AND DNA / RNA
Ivo Piantanida
Ruđer Bošković Institute, Division of Organic Chemistry & Biochemistry, Zagreb, Croatia [email protected]
Small molecules targeting DNA, RNA and/or proteins have attracted significant scientific interest not only because of their biomedicinal applications, but also due to widespread use of spectrophotometric markers in the related scientific research. For instance, fluorescent techniques significantly developed during the last three decades and now represent about 70% of the detection enabling technologies used in molecular biology and medicine. However, design of small molecule (Mw<600) for recognition of ds-DNA/RNA sequence or particular protein is very challenging due limited number of modifications in such restricted molecule size. Quite often, small modifications lead to change of target preference, for instance from DNA-targeting to protein-targeting molecule.
Scheme: Aggregation-prone dye interacting with various targets and reporting interaction with each target by sensitive and bio-applicable spectrometric method.
One of our research lines is focused on the generally under-investigated approach: exploitation of intrinsic property of some dyes for aggregation, whereby monomeric and aggregated dye differ strongly not only in target recognition but also in spectroscopic properties.[1] Thus, one dye molecule could bind with similar affinity to several targets (DNA, RNA, protein) giving different spectroscopic responses for each target: to some polynucleotide sequence dye would bind as monomer, for other sequence as dimer, and protein binding site would induce different spectroscopic response (Scheme). The ongoing research endeavours to establish for the low molecular weight dyes the structure-activity guidelines for fine tuning of DNA - RNA - protein preferences combined with recognition by set of sensitive and bio-applicable spectrometric methods.
[1] J. Matić at al, RSC Advances, 2016, 6, 83044; J. Suć at al, Org. Biomol. Chem, 2016, 14, 4865; J. Gershberg at al, Chem. Eur. J., 2015, 21, 7886; I. Crnolatac at al, Anal. Chim. Acta, 2016, 940, 128; L.-M. Tumir at al, Chem., Eur. J., 2012, 18, 3859.
41 The 10th Joint Meeting on Medicinal Chemistry 2017
PL-12
FROM EXCEPTIONAL KINASE CONFORMATION TO DUAL KINASE INHIBITORS - CHEMISTRY OF 2-AMINOOXAZOLES
Andrej Boháč,[a,b],* Peter Šramel,[a,c] Juraj Dobiaš,[a] Miroslav Murár,[a] Matúš Hlaváč,[a] Maroš Smolíček[a] and Gilles Hanquet[c]
[a] Department of Organic Chemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Ilkovičova 6, 842 15 Bratislava, Slovakia [b] Biomagi, Ltd., Mamateyova 26, 851 04 Bratislava, Slovakia [c] Université de Strasbourg, Ecole européenne de Chimie, Polyméres et Matériaux (ECPM) Laboratoire de Synthése et Catalyse (UMR CNRS 7509), 25, rue Becquerel, F-67087 Strasbourg, France * [email protected]
The Human Kinom contains 518 Protein Kinases (PKs) collected in 7 major groups. PKs direct the activity of up to 30 % of cellular proteins and orchestrate the activity of almost all cellular processes. Many kinases represent important therapeutic targets. Currently PDB database contains around 5 000 structures of human kinases or their complexes. The different conformers of particular kinase can influence the predictions by false positive or false negative results. This knowledge is important by development of new inhibitors. By analysis of selected PDB kinases, protein conformers with rare arrangement of their DFG fragments were identified. Our research focused on rationale development of series of inhibitors possessing N,5-diaryloxazol-2-amine skeleton was inspired by an exceptional structure of VEGFR2 TK complex (PDB: 1Y6A; AAZ ligand). (Figure) We have reviewed [1] and improved the synthesis of aminooxazoles. At about 80 substituted aminooxazoles and their analogues were prepared. From them 31 compounds reached their IC50 kinase activity below 500 nM. Interactions of aminooxazoles with kinase subdomains, chimera constructs,[2] aminooxazole isosteric[3] or regioisomeric replacements and some interactions with hepatocellular carcinoma[4] were / are studied. Recently some of our aminooxazoles were uncovered to be suitable for dual VEGFR2 / CLK1 inhibition.[5]
N N
O S O O S O
O O
N N N N H H O O
AAZ conformers from PDB: 1Y6A Figure: The structures of two conformers of AAZ ligand present in the complex with VEGFR2 tyrosine kinase (PDB: 1Y6A).
Acknowledgements: We are thankful for support to Biomagi, Slovakia and VEGA 1/0634/13.
[1] L. Lintnerová, L. Kováčiková, G. Hanquet, A. Boháč, J. Het. Chem., 2015, 52, 425. [2] L. Lintnerová, M. García-Caballero, F. Gregáň, M. Melicherčík, A.R. Quesada, J. Dobiaš, J. Lác, M. Sališová, A. Boháč, Eur. J. Med. Chem., 2014, 72, 146. [3] M. Vojtičková, J. Dobiaš, G. Hanquet, G. Addová, R. Cetin-Atalay, D.C. Yildirim, A. Boháč, Eur. J. Med. Chem., 2015, 103, 105. [4] D.C. Kahraman, G. Hanquet, L. Jeanmart, S. Lanners, P. Šramel, A. Boháč, R. Cetin-Atalay, RCS MedChemComm, 2017, 8, 81. [5] M. Murár, J. Dobiaš, P. Šramel, G. Addová, G. Hanquet, A. Boháč, Eur. J. Med. Chem., 2017, 126, 754.
42 The 10th Joint Meeting on Medicinal Chemistry 2017
KEYNOTE LECTURES
43 The 10th Joint Meeting on Medicinal Chemistry 2017
KL-1
A PLATFORM FOR THE DISCOVERY OF NEW MACROLIDE ANTIBIOTICS
Ian B. Seiple,[a] Ziyang Zhang,[a] Pavol Jakubec,[a,b],* Peter M. Wright,[a] Audrey Langlois- Mercier,[a] Daniel T. Hog,[a] Kazuo Yabu,[a] Senkara Rao Allu,[a] Takehiro Fukuzaki,[a] Peter N. Carlsen,[a] Yoshiaki Kitamura,[a] Xiang Zhou,[a] Matthew L. Condakes,[a] Filip Szczpinski,[a] William D. Green[a] and Andrew G. Myers[a]
[a] Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA., [b] Present addresses: Department of Organic Chemistry, Slovak University of Technology, Radlinského 9, Bratislava 812 37, Slovakia * [email protected]
Chemically modifying structurally complex fermentation products, a process referred to as semisynthesis, has been a primary tool for the discovery and manufacture of antibiotics for the treatment of human infectious diseases. Many of the medicines obtained in this way are no longer efficacious as the result of the development of bacterial resistance. Here we present a practical, fully synthetic route to macrolide antibiotics by the convergent assembly of simple chemical building blocks, enabling structural diversification not possible by semisynthesis (Figure). More than 300 novel macrolide antibiotic candidates as well as the investigational drug solithromycin were synthesized by our convergent approach. Evaluation of the novel compounds against a panel of pathogenic bacteria revealed many antibiotic candidates, with efficacy against strains resistant to macrolides in current use. The chemistry we describe provides a platform for the discovery of new macrolide antibiotics and may also serve as a basis for their manufacture.[1]
[1] I.B. Seiple, Z. Zhang, P. Jakubec, A. Langlois-Mercier, P.M. Wright, D.T. Hog, K. Yabu, S.R. Allu, T. Fukuzaki, P.N. Carlsen, Y. Kitamura, X. Zhou, M.L. Condakes, F.T. Szczypiński, W.D. Green, A.G. Myers, Nature, 2016, 533, 338.
44 The 10th Joint Meeting on Medicinal Chemistry 2017
KL-2
DISCOVERY OF N-PHENYLPYRROLAMIDES AS ATPase INHIBITORS OF DNA GYRASE AND TOPOISOMERASE IV
Nace Zidar
Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia [email protected]
Bacterial topoisomerases are enzymes that catalyse changes in DNA topology and are clinically validated targets of antibacterial drugs. DNA gyrase and topoisomerase IV belong to type IIA topoisomerases and display high structural and functional similarities. They are both heterotetrameric enzymes composed of two pairs of subunits. DNA gyrase is composed of two GyrA and two GyrB subunits, while topoisomerase IV is composed of two ParC and two ParE subunits. The function of DNA gyrase and topoisomerase IV is to catalyse the transient break and reunion of the DNA double strand, a process crucial for winding and unwiding the DNA molecule during its replication or transcription. There are currently no GyrB or ParE inhibitors in clinical use. Using structure-based design and starting from marine alkaloids clathrodin and oroidin, we have discovered a new, N-phenylpyrrolamide structural class of GyrB and ParE inhibitors. We have determined the crystal structure of the N-phenyl-4,5-dibromopyrrolamide inhibitor-DNA gyrase B complex (Figure).[1] Based on this structural information we have designed and prepared novel series of N-phenyl-4,5-dibromopyrrolamides and N-phenyl-3,4-dichloro-5-methylpyrrolamides and evaluated them against DNA gyrase from Escherichia coli (E. coli). The most potent inhibitors had low nanomolar IC50 values against E. coli gyrase. A selected set of compounds was evaluated against DNA gyrase from Staphylococcus aureus (S. aureus) and against topoisomerase IV from E. coli and S. aureus. The binding affinities of selected compounds to E. coli gyrase were studied using surface plasmon resonance (SPR). The structure-activity relationship (SAR) was examined and the results were rationalised with molecular docking. Antibacterial activities of the most promising compounds were evaluated against two Gram-positive and two Gram-negative bacterial strains. The most active compound had a low micromolar minimum inhibitory concentration (MIC90) against Enterococcus faecalis.[2]-[4] Arg76 NH2 HN NH + - H 2 O O Arg136 Asp73 H Gly77 O O O O N H H Val71 N OH Br N Val167 H Pro79 Ile78 Val43 Br O H Ala47 H Val120 O Asn46 NH2 Figure: Structure of the N-phenyl-4,5-dibromopyrrolamide inhibitor of DNA gyrase B and X-ray crystal structure of the inhibitor in the active site of E. coli GyrB (PDB code: 4ZVI [2]).
[1] N. Zidar, H. Macut, T. Tomašič, M. Brvar, S. Montalvão, P. Tammela, T. Solmajer, L. Peterlin Mašič, J. Ilaš, D. Kikelj, J. Med. Chem., 2015, 58, 6179. [2] N. Zidar, T. Tomašič, H. Macut, A. Sirc, M. Brvar, S. Montalvão, P. Tammela, J. Ilaš, D. Kikelj, Eur. J. Med. Chem., 2016, 117, 197. [3] M. Gjorgjieva, T. Tomašič, M. Barančokova, S. Katsamakas, J. Ilaš, P. Tammela, L. Peterlin Mašič, D. Kikelj, J. Med. Chem., 2016, 59, 8941. [4] T. Tomašič, M. Mirt, M. Barančokova, J. Ilaš, N. Zidar, P. Tammela, D. Kikelj, Bioorg. Med. Chem., 2017, 25, 338-349.
45 The 10th Joint Meeting on Medicinal Chemistry 2017
KL-3
ANTIMICROBIAL POTENTIAL OF 1,2,4-OXADIAZOLES AND THEIR SYNTHESIS
Marta Kucerova-Chlupacova,[a],* Anastasia Katirtzi,[a] Pavlina Dzamova,[b] Lucie Kolcarkova,[a] Klara Konecna,[c] Ondrej Jandourek[c] and Veronika Opletalova[a]
[a] Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Kralove, Charles University, Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic [b] Department Pharmaceutical Technology, Faculty of Pharmacy in Hradec Kralove, Charles University, Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic [c] Department of Biological and Medical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University, Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic * [email protected]
1,2,4–Oxadiazole ring represents an emerging scaffold in medicinal chemistry used as heterocyclic bioisoster of amide or ester in the synthesis of peptide building blocks and in the formation of dipeptidomimetics.[1] In comparison with amide or ester group, the oxadiazole ring showed increased hydrolytic and metabolic stability.[2] Apart from various biological activities, 1,2,4-oxadiazoles showed antimicrobial activity. 1,2,4–Oxadiazole moiety seems to perfectly mimic the function of the morpholinic ring in linezolid derivatives.[3] 1,2,4–Oxadiazoles have been linked to cephalosporins or carbapenems in order to obtain new efficient antibacterial agents.[4] 1,2,4–Oxadiazole derivatives have also emerged from a high-throughput virtual screening study on penicillin-binding protein 2a as novel non-β-lactam bactericidal antibiotics active against Gram-positive bacteria with in vivo efficacy and 100% oral bioavailability.[5] Antiprotozoal activity has been described as well.[1] Among various synthetic procedures, amidoxime route and 1,3 dipolar cycloaddition are the most commonly used,[6] however 1,2,4-oxadiazole derivatives have been identified in nature as well, e.g. antibacterial metabolite of a fish pathogen Vibrio parahaemolyticus.[7] As 3-pyrazinyl-1,2,4- oxadiazoles proved to inhibit growth of clinical strains of Mycobacterium,[4] we tried to synthesize 3- pyrazinyl-5-substituted-1,2,4-oxadiazoles combining amidoximes and reactive carbonyl compounds. All identified compounds have been tested on antifungal and antibacterial including antimycobacterial effects.
[1] Y. Durust, H. Karakus, M. Kaiser, D. Tasdemir, Eur. J. Med. Chem., 2012, 48, 296. [2] R: H. Tale, A. H. Rodge, A. P. Keche, G. D. Hatnapure, P. R. Padole, G. S. Gaikwad, S. S. Turkar, J. Chem. Pharm. Res., 2011, 3, 496. [3] C. G. Fortuna, C. Bonaccorso, A. Bulbarelli, G. Caltabiano, L. Rizzi, L. Goracci, G. Musumarra, A. Pace, A. P. Piccinello, A. Guarcello, P. Pierro, C. E. A. Cocuzza, R: Musumeci, Eur. J. Med. Chem., 2013, 65, 533. [4] a) A. Malabarba, B. Cavalleri, M. Berti, V. Arioli, Farmaco Sci., 1977, 32, 650. b) W. J. Wheeler, J. B. Deeter, D. R. Finley, M. D. Kinnick, R. Koehler, H. E. Obsorne, J. T. Ott, J. K. Swartzendruber, D. G. Wishka, J. Antibiot. ,1986, 39, 111. c) C.-H. Oh, H.-G. Dong, J.-S. Lee, S.-C. Lee, J. H. Hong, J.-H. Cho, Arch. Pharm. Pharm. Med. Chem., 2003, 336, 567. [5] P. I. O´Daniel, Z. Peng, H. Pi, S. A. Testero, D. Ding, E. Spink, E. Leemans, M. A. Boudreau, T. Yamaguchi, V. A. Schroeder, W. R. Wolter, L. I. Llarull, W. Song, E. Lastochkin, M. Kumarasiri, N. T. Antunes, M. Espahbodi, K. Lichtenwalter, M. A. Suckow, S. Vakulenko, S. Mobashery, M. Chang, J. Am. Chem. Soc., 2014, 136, 3664. [6] A. Pace, P. Pierro, Org. Biomol. Chem., 2009, 7, 4337. [7] A. Pandey, M. M. Naik., S. K. Dubey, Afric. J. Biotechnol., 2010, 9, 7134. [8] D. Pancechowska-Ksepko, H. Foks, M. Janowiec, Z. Zwolska-Kwiek, Acta Polon. Pharm., 1986, 43, 211.
46 The 10th Joint Meeting on Medicinal Chemistry 2017
KL-4
RATIONAL DESIGN OF PI4KB INHIBITORS AS POTENTIAL BROAD- SPECTRUM ANTIVIRAL AGENTS
Radim Nencka,[a],* Ivana Mejdrová,[a] Dominika Chalupská,[a] Pavla Plačková,[a] Christin Müller,[b] Michal Šála,[a] Eliška Procházková,[a] Adriana Baumlová,[a] Milan Dejmek,[a] Dmytro Strunin,[a] Jan Weber,[a] Gary Lee,[c] Helena Mertlíková- Kaiserová,[a] John Ziebuhr,[b] Gabriel Birkus[c] and Evzen Boura[a]
[a] Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic [b] Institute of Medical Virology, Justus Liebig University Giessen, Schubertstrasse 81, D-35392 Giessen, Germany [c] Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States. * [email protected]
Phospatidylinositol 4-kinases (PI4Ks) are enzymes responsible for phosphorylation of phosphatidylinositols, common constituents of the plasmatic membranes inside of cells. Numerous positive-sense single stranded RNA (+ssRNA) viruses hijack phosphatidylinositol 4-kinase IIIβ (PI4KB), one of four different isoforms of PI4K present in human cells, in order to alter plasmatic membranes and set up bases for a functional replication machinery. Among others, important human pathogens such as hepatitis C virus (HCV) from Flaviviridae family or human rhinovirus (HRV) and coxsackie B3 (CVB3), both from Picornaviridae family, utilize PI4KB to rapidly invade host cells and start the replication process. Therefore, selective inhibition of PI4KB leads to arrest of viral replication.[1] We have recently performed an extensive study of novel selective PI4KB inhibitors. Their rational design was based on the comparison of crystal structures with a selective inhibitor MI14 [2] and non-selective derivative PIK93 [3] (Figure). The resulting hybrid structures, e.g. MI247, exerted significantly elevated inhibitory potency and retained selectivity towards PI4KB in comparison with other cellular lipid and protein kinases as well as outstanding antiviral activities against HCV, HRV and CVB3.[4]
Figure: Structures of MI14, PIK93 and MI247 (left) and docking of MI247 (right).
Acknowledgments: The work was supported by Czech Science Foundation (No. 15-09310S) and Gilead Sciences, Inc.
[1] E. Boura, R. Nencka, Exp. Cell. Res., 2015, 337, 136. [2] I. Mejdrová, D. Chalupská, et al, J. Med. Chem., 2015, 58, 3767. [3] J.E. Burke, A.J. Inglis, et al, Science, 2014, 344, 1035. [4] I. Mejdrová, D. Chalupská, et al, J. Med. Chem., 2017, 60, 100.
47 The 10th Joint Meeting on Medicinal Chemistry 2017
KL-5
DESIGN AND SYNTHESIS OF NOVEL MODULATORS OF TOLL-LIKE RECEPTORS AND INHIBITORS OF INDOLEAMINE 2,3-DIOXYGENASE
Matej Sova,[a],* Urban Švajger,[b] Kaja Rožman,[a] Damijan Knez,[a] Samo Lešnik,[c] Janez Konc[c] and Stanislav Gobec[a]
[a] Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia [b] Blood Transfusion Centre of Slovenia, Šlajmerjeva 6, 1000 Ljubljana, Slovenia [c] National Institute of Chemistry, Hajdrihova 19, SI-1000, Ljubljana, Slovenia * [email protected]
Two targets, namely Toll-like receptors (TLRs) and indoleamine 2,3-dioxygenase (IDO), have been of high interest for the design of small-molecule agents for autoimmune, inflammatory or infectious diseases and cancer. TLRs as the key component of human innate immune system recognize specific structurally diverse molecular patterns, such as molecular components of microorganisms or endogenous molecules resulting from tissue damage.[1]-[2] Among 13 different mammalian TLRs, we focused our attention on TLR4 and TLR7. On the other hand, high IDO1 expression found in tumor cells triggers the escape from immune system and has been associated with poor prognosis in several cancer types.[3] Therefore, our aim was to design and develop novel TLR modulators and IDO1 inhibitors as potential anti-inflammatory and anticancer agents. The compounds of interest were designed by advanced in silico drug design approaches. Structure- and ligand-based virtual screening was performed on the basis of crystallographic structural data for selected target. Targeting the TLR4–MD-2 interface enabled the discovery of three hit compounds with promising TLR4 antagonist activity.[4] The most potent hit 1-(4-fluorophenyl)-2-(5-(2-hydroxy-5- methoxybenzoyl)pyrimidin-2-yl)guanidine also suppressed cytokine secretion by human PBMC. In a follow-up study, three-step synthetic route was designed and optimized to obtain a series of N-aryl- N’-(5-(2-hydroxybenzoyl)pyrimidin-2-yl)guanidine derivatives as TLR4 antagonists with EC50 values in the low micromolar range.[5] Furthermore, 3D similarity-based virtual screening using ROCS software lead to the discovery of 1-isobutylchromeno[3,4-d]imidazol-4(1H)-one.[6] Additionally, sixteen novel chromeno[3,4-d]imidazol-4(1H)-one derivatives were synthesized in the optimized straightforward synthetic pathway and evaluated for TLR7 modulatory activity in a HEK-Blue™ TLR7 reporter assay. The most promising compound exhibited potent TLR7 agonist activity (IC50 of 1.8 µM) which was in the same range as a marketed drug imiquimod. Recently, the ligand-based virtual screening using IDO1 inhibitor epacadostat as a query was performed with our software LiSiCA.[7] Moreover, application of structure-based screening protocol on the human form of IDO1 enzyme using our newly developed ProBiS plugin software [8] enabled the discovery of structurally diverse hits which were further evaluated for IDO1 inhibitory activity in an optimized highly sensitive fluorescence-based end-point assay. Altogether, we obtained useful information about SAR of chromeno[3,4-d]imidazol-4(1H)-one TLR7 agonists, which represent an important starting point for further studies of small-molecule agents targeting TLRs. Furthermore, novel IDO1 inhibitors were also discovered.
[1] Y. Kumagai, O. Takeuchi, S. Akira. J. Infect. Chemother., 2008, 14, 86. [2] X. Wang, C. Smith, H. Yin, Chem Soc Rev., 2013, 42, 4859. [3] U.F. Röhrig et al. J. Med. Chem., 2015, 58(24), 9421. [4] U. Švajger et al. Eur. J. Med. Chem., 2013, 70, 393. [5] M. Sova et al. Med. Chem., 2016, 12(8), 742. [6] U. Švajger et al. Med. Chem. Res., 2015, 24(1), 362. [7] S. Lešnik et al. J. Chem. Inf. Model., 2015, 55(8), 1521. [8] T. Štular et al. J. Med. Chem., 2016, 59(24), 11069.
48 The 10th Joint Meeting on Medicinal Chemistry 2017
KL-6
NEW DRUG CONJUGATES BASED ON AZASTEROIDS OR PEPTIDES FOR TARGETED DRUG DELIVERY IN CANCER THERAPY
Vasiliki Sarli
Department of Chemistry, Aristotle University of Thessaloniki, Greece [email protected]
Targeted drug delivery systems (TDDS) offer an attractive strategy to minimize systemic toxicity and achieve the best therapeutic effect with a lower dose. Peptides (e.g. Arg-Gly-Asp (RGD) peptides, poly-Arg peptides, octreotide, bombesin) and steroids, have been widely applied to selectively direct drugs to cancer cells with upregulated receptors. The synthesis and evaluation of peptide-drug conjugates that target integrin receptors will be thoroughly discussed. One derivative is designed to carry together with the cytotoxic drug a luminescent probe for either in vivo or in vitro imaging in order to ensure efficient monitoring of drug delivery. Classical chemotherapeutic drugs for instance nitrogen mustards, platinum complexes and 5- fluorouracil are linked to the peptide by different linkers. In addition, the synthesis of conjugates combining a cytotoxic compound and azasteroidal lactams will be analyzed. These conjugates improve the physicochemical properties (lipophilicity and solubility) of known classical alkylators, such as POPAM ((bis(2-chloroethyl)amino)phenoxy) propanoic acid). The synthesized homo-azasteroidal alkylators showed relatively lower acute toxicity, very promising and prominent antileukemic activity both in vitro and in vivo.
49 The 10th Joint Meeting on Medicinal Chemistry 2017
KL-7
A "LIBRARY-ON-LIBRARY" SCREENING APPROACH TO IDENTIFY SMALL-MOLECULE LIGANDS OF METHYL-LYSINE READER PROTEINS
Gianluca Sbardella
Dipartimento di Farmacia, Epigenetic Med Chem Lab, Università degli Studi di Salerno, Via Giovanni Paolo II 132, I-84084 Fisciano (SA), Italy. [email protected]
The discovery of inhibitors of methyl- and acetyl-binding domains has provided evidence for the “druggability” of epigenetic effector molecules. Using a library of biotin-tagged analogs we screened a protein domain microarray of methyl-lysine effector molecules to rapidly detect compounds with novel binding profiles - either improved or loosened specificity. Using this approach, we identified compounds that acquired novel interactions with Tudor domain-and MBT domain-containing proteins.
50 The 10th Joint Meeting on Medicinal Chemistry 2017
KL-8
DISRUPTING THE PEX14-PEX5 INTERACTION BY SMALL MOLECULES PROVIDES A NOVEL STRATEGY FOR TREATMENT OF TRYPANOSOMA INFECTIONS
Maciej Dawidowski,[a,b,c],* Leonidas Emmanouilidis,[a,b] Vishal Kalel,[d] Wolfgang Schliebs,[d] Ralf Erdmann,[d] Kostas Tripsianes,[e] Kenji Schorpp,[f] Kamyar Hadian,[f] Marcel Kaiser,[g,h] Pascal Mäser,[g,h] Marta Kolonko,[a] Scott Tanghe,[i] Ana Rodriguez,[i] Michael Sattler,[a,b] Grzegorz M. Popowicz,[a,b]
[a] Institute of Structural Biology, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany [b] Munich Center for Integrated Protein Science at Chair of Biomolecular NMR, Department Chemie, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany [c] Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of Warsaw, Banacha 1, 02-097 Warsaw; present address [d] Institute of Biochemistry and Pathobiochemistry, Department of Systems Biology, Faculty of Medicine, Ruhr University Bochum, 44780 Bochum, Germany [e] CEITEC - Central European Institute of Technology, Masaryk University, Kamenice 5, 62500 Brno, Czech Republic. [f] Assay Development and Screening Platform, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany. [g] Swiss Tropical and Public Health Institute, Socinstrasse 57, P.O. Box, 4002 Basel, Switzerland. [h] University of Basel, 4001 Basel, Switzerland. [i] New York University School of Medicine, Department of Microbiology, 341 E. 25th St. room 513, New York NY 10010 USA. * [email protected]
Trypanosoma parasites couple glycolytic and peroxisomal function in a unique organelle, called the glycosome. Glycosomes lack genetic information, therefore the enzymes that are active in the lumen of the organelle need to be translocated post-translationally. Small peroxisomal proteins (Peroxins, PEX#) play an important role in this process. The PEX14-PEX5 protein-protein interaction (PPI) has a crucial role for protein translocation into glycosomes by docking of the cytosolic shuttling receptor PEX5 with the membrane-associated protein PEX14.[1] Inhibition of this PPI has been suggested a potential way of disrupting glycosome function in parasites, leading to ATP depletion and fatal metabolic catastrophe.[2] We have recently reported first small molecule inhibitors that kill Trypanosomes by disrupting the PEX14-PEX5 PPI.[3] In a structure-based design, we mimicked the binding mode of the PEX5 WxxxF motifs to the respective binding pockets on PEX14 surface. In a multidisciplinary, collaborative effort we combined computational methods, NMR, X-ray crystallography, cellular studies and medicinal chemistry. As a result, we obtained PEX14-PEX5 PPI inhibitors with trypanocidal activity comparable or better than current therapeutics. In this lecture, a complete research workflow leading to a proof-of-concept is presented.
[1] Neufeld, C. et al., EMBO J. 2009, 28, 745-754. [2] Furuya, T. et al., PNAS 2002, 99, 14177-14182. [3] Dawidowski, M. et al., Science 2017, 355, 1416–1420.
51 The 10th Joint Meeting on Medicinal Chemistry 2017
KL-9
HYBRID COMPOUNDS IN THE SEARCH FOR THE NEW HIGHLY EFFECTIVE ANTICONVULSANTS
Krzysztof Kamiński
Department of Medicinal Chemistry, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland [email protected]
The multifunctional ligands approach is one of the modern strategies in drug discovery especially in relation to diseases with complex pathomechanism, such as Alzheimer’s disease, cancer, or epilepsy. This strategy assumes that a single chemical entity is capable of modulating biological targets simultaneously and overcoming problems related to the use of “multicomponent drugs” such as different bioavailability or pharmacokinetics, as well as poor compliance in case of “drug cocktails.” According to this method two (or more) molecules, each with different molecular target or with specific biological properties, are combined in a single chemical entity to provide complex and broad activity.[1] Bearing in mind the assumptions of aforementioned strategy, and with the aim of obtaining more efficacious antiepileptic drugs (AEDs) that will suppress different types of human seizures, the new hybrid anticonvulsants based on the pyrrolidine-2,5-dione scaffold have been obtained.[2-4] These hybrid molecules join on the one chemical template the structural fragments of clinically relevant AEDs such as ethosuximide, levetiracetam, and lacosamide. As a result, the hybridization process yielded substances effective in three the most important animal seizure models, namely the maximal electroshock (MES) test, the subcutaneous pentylenetetrazole (scPTZ) test, and notably the six- Hertz (6 Hz) model of pharmacoresistant limbic seizures in mice. These substances displayed wider spectrum of protection, more potent efficacy or/and better safety profile than respective AEDs creating hybrid structure (ethosuximide, levetiracetam, and lacosamide). Additionally, several compounds diminished the pain responses in the formalin model of tonic pain and notably in the neurogenic pain models (capsaicin-induced nociception and oxaliplatin-induced neuropathy) in mice.
Acknowledgements: The studies were supported by the Polish National Science Centre grant 2015/18/E/NZ7/00509.
[1] R. Morphy, Z. Rankovic, J. Med. Chem,. 2005, 48, 6523. [2] K. Kamiński, M. Zagaja, J.J. Łuszczki, A. Rapacz, M. Andres-Mach, G. Latacz, K. Kieć-Kononowicz, J. Med. Chem., 2015, 58, 5274. [3] K. Kamiński, M. Zagaja, A. Rapacz, J.J. Łuszczki, M. Andres-Mach, M. Abram, J. Obniska, Bioorg. Med. Chem., 2016, 15, 606. [4] K. Kamiński, Curr. Top. Med. Chem., 2017, 17, 858.
52 The 10th Joint Meeting on Medicinal Chemistry 2017
KL-10
CAN MULTIVARIETE STATISTICS AID TO THE REVEAL OF BIOACTIVE COMPOUNDS? AN NMR AND HPTLC APPROACH
V. I. Boka,[a] K. Stathopoulou,[a] D. Benaki,[b] E. Gikas,[b] E. Mikros[b] and N. Aligiannis[a],*
[a] Department of Pharmacognosy & Natural Products Chemistry, Faculty of Pharmacy, University of Athens, Zografou, 15771, Greece; [b] Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Athens, Panepistimiopolis Zografou, Athens, Greece * [email protected]
Greece has an exceptionally rich flora which forms, geographically and historically, a link between the plant-life of Europe and that of Asia.[1] It is characterized by high biodiversity, consisting of 6300 species of which 950 are endemic and thus could be an ideal source for the discovery of bioactive compounds.[2] The aim of this project is to discover natural compounds with skin whitening properties via the establishment of a high-throughput platform relying on FCPC, HPTLC and NMR, for their direct detection and identification prior to any isolation. 600 plants existing in a unique plant-library comprising around 32% of the Greek flora were selected and the plant extracts were produced by ASE. The extracts were in vitro investigated for their tyrosinase inhibition activity and nine among the most promising were selected for further elaboration. More specifically, the extracts were fractionated by FCPC utilizing a gradient step-wise solvent system consisted of Heptane/Ethyl acetate/Butanol/Methanol/Water providing 45 fractions per extract. The resulted fractions were assayed for tyrosinase inhibition potential and further analyzed by HPTLC and NMR. An integrated HPTLC-based procedure for the tracing of compounds that contributed to tyrosinase inhibitory effect in active fractions was established with the use of multivariate data analysis. Additionally, NMR spectral data were correlated with the activity towards tyrosinase resulting in the identification of bioactive compounds through the combination of the Heterocovariance approach (HetCA) and the statistical total correlation spectroscopy (STOCSY). The combined data deriving from NMR and HPTLC correlated to the results of the biological activity by the statistically driven approach, revealed flavans, flavonols, phenolic compounds and stilbenoids as the most promising whitening agents, providing a major reduction in workload by direct use of routine information.
[1] Kokkini S., Karagiannakidou V., Hanlidou E., Vokou D.: Phyton (Austria), 1988, 28, 215. [2] Dimopoulos P., Raust T., Bergmeier E., et al., Berlin 2013.
53 The 10th Joint Meeting on Medicinal Chemistry 2017
KL-11
ENDOCANNABINOID SYSTEM MODULATION: THERAPEUTIC IMPLICATIONS AND FUTURE PERSPECTIVES
Marco Macchia
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy [email protected]
The endocannabinoid system (ECS) consists of two G protein-coupled receptors (CB1R and CB2R), their endogenous ligands, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and the enzymes involved in the biosynthesis and degradation of endocannabinoids, such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). The ECS is involved in several physiological and pathological conditions, including cancer and neurodegenerative diseases. The CB2R has gained a great interest as a therapeutic target in drug discovery. Recent in vitro and in vivo studies highlight that activation of the CB2R induces apoptosis and inhibits tumour growth and neo-angiogenesis. It has been also demonstrated that potent and selective CB2R agonists produce beneficial actions in the brain and in the periphery, with the additional advantage of being devoid of CB1R-mediated psychotropic side effects. On the other hand, the enhancement of the levels of AEA and 2-AG, by inhibiting MAGL/FAAH, could preserve the beneficial effects derived from the direct activation of CBRs. Recent investigations hypothesize an important role for MAGL in cancer cells, regulating a set of pro-tumorigenic signaling molecules and promoting migration, survival, and in vivo tumor growth. Hence, overexpression of this enzyme results in increased pathogenicity of cancer cells, whereas its inhibition reduces cancer growth, indicating that it might constitute a promising antitumor target. Furthermore, the current comprehension of the complexity of the ECS seems to indicate a need of multi-target drugs, which exert their pro-cannabinoid activities by means of more than one mechanism of action. These molecules could offer the advantage of modulating the ECS in a safer and more therapeutically efficacious way. The development of these multi-target tools could provide a foothold to investigate the polypharmacology of the ECS in different pathologies. In our research program aimed at obtaining modulators of the ECS, we focused our attention on compounds of general structure A, B and C as selective CB2R agonists, selective MAGL inhibitors and multi-target ECS modulators, respectively.
R3 O O O R R4 Cl 3 NHR2 N NHR2
R4 X N O R1 R3 N O R1 O R2 R1 C A B
54 The 10th Joint Meeting on Medicinal Chemistry 2017
KL-12
COMPUTATIONAL INSIGHT INTO THE CATALYTIC ACTIVITY OF MONOAMINE OXIDASE FOR TARGETING NEUROLOGICAL DISEASES
Robert Vianello
Computational Organic Chemistry and Biochemistry Group, Ruđer Bošković Institute, Zagreb, Croatia [email protected]
Monoamine oxidase (MAO) is an FAD-dependent flavoenzyme responsible for metabolizing a very broad range of biogenic and dietary amines including many neurotransmitters in the brain, such as dopamine and serotonin, whose imbalance is extensively linked with the development and progression of many neurological disorders. That is why MAO has been a central pharmacological target in treating neurodegeneration for over 60 years.[1] Still, despite decades of extensive research, neither its catalytic nor inhibition mechanisms have yet been clearly determined, which is of paramount importance in designing novel and effective MAO inhibitors as transition state analogues, particularly since current drugs show serious adverse effects and tend to address only the symptoms rather than the cause of the dysfunction. On the basis of QM calculations and EVB QM/MM simulations, we have proposed a new two-step hydride mechanism for the MAO catalysis (Figure 1),[2] which is gaining some affirmation in the literature,[3] and is fully corroborated by a very recent 13C kinetic isotope effect measurements.[3c] [4] Calculations of the pKa values of three tyrosine residues (Figure 2) revealed that MAO active site is hydrophilic, but turns hydrophobic upon the substrate entrance that binds in the monocationic form. MAO selectivity has been investigated in the case of histamine,[5] which is not a physiological MAO substrate, yet is efficiently metabolized by MAO upon the N-methylation of the imidazole ring. Our results rationalized the MAO specificity with two substrates, histamine and N-methylhistamine, differing only in a single methyl group distant from the reactive centre. The insight gained through all these results led us to propose several promising strategies for preventing neurodegeneration.[6]
Figure 1: Free energy profiles for the MAO B catalyzed Figure 2: MAO B active site with degradation of histamine and N-methylhistamine. dopamine bound as the substrate.
[1] a) R.R. Ramsay, Prog. Neuropsychopharmacol. Biol. Psychiatry, 2016, 69, 81.; b) S. Chajkowski-Scarry, J.M. Rimoldi, Future Med. Chem., 2014, 6, 697.; c) R.R. Ramsay, Curr. Top. Med. Chem. 2012, 12, 2189. [2] a) R. Vianello, M. Repič, J. Mavri, Eur. J. Org. Chem., 2012, 7057.; b) M. Poberžnik, M. Purg, M. Repič, J. Mavri, R. Vianello, J. Phys. Chem. B, 2016, 120, 11419. [3] a) V.E. Atalay, S.S. Erdem, Comp. Biol. Chem., 2013, 47, 181.; b) G. Zapata-Torres et al., J. Chem. Inf. Model., 2015, 55, 1349.; c) J.R. Tormos et al., Arch. Biochem. Biophys., 2016, 612, 115. [4] R. Borštnar, M. Repič, S.C.L. Kamerlin, R. Vianello, J. Mavri, J. Chem. Theory Comput., 2012, 8, 3864. [5] A. Maršavelski, R. Vianello, Chem. Eur. J., 2017, 23, 2915. [6] M. Pavlin, M. Repič, R. Vianello, J. Mavri, Mol. Neurobiol., 2016, 53, 3400.
55 The 10th Joint Meeting on Medicinal Chemistry 2017
KL-13
LIGAND-BASED DRUG DESIGN OF NOVEL ALDOSE REDUCTASE INHIBITORS FROM DATABASES OF INDOLE-1-ACETIC ACIDS
Magdaléna Májeková,* Jana Ballekova, Marta Soltesova Prnova and Milan Stefek
Department of Biochemical Pharmacology, Institute of Experimental Pharmacology and Toxicology Slovak Academy of Sciences, Dubravska cesta 9, 541 04 Bratislava, Slovakia * [email protected]
Aldose reductase (ALR2) is a frequent therapeutic target in searching for efficient treatment of long- term diabetic complications and other chronic diseases. Compounds with indole-1-acetic acid moiety are known as promising leads for design of aldose reductase inhibitors (ARIs). Ligand-based strategy was used in searching for novel ARIs in databases of purchasable compounds. Among the compounds studied, 2-(2-(ethoxycarbonyl)-8-methoxy-3,4-dihydro-1H-pyrido[4,3-b]indole-5(2H)-yl) acetic acid (Figure) was identified as the most promising inhibitor of aldose reductase (ALR2), with [1] IC50 in nanomolar region and selectivity factor relative to aldehyde reductase (ALR1) around 750. Profitable inhibition properties were also confirmed for isolated rat lens red blood cells. In vivo experiment of streptozotocin induced diabetes on rats revealed an early ability of DPI-1 to inhibit sorbitol accumulation in sciatic nerve and blood.
O O N
H3CO
N OH
O
Figure: Structure of DPI-1.
Concurrently, we started to build up the systematic database of compounds with indole scaffold, whose properties have been studied by a virtual screening method to find optimal pharmacokinetic and pharmacodynamics properties. The compounds proposed by this study are to be synthesized and tested for their activities as aldose reductase inhibitors and the modulators of other proteins occurring in the development of chronic diseases together with aldose reductase.
Acknowledgements: This work was supported by VEGA 2/0041/15 and VEGA 2/0033/14. We also thank the Slovak Research and Development Agency under the contract No. APVV-15-0455 and SAS – TÜBİTAK Joint Project No. JRP 2015/7 for funding.
[1] M. Stefek, J. Ballekova, M. Soltesova Prnova and M. Majekova. Use of 5-carboxymethyl-1,2,3,4- tetrahydro-1H-pyrido[4,3-b]indoles and pharmaceutical preparation containig them: Patent Application PP 50049-2016, Industrial Property Office of the Slovak Republic, 2016.
56 The 10th Joint Meeting on Medicinal Chemistry 2017
KL-14
PRETARGETED PRODRUG ACTIVATION THROUGH BIOORTHOGONAL ELIMINATION
Hannes Mikula
Institute of Applied Synthetic Chemistry, Vienna University of Technology (TU Wien), Getreidemarkt 9/163, 1060 Vienna, Austria [email protected]
The field of bioorthogonal chemistry has been growing steadily and fascinating scientists worldwide for more than 15 years with the challenge of engineering chemical transformations that can proceed within the molecularly complex environment of living systems. In spite of tremendous progress in recent years, when compared to classic reaction methodology, bioorthogonal chemistry remains in its infancy. Considering the vast range of organic reactions available to synthetic chemists (additions, eliminations, substitution, oxidations, reductions, etc.), bioorthogonal chemistry has until recently been restricted to just one reaction type—bioorthogonal addition—limiting its full potential. In recent years, bioorthogonal bond cleavage (or bioorthogonal elimination) reactions have emerged as a thriving area of chemical research, with examples such as the palladium-mediated cleavage of allyl and propargyl carbamates [1-3] or the elimination of a carbamate-functionalized trans- cyclooctene (release-TCO, rTCO) upon reaction with a 1,2,4,5-tetrazine (Tz).[4] The latter reaction has recently led to novel therapeutic concepts, and applications in chemical biology.[4-6] We have designed and prepared several prodrugs using carbamates and rTCO as protective triggers also in combination with self-immolative linkers. In general, we have observed that these prodrugs are significantly less toxic to tumor cells than the respective parent drugs, but can be activated by co-treatment with a palladium catalyst or tetrazines, respectively. For example, a Tz-moiety was attached to a highly selective covalent inhibitor affording a bioorthogonal probe that was successfully applied for pretargeted activation of rTCO-modified prodrugs. In this talk, an overview will be given of these studies and our recent activities regarding prodrug activation through bioorthogonal elimination.
[1] R.M. Yusop, A. Unciti-Broceta, E. M. V. Johansson, R. M. Sánchez-Martín, M. Bradley, Nat. Chem., 2011, 3, 239. [2] J. Li, J. Yu, J. Zhao, J. Wang, S. Zheng, S. Lin, L. Chen, M. Yang, S. Jia, X. Zhang, P. R. Chen, Nat. Chem., 2014, 6, 352. [3] J. Li, P. R. Chen, Nat. Chem. Biol., 2016, 12, 129. [4] R.M. Versteegen, R. Rossin, W. ten Hoeve, H. M. Janssen, M. S. Robillard, Angew. Chem. Int. Ed., 2013, 52, 14112. [5] J. Li, S. Jia, P. R. Chen, Nat. Chem. Biol., 2014, 10, 1003. [6] G. Zhang, J. Li, R. Xie, X. Fan, Y. Liu, S. Zheng, Y. Ge, P. R. Chen, ACS Cent. Sci., 2016, 2, 325.
57 The 10th Joint Meeting on Medicinal Chemistry 2017
KL-15
PATIENT DERIVED TESTING SYSTEMS – REACHING BEYOND TARGED BASED DRUG DISCOVERY
Vesna Eraković Haber
Translational Research and Alliances, Fidelta Ltd., Zagreb, Croatia [email protected]
Great advances in modern science have provided a clear rational and powerful tools for target based drug discovery. Combinatorial chemistry and parallel synthetic methods have increased significantly number of molecules synthetized by chemists. Nevertheless, number of new drugs approved per billion US dollar spent on R&D has halved approximately every 9 years since 1950s.[1] At least partially, the cause of that could be found in reductionist approach to biological systems and human disease. Current efforts aimed at setting up disease relevant ex vivo system, as well as their use for better understanding of human disease and testing of novel pharmacological interventions, will be presented. Donated patient derived material, hand in hand with state of the art micro technologies, rises a hope of better translation between preclinical and clinical research. Illustrations from several disease areas will be given, with special focus on inflammation.
[1] J.W. Scannell, A. Blanckley, H. Boldon, B. Warrington, Nat. Rev. Drug Discov., 2012, 11, 191.
58 The 10th Joint Meeting on Medicinal Chemistry 2017
ORAL PRESENTATIONS
59 The 10th Joint Meeting on Medicinal Chemistry 2017
OP-1
ANTI-HELICOBACTER PYLORI ACTIVITY OF A NOVEL DERIVATIVE OF INTERVENOLIN
Manabu Kawada,[a,b],* Tomokazu Ohishi,[b] Hikaru Abe,[c] Chigusa Hayashi,[d] Chiharu Sakashita,[c] Shun-ichi Ohba,[b] Hiroyuki Inoue,[b] Masayuki Igarashi,[d] Takumi Watanabe[c] and Masakatsu Shibasaki[c],*
[a] Institute of Microbial Chemistry (BIKAKEN), Laboratory of Oncology, 3-14-23 Kamiosaki, Shinagawaku, Tokyo 141-0021, Japan [b] Institute of Microbial Chemistry (BIKAKEN), Numazu, 18-24 Miyamoto, Numazu-shi, Shizuoka 410- 0301, Japan [c] Institute of Microbial Chemistry (BIKAKEN), Laboratory of Synthetic Organic Chemistry, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan [d] Institute of Microbial Chemistry (BIKAKEN), Laboratory of Microbiology, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan * [email protected]
Helicobacter pylori (H. pylori) infection plays a critical role on pathogenesis of gastric ulcer and gastric cancer. Thus, the eradication of H. pylori could prevent the onset of these diseases. At present the standard therapy against H. pylori infection is a combination therapy of a proton pump inhibitor and two antibiotics such as clarithromycin and amoxicillin. However, there exist H. pylori strains that show resistance against these antibiotics. Furthermore, adverse effect of these antibiotics against intestinal bacteria is unavoidable. We previously discovered a novel compound, intervenolin, from the culture broth of Nocardia sp. ML96-86F2.[1] [2] Intervenolin is a very unique compound having both antitumor and anti-H. pylori activities. To create a potent anti-H. pylori compound, we synthesized various derivatives of intervenolin.[3] Among them we identified compounds that show selective anti-H. pylori activity in vitro without effect on other bacteria including intestinal bacteria. Oral monotherapy of the derivative exerts significant eradicative effect against H. pylori-infected mice more than the standard combination therapy. Taken together, we have successfully created a potent new anti-H. pylori compound.
[1] M. Kawada, et al, J. Antibiot., 2013, 66, 543. [2] H. Abe, et al, Org. Lett., 2013, 15, 2124. [3] H. Abe, et al, Tetrahedron, 2013, 69, 7608.
60 The 10th Joint Meeting on Medicinal Chemistry 2017
OP-2
IN VITRO PHOTODYNAMIC ACTIVITY OF A NEW TRI-CATIONIC AMPHIPHILIC PORPHYRIN AGAINST HERPES SIMPLEX VIRUS 1, BACTERIA AND CANCER CELLS
Nela Malatesti,[a],* Maja Cokarić Brdovčak,[a] Lara Djaković,[a] Igor Jurak,[a] Anđelo Šuvak,[a] Ivana Gobin,[b] Anja Harej[a] and Sandra Kraljević Pavelić[a]
[a] Department of Biotechnology, University of Rijeka, Radmile Matejčić 2, 51000 Rijeka, Croatia [b] Department of Microbiology and Parasitology, Faculty of Medicine, Braće Branchetta 20, 51000 Rijeka, Croatia * [email protected]
Photodynamic therapy (PDT) is a type of phototherapy that uses harmless red light for the activation of a photosensitiser (PS) and consequential, localised formation of the cytotoxic singlet oxygen or other reactive oxygen species.1 Even though PDT was first discovered on a microorganism, it has been primarily developed to treat cancer, and is only recently getting more attention as an antimicrobial therapy.2 We have synthesized 5-(4-octadecanamidophenyl)-10,15,20-tris(N-methylpyridinium-3-yl)porphyrin trichloride (C18PyP3) in order to investigate the effect of the lipophilic moiety on PDT activity of this amphiphilic porphyrin, in comparison to the hydrophilic analogue, 5-(4-acetamidophenyl)-10,15,20- tris(N-methylpyridinium-3-yl)porphyrin trichloride (C2PyP3). Both porphyrins have very similar optical properties and PDT activity in relation to both drug-dose and light-dose, but significantly higher activity of the amphiphilic porphyrin was demonstrated as the obtained IC50 value for C18PyP3 was 37 times lower than for C2PyP3, after PS activation with low dose of red light (1.8 J cm-2, 643 nm) on HeLa cells in vitro.3 Cationic tetraarylporphyrins have been previously used to destroy both Gram positive and Gram negative bacteria,4 and are also interesting as possible antiviral agents.5 To test the antibacterial activity of C18PyP3, the minimum inhibitory (MIC) and minimum bactericidal (MBC) concentration was determined, with the dilution method, on several Gram (+) and Gram (-) bacteria. After 30 minutes incubation with C18PyP3 and further 1 hour of irradiation (overall dose 7.2 J cm-2), there was no difference between MIC and MBC values, and the lowest values were obtained on Gram (+) bacteria, namely, Staphylococcus aureus (6.25 µM), including methicillin-resistant strain (MRSA), Enterococcus faecalis (12.5 µM) and Listeria monocytogenes (12.5 µM). Finally, to test antiviral activity of C18PyP3, we infected Vero cells treated with different concentrations of the compound with herpes simplex virus 1 (HSV-1) and measured virus yield. Replication of the virus was greatly reduced in cells that were treated and irradiated (1.8 J cm-2) compared to untreated or treated but not irradiated cells. Moreover, the inhibition of replication was drug-dose dependent. These results strongly indicate that C18PyP3 activated by light exerts antiviral properties. Furthermore, our preliminary results show that it affects HSV-1 replication by inhibiting virus gene expression and by limiting the infectivity of HSV-1 virions. Important to note, the concentrations of C18PyP3 used in these experiments did not show a significant toxicity in Vero cells.
[1] R.R. Allison, K. Moghissi, Clin. Endosc., 2013, 46, 24. [2] S.K. Sharma, P. Mroz, T. Dai, Y-Y. Huang, T.G. St. Denis, M.R. Hamblin, Isr. J. Chem., 2012, 52, 691. [3] N. Malatesti, A. Harej, S. Kraljević Pavelić, M. Lončarić, H. Zorc, K. Wittine, U. Andjelkovic, D. Josic, Photodiagnosis Photodyn. Ther., 2016, 15, 115. [4] E. Alves, L. Costa, C.M. Carvalho, J.P. Tomé, M.A. Faustino, M.G. Neves, A.C. Tomé, J.A. Cavaleiro, A. Cunha, A. Almeida, BMC Microbiol., 2009, 9, 70. [5] L. Costa, M.A.F. Faustino, M.G.P.M.S. Neves, A. Cunha, A. Almeida, Viruses, 2012, 4, 1034.
61 The 10th Joint Meeting on Medicinal Chemistry 2017
OP-3
DISCOVERY OF NEW, POTENTIAL ANTI-INFECTIVE COMPOUNDS BASED ON CARBONIC ANHYDRASE INHIBITORS BY RATIONAL TARGET-FOCUS REPURPOSING APPROACH
G. Annunziato,[b] A. Angeli,[c] F. D’Alba,[a] A. Bruno,[a],* M. Pieroni,[a] D. Vullo,[d] V. De Luca,[e] C. Capasso,[e] C. T. Supuran[c,d],* and G. Costantino[a]
[a] Dipartimento di Scienze degli Alimenti e del Farmaco, P4T group, University of Parma; Parco Area delle Scienze, 27/A, 43124, Parma (Italy) [b] CIM-Centro Interdipartimentale Misure “Giuseppe Casnati”, University of Parma, Parco Area delle Scienze 23/A, 43124, Parma (Italy) [c] Neurofarba Dept., Section of Pharmaceutical and Nutriceutical Sciences, University of Florence, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence (Italy) [d] Polo Scientifico, Laboratorio di Chimica Bioinorganica, University of Florence, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence (Italy) [e] Istituto di Bioscienze e Biorisorse, CNR, Via Pietro Castellino 111, 80131 Napoli (Italy) * [email protected]; [email protected]
Drug-repurposing or repositioning (DR) denotes an ensemble of tasks aimed to the identification of new drug indications for existing drugs, and is an alternative strategy in drug discovery program, both in pharma and academia. In academia, DR can be also translated into compound-recycling (CR) that is the repurposing of compound library collections already available in-house. Indeed, small molecules already synthesized, that resulted inactive against a target of interest, can be tested on other targets, leading to a new-purpose for an old molecule.[1] We embarked in a project aimed at the repurposing of the compound libraries available in-house, looking for a new potential applications for our compounds. In this scenario a rational target-based drug repurposing approach was applied.[2] The analysis of the data available in literature, for similar classes of chemical structures, allowed us to identify the Carbonic Anhydrase (CA, EC 4.2.1.1) metalloenzyme family as potential target of some of our compound series. A thoroughly validated docking screenings protocol was combined with chemical synthesis and in vitro assays to disclose new potential CA inhibitors which are characterized by a low μM affinity for microbial CA and unprecedented selectivity profile for this class of molecules (Figure). Even if, the activity profile of the compounds needs to be improved, the identified molecules can represent excellent hits to be further optimized in hits-to-lead campaigns.
Figure: Compound 18 docked into the SspCA active site, and its corresponding Ki on other relevant CA families and human isoforms.
[1] M. Mori, Y. Cau, G. Vignaroli, I. Laurenzana, A. Caivano, D. Vullo, C. T. Supuran, M. Botta, ACS Chem. Biol., 2015, 10, 1964. [2] J. Langedijk, A. K. Mantel-Teeuwisse, D. S. Slijkerman, M.-H. D. B. Schutjens, Drug Discov. Today, 2015, 20, 1027.
62 The 10th Joint Meeting on Medicinal Chemistry 2017
OP-4
DISCOVERY OF NOVEL GYRASE B INHIBITORS AND GYRASE B/TOPOISOMERASE IV (ParE) DUAL INHIBITORS WITH IN VITRO ANTIBACTERIAL ACTIVITY
Michaela Barančoková,[a] Janez Ilaš,[a] Tihomir Tomašič,[a] Nace Zidar,[a] Andraž Lamut,[a] Davide Benedetto Tiz,[a] Päivi Tammela,[b] Antonio Felici,[c] Vanesa Garrido[c] and Danijel Kikelj[a],*
[a] Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia [b] Centre for Drug Research, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland [c] Aptuit Verona S.r.l. - Centre of Drug Discovery and Development, Via A. Fleming 4, 37135 Verona, Italy * [email protected]
With increasing threat of bacterial resistance, topoisomerases became attractive targets for antibacterial drug discovery. Currently there is no ATP-competitive inhibitor in clinical use, since novobiocin as representative of aminocoumarines was withdrawn from the market in 1960s due to eukaryotic toxicity.[1] Topoisomerases are essential enzymes changing topological state of DNA by binding and cleaving DNA strand at GyrA/ParC subunit. Energy required for this process is obtained by ATP hydrolysis on GyrB or ParE subunit containing ATP-binding site.[2] Based on studies of solved crystal structure of E. coli GyrB with ligand (PDB code 5L3J) recently published by our group,[3] we replaced dibromopyrrole-/dichloropyrrolecarboxamide moiety attached to position 2 or 6, respectively, of benzo[d]thiazole-2,6-diamine scaffold with 3,4-dichloro-5- methylpyrrole-2-carboxamide group to complete structure-activity relationship in the series. We obtained improved analogues with increased inhibitory activity against both gyrase B and topoisomerase IV. Scaffold hopping approach was used to prepare compounds with benzo[d]imidazole-2,6-diamine core with improved physico-chemical properties and increased in vitro antibacterial activity. Introducing different acyl moieties such as imidazolidinones or acyl groups optionally containing basic moieties such as piperazin ring is another example of our efforts to improve antibacterial activity. O R1 NH 2 O O H R H 1 N X n R O N X NH n NH O N X = S, N O O N R2 n = 0; 1 O N H R1 = Me; Et; H R2 = 4,5-dibromo; 3,4-dichloro-5-methyl Figure: General structures of series of compounds with benzo[d]thiazole- or benzo[d]imidazole-2,6-diamine scaffold.
[1] G.S.Bisacchi, J.I. Manchester, ACS Infect. Dis., 2015, 1, 4. [2] J.J. Champoux, Annu. Rev. Biochem., 2001, 70, 369. [3] M. Gjorgjieva, T. Tomasic, M. Barancokova, S. Katsamakas, J. Ilas, P. Tammela, L.P. Masic,D. Kikelj, J. Med. Chem., 2016, 59 (19), 8941.
63 The 10th Joint Meeting on Medicinal Chemistry 2017
OP-5
FIGHTING ANTIMICROBIAL RESISTANCE BY BREAKING RESISTANCE MECHANISMS
Tommaso Felicetti,* Rolando Cannalire, Giuseppe Manfroni, Maria Letizia Barreca, Sabatini Stefano, and Violetta Cecchetti
Department of Pharmaceutical Science, University of Perugia, via del Liceo, 1 - 06123 Perugia, Italy * [email protected]
Antimicrobial resistance is an increasingly risk for global public health and it threatens an ever- increasing range of infections caused by bacteria, viruses, fungi, and parasites.[1] It is therefore of crucial importance to find, as soon as possible, a way to fight antimicrobial resistance. In this scenario, the development of molecules able to inhibit the efflux of the antimicrobial agents from the bacterial cells shows a huge potential in order to address the global threat of antimicrobial resistance. S. aureus overexpresses several efflux pumps; among them NorA is the most expressed and responsible for the extrusion of different substrates such as fluoroquinolones (i.e. ciprofloxacin – CPX) and dyes (i.e. ethidium bromide – EtBr) out of the bacterial cells.[2] Thus, taking into account the strong inhibitory activity on NorA efflux pump displayed from our previously reported 2- phenylquinoline derivatives,[3,4] in this work we have explored the effects of the introduction of a methoxy group, a substituent frequently recurrent in both natural and synthetic NorA efflux pump inhibitors, in different positions of the quinoline core. The O-alkylamino chains at the C-4 position were selected on the basis of the structure-activity relationship previously delineated.
All the synthesized compounds were preliminary tested in order to evaluate their ability to inhibit EtBr efflux in S. aureus strain overexpressing norA gene. Then, compounds with EtBr efflux inhibition higher than 80% were assayed to assess their capability to restore CPX MIC in different S. aureus resistant strains. Results of this study will be presented.
[1] LJ. Piddock, Lancet Infect. Dis. 2012, 12, 249. [2] D. Patel, C. Kosmidis, S.M. Seo, and G.W. Kaatz, Antimicrob. Agents Chemother., 2010, 54, 5070. [3] S. Sabatini, F. Gosetto, G. Manfroni, O. Tabarrini, G.W. Kaatz, D. Patel, and V. Cecchetti, J. Med. Chem., 2011, 54, 5722. [4] S. Sabatini, F. Gosetto, N. Iraci, M.L. Barreca, S. Massari, L. Sancineto, G. Manfroni, O. Tabarrini, M. Dimovska, G.W. Kaatz, and V. Cecchetti, J. Med. Chem., 2013, 56, 4975.
64 The 10th Joint Meeting on Medicinal Chemistry 2017
OP-6
α-ENAMINONES: NEW BUILDING BLOCKS FOR DIRECT SYNTHESIS OF BIOLOGICALLY ACTIVE ALKALOIDS
David Lankri, Ghassan Albarghouti and Dmitry Tsvelikhovsky*
The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel * [email protected]
We disclose novel reactivity of α,β-unsaturated enaminones driven by their "dual electronic attitude". We introduce unexplored, stable α-enaminone synthones, radically different from the β-counterparts by their chemical behavior, and unlock unusual, and never before observed functionalities of these building blocks. The feasibility of new concept and its potential general applicability is demonstrated in direct metal- or radical-free functionalization of enaminone precursors such as: amination, 1,2- 1,3- or 1,4-addition, alkylation, C-O bond formation, and many others. We designed general and collective synthesis of several important classes of heterocycles via controlled cyclizations of easily accessible collective precursor.[1-3] The rapid composition of novel key α-enaminone synthones yields an assembly of Oxazines, Azaspirones, Quinolinones, Quinolinoles, Azepines, Oxazepines and many other bi- and polycyclic systems in a regio- and chemoselective fashion via controlled intramolecular cyclizations of a single molecular unit. To the best of our knowledge, a general and collective approach toward the construction of all the above-mentioned scaffolds has yet to be reported. We unite these families under a common synthetic strategy and devise a simple means for building these heterocyclic motives in a rapid and efficient manner. Oxazines, Azaspirones, Quinolinones, Quinolinoles, Azepines, Oxazepine structures are frequently observed as scaffold segments of various biochemical compounds, natural products and pharmaceuticals. These architectures have been identified as building blocks of numerous alkaloids, as well as other families of diverse, and often remotely related metabolites. Unfortunately, access to a large number of these target molecules and their structural analogues is either unknown or hindered by their multistep syntheses. An in-depth analysis of the introduced cores reveals that α-enaminones have the potential to serve as operational, collective key precursors for their construction, via controlled intramolecular cyclizations. This is the first attempt to link simple and single enaminone core with such a diverse, heterocyclic architectures. With this in mind, our current interest is to develop a streamlined, synthetic methodology allowing for rapid, collective composition of multiple targets, using a single, common precursor.
[1] Y. Mostinski, V. Valerio, D. Lankri, D. Tsvelikhovsky‚ J. Org. Chem., 2015, 80, 10464. [2] V. Valerio, Y. Mostinski, R. Kotikalapudi, D. Tsvelikhovsky‚ Chem. Eur. J., 2016, 22, 2640. [3] G. Elbarghouti, R. Kotikalapudi, D. Lankri, D. Tsvelikhovsky‚ Chem. Commun., 2016, 52, 3095.
65 The 10th Joint Meeting on Medicinal Chemistry 2017
OP-7
NOVEL BENZO[B]FURAN DERIVATIVES – BIOLOGICAL ACTIVITY AND PROTEIN TARGET IDENTIFICATION IN LEUKEMIC CELLS
Marcin J. Cieślak,[a],* Karolina Królewska,[a] Julia Kaźmierczak-Barańska,[a] Milena Sobczak,[a] Bożena Kuran,[b] Mariola Napiórkowska,[c] Jerzy Kossakowski,[b] Iwona Wybrańska[d,e] and Barbara Nawrot[a]
[a] Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Department of Bioorganic Chemistry, 112 Sienkiewicza Str., 90-363 Lodz, Poland [b] Chair and Department of Biochemistry, Medical University of Warsaw, 1 Banacha Str., 02-097 Warsaw, Poland [c] Department of Medical Chemistry, Medical University of Warsaw, 3 Oczki Str., 02-007 Warsaw, Poland [d] Department of Genetic Diagnostics and Nutrigenomics, Chair of Clinical Biochemistry, The Jagiellonian University, Medical College, 15 Kopernika Str., 31-501 Krakow, Poland [e] Department for Genetic Research and Nutrigenomics, The Malopolska Centre of Biotechnology Jagiellonian University, 7 Gronostajowa Str., 30-387 Krakow, Poland * [email protected]
Novel derivatives of benzo[b]furan were found to be selectively toxic towards human chronic myelogenous (K562), acute myelogenous (HL-60) and acute lymphoblastic (MOLT-4) leukemia cells and much less toxic to primary human endothelial cells. The cytotoxicity of novel benzofurans (expressed as IC50 values) in K562 and HL-60 cells was similar or higher compared to registered drugs, such as cytarabine, sorafenib or CPT-11. The caspase 3/7 activity assay and annexin V- FITC/PI flow cytometry analysis have shown that benzofurans induce apoptosis in K562 and MOLT- 4 cells. Both, receptor and mitochondrial apoptotic pathways were activated in leukemic cells in the presence of test compounds, what was evidenced by increased activity of caspase 8 and 9. To explain the mechanism of apoptosis induced by novel benzo[b]furans, the profiling of apoptosis- associated genes expression was performed in leukemia K562 cells. Benzofuran derivatives increased the expression of several proapoptotic genes involved in both receptor (e.g. TNFRSF 10A, TNFRSF 10B, CASP8) and mitochondrial (e.g. BAX, BID, NOXA, APAF1) pathways of apoptosis. To identify cellular proteins targeted by test benzofurans, the biotinylated derivative has been synthesized and used in pull-down experiments in K562 leukemic cells. The proteomic analysis revealed that tubulin is a target for biotinylated probe. Moreover, incubation of K562 cells with test benzofurans resulted in depolymerization of microtubules. Biological activity of novel derivatives of benzo[b]furans makes them potential candidates as lead compounds for synthesis and evaluation of new anticancer drugs.
Acknowledgments: The financial support from Polish Ministry of Science, project NCN OPUS UMO-2014/15/B/NZ7/00966 is acknowledged.
66 The 10th Joint Meeting on Medicinal Chemistry 2017
OP-8
DEVELOPMENT OF NOVEL DRUG CANDIDATE AGAINST PROSTATE CANCER
Moran Shubely,[a],* Dhanoop Manikoth Ayyathan,[b] Michael Shokhen,[a] Michael Blank[b] and Arie Gruzman[a]
[a] Department of Chemistry, Bar-Ilan University, Ramat-Gan, 5290002, Israel [b] Faculty of Medicine, Bar-Ilan University, Safed, 1311502, Israel * [email protected]
Prostate cancer is the third highest cause of death from cancer in men of all ages. Despite progress in early diagnostics and treatment, prostate cancer still is one of the most devastating human diseases. Thus, the development of anti-prostate cancer drugs remains urgent. Smurf2 (Smad ubiquitin regulatory factor 2) is an E3 ubiquitin ligase that plays an important role in the regulation of protein homeostasis. Previous studies[1] demonstrated that the distribution of Smurf2 is different in normal and cancer tissues: Nuclear Smurf2 is a negative regulator of RNF20 that causes modifications in the epigenetic landscape, in particularly in monoubiquitination of histone H2B. The H2B histone packs and orders the DNA and plays an important role in gene expression regulation and DNA damage response. On the other hand, cytosolic Smurf2 has been reported to reduce the steady-state of Axin and GSK3β (two negative regulator of Wnt/β-catenin signaling). The activation of this signaling pathway leads to uncontrolled cell growth. Smurf2 is a member of HECT-type family of E3s. This family is characterized by a common modular organization: an N-terminal C2 domain, two to four WW domains, and a C-terminal HECT domain. The HECT domain is responsible for the attachment of ubiquitin moieties to target proteins. We hypothesized that targeting of Smurf2 for inactivation might affect the ability of cancer cells to proliferate and/or withstand anticancer treatments. Based on the computer modeling several Smurf2 HECT domain specific binders (activators and inhibitors) were designed[2] and synthetized. Then, in vitro evaluation in prostate cancer models showed that two novel peptidomimetic compounds were active in an nM concentration range. This novel approach for the possible treatment of prostate cancer which based on the modulation of Smurf2 function is not reported yet.
[1] M.Blank et al., Nat. Med., 2012, 18, 227. [2] M.Shokhen et al., ChemBioChem, 2011, 12, 1023.
67 The 10th Joint Meeting on Medicinal Chemistry 2017
OP-9
EVALUATION OF HALOGEN BONDING HOT SPOTS BY VIRTUAL SCREENING OF COMMERCIAL DATABASES – A CASE STUDY OF 5- HT7R
Rafał Kurczab,* Grzegorz Satała and Andrzej J. Bojarski
Department of Medicinal Chemistry, Institute of Pharmacology Polish Academy of Sciences, 12 Smętna Street, 31-343 Krakow, Poland * [email protected]
A halogen bond (XB) is a non-covalent interaction defined as a directional bond between a covalently bound halogen atom (acting as a donor) and a Lewis base as an acceptor.[1-3] The XB strength is comparable to weak or moderate hydrogen bonds and increases in the order of Cl < Br < I. XB has been indicated to play an essential role in supramolecular systems, liquid crystal engineering, nanomaterials, nanowire formation, catalysis, and also recently, in drug design and lead optimization processes.[4,5] The main aim of early stages of rational drug design is to rank drug candidates to select the ones with a significant probability of becoming a drug. Virtual screening is generally used with large databases of compounds which are purchasable or easy to synthesize. Herein, the recently developed and used systematic molecular modeling approach to search of XB amino acids hot spots among all crystallized GPCRs A was applied to one of the not yet crystallized family member, i.e. 5-HT7R. The sets containing the halogenated and unsubstituted derivatives were extracted from purchasable collection of Mcule database (https://mcule.com/), which contains more than 35M compounds (access: 14.12.2016). Next, the resultant sets were filtered by CNS MPO (>4), 3D pharmacophore models, and finally docked to a set of 5-HT7R homology models using previously tested QM/MM-GBSA procedure.[7] The sets in which halogenated derivative showed increase of the free binding energy upon formation of halogen bonding with any of the predicted hot spots were purchased and tested in 5-HT7R radioligand binding assay. The results revealed that for the majority of sets the halogenated derivatives exhibited higher affinity for 5-HT7R than their unsubstituted analogue. The studies provide evidence that only specific amino acids (XB hot spots) are able to create halogen bonding in the binding site and, hence, can be used in rational optimization and design of new drug candidates.
Acknowledgments: The study was supported by the National Science Center, Poland, Grant No 2014/15/D/NZ7/01782.
[1] P. Politzer, J.S. Murray, T. Clark, Phys. Chem. Chem. Phys., 2010, 12, 7748. [2] P. Auffinger, F. Hays, E. Westhof, P.S. Ho, Proc. Natl. Acad. Sci., 2004, 101, 16789. [3] T. Clark, M. Hennemann, J.S. Murray, P. Politzer, J. Mol. Model., 2007, 13, 291. [4] G. Cavallo, P. Metrangolo, R. Milani, T. Pilati, A. Priimagi, G. Resnati, et al., Chem. Rev., 2016, 116, 2478. [5] R. Wilcken, M.O. Zimmermann, A. Lange, A.C. Joerger, F.M. Boeckler, J. Med. Chem., 2013, 56, 1363. [6] T.T. Wager, X. Hou, P.R. Verhoest, A. Villalobos, ACS Chem. Neurosci., 2010, 1, 435. [7] R. Kurczab, Acta Cryst. B, 2017, manuscript accepted.
68 The 10th Joint Meeting on Medicinal Chemistry 2017
OP-10
BIG DATA: AVOGADRO STOICHIOMETRY EXPLAINS HYPERBOLIC LIGAND EFFICIENCY TREND
Jaroslaw Polanski,* Urszula Kucia, Aleksandra Tkocz, Roksana Duszkiewicz and Anna Pedrys
Institute of Chemistry, University of Silesia, 9 Szkolna Street, 40-006 Katowice, Poland * [email protected]
The relationship between a structure and property is an essential concept in chemistry and this method is an important decision-making guide in drug design. Eventually however it is the market that decides on the fate of a drug. As recently big data got an importance in the analysis of economic effects, e.g., the potential use of big data in US health care could reduce costs by $300 billion a year,[1] this should also appear in medicinal chemistry. Unexpectedly however, this strategy is not widespread here, even despite, common belief of a data flood in drug design. It is social science, psychology or economy where big data are commonly generated. The explanation comes with a comparison of 120 mln chemical compounds that have been registered to human society having 7 bln individuals. Therefore, human interactions, e.g. (pharmaco)economics generate bigger data, e.g., we have recently analyzed market price of a large library of 2.5 mln chemical compounds.[2] During the lecture we will discuss big data structure and applications in drug design and (pharmaco)economics. Below we discuss an example how important big data can be for the understanding of the substantial chemical effects in these areas.
Figure: Hyperbolic plots of LE [kcal/g] (BindingDB, left) and market price PE [$/g] big data (center) vs MW (left) or atom counts (center). MW vs atom count forms a linear plot (right).
In Figure we compared the prices of the large 2.5 mln chemical compound library[2] charged in [$/g] with the ligand efficiency LE, i.e. binding data per heavy atom count, or per MW [binding data/g] with typical hyperbolic plots. Below we are solving hyperbolic LE trend, an unexplained puzzle of medicinal chemistry.[3] Replicated molecules can be normalized by a fixed number (usually an Avogadro number NA) of molecules. Alternatively, we can use a fixed weight metric, e.g., one gram of a substance, which is commonly used while measuring biological activity in lab. Then this is recalculated into the molar metric. We will show that one gram of a substance contains 1/MW molecules. In turn, LE is a direct measure of binding efficiency measured in a fixed weight metric. However, unlike in a molar metric of a fixed NA number of molecules, a number of molecules will change here according to a 1/MW factor; therefore; decreasing hyperbolically with the increasing MW. Accordingly, a lower number of molecules will be available for ligand-receptor interaction for high MW. It is interesting that LE that was designed as molecular descriptor, appears in fact a direct property measure.[4] This brings a need for critical evaluation of previous LE models reported.
[1] N. Szlezák, M. Evers, J. Wang, L. Pérez, Clin. Pharmacol. Ther., 2014, 95, 492. [2] J. Polanski, U. Kucia, R. Duszkiewicz, A. Kurczyk, T. Magdziarz, J. Gasteiger, J. Sci. Rep., 2016, 23;6:28521. [3] A.L. Hopkins, G.M. Keseru, P.D. Leeson, D.C. Rees, C.H. Reynolds, Nat.Rev.Drug Disc., 2014, 13, 105. [4] J. Polanski, J. Gasteiger, in: Leszczynski ed. Handbook of Computational Chemistry, Springer, 2016.
69 The 10th Joint Meeting on Medicinal Chemistry 2017
OP-11
FROM PUBLIC DOMAIN COMPOUND COLLECTIONS TO CELL-ACTIVE EPIGENETIC MODULATORS. THE CASE OF THE NCI REPOSITORY.
Vassilios Myrianthopoulos,[a] Nadine Martinet,[b] Christian Bronner,[c] Jessica Ann Downs,[d] Susanne Müller,[e-g] Stefan Knapp[e-g] and Emmanuel Mikros[a],*
[a] Department of Pharmacy, University of Athens, Panepistimiopolis Zografou, GR-15771 Athens, Greece [b] CNRS UMR 7272, Institut de Chimie, Universite de Nice-Sophia Antipolis, Nice, France [c] Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS, INSERM, Universite de Strasbourg, France [d] Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton BN1 9RQ, U.K [e] Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K [f] Nuffield Department of Clinical Medicine, Target Discovery Institute (TDI), University of Oxford, Roosevelt Drive, Oxford OX37BN, U.K [g] Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Johann Wolfgang Goethe-University, Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany * [email protected]
A continuously increasing number of epigenetic proteins are identified as potential drug targets of high importance for numerous therapeutic fields. To efficaciously validate those targets and enable dissection of their possible roles in a therapeutic perspective, small-molecule cell-active and highly selective modulators of their biological activity are needed. Utilization of in-silico screening methodologies coupled with high-throughput biophysical techniques can advance efficient exploration of the chemodiversity available within academic or commercial compound collections, thus maximizing the anticipated success rate by guiding the whole procedure towards the most favored chemical space. In this study, the results of a tandem virtual screening campaign undertaken for evaluating the public domain NCI Repository collection towards epigenetic modules of emerging interest are presented. The epigenetic proteins targeted were readers involved in recognition of either acetyl-lysine marks (Bromodomains related to SWI/SNF chromatin remodeling complexes, PB1) or hemi-methylated DNA (Ubiquitin-like protein that contains PHD and RING finger 1, UHRF1). Screening was based on a consensus approach combining various ligand-based and structure- based search techniques of significant orthogonality, such as docking-scoring calculations, two- dimensional fingerprint analysis or three-dimensional shape similarity screening. Top-ranked compounds were evaluated experimentally using DSF, ITC, MS and X-ray crystallography and a number of primary hits were identified, showing high affinity for their respective targets, marked selectivity and, most interestingly, measurable activity in cell-based assays based on the FRAP and P-LISA settings. Those hits comprise highly promising starting points for sustaining hit-to-lead optimization studies.
70 The 10th Joint Meeting on Medicinal Chemistry 2017
OP-12
MASS SPECTROMETRIC IMAGING AS A PRECLINICAL TOOL FOR MEDICINAL CHEMISTS
Thavendran Govender
Catalysis and Peptide Research Unit, University of KwaZulu Natal, South Africa [email protected]
Mass spectrometry imaging (MSI) allows for the label-free detection and mapping of a broad range of molecules from complex surfaces, and it has become a fascinating molecular histology tool in pharmaceutical and medical research. The fundamental contributions of this method are rapid provision of molecular weight-specific maps or images at high resolution and sensitivity, offering a new powerful medical tool for pathology,[1] chemotherapeutics,[2] and discovery of disease biomarkers.[3] Over the past decade this technique has been adopted for the investigation of TB, HIV and many other diseases. Our group is currently involved in understanding the neuroprotective potential of current and pipeline anti TB drugs.[4-7]
[1] P. Chaurand, M.E. Sanders, R.A. Jensen, R.M. Caprioli, Am. J. Pathol., 2004, 165(4),1057. [2] G. Marko-Varga, T.E. Fehniger, M. Rezeli, B. Döme, T. Laurel, Á. Végvári, J. Proteomics, 2011, 74(7),982. [3] M.L. Reyzer, R.M. Caprioli, J. Proteome Res., 2005, 4(4),1138. [4] A. Shobo, D. Bratkowska, S. Baijnath, S. Naiker, L.A. Bester, S. Singh, G.E.M. Maguire, H.G. Kruger, T. Govender, Assay Drug Dev. Techn., 2015, 13, 277. [5] S. Baijnath, S. Naiker, A. Shobo, C. Moodley, J. Adamson, B. Ngcobo, L.A. Bester, S. Singh, H.G. Kruger, T. Naicker, T. Govender, J. Mol. Histol., 2015, 46, 439. [6] A. Shobo, S. Baijnath, D. Bratkowska, S. Naiker, A.M. Somboro, L.A. Bester, S. Singh, T. Naicker, H.G. Kruger, T. Govender, Drug Test Anal., 2016, 8, 832. [7] C.F. Munyeza, A. Shobo, S. Baijnath, D. Bratkowska, S. Naiker, L.A. Bester, S. Singh, G.E.M. Maguire, H.G. Kruger, T. Naicker, T. Govender, Xenobiotica, 2016, 46, 385.
71 The 10th Joint Meeting on Medicinal Chemistry 2017
OP-13
PYRAZOLOQUINOLINONES, REVISITED GABAA RECEPTOR TOOL COMPOUNDS
David Chan Bodin Siebert,[a] Xenia Simeone,[b] Konstantina Bampali,[b] Marko Mihovilovic,[a] Michael Schnürch[a] and Margot Ernst[b],*
[a] TU Wien, Institute of Applied Synthetic Chemistry, Getreidemarkt 9/163-OC, 1060 Vienna, Austria [b] Medical University of Vienna, Department of Molecular Neurosciences, Spitalgasse 4, 1090 Vienna, Austria * [email protected]
γ – Aminobutyric acid (GABA) is a wide-spread transmitter which binds to two pharmacologically diverging GABA receptors, GABAA and GABAB. GABAA receptors (GABAARs) are transmembrane pentameric ligand-gated chloride ion channels and represent an important target of many clinically relevant drugs (e.g. benzodiazepines, barbiturates, etc.). These receptors consist of different subunits (e.g. α,β,γ, etc.), which are drawn from nineteen subunit isoforms that are grouped into classes (e.g. α1-α6, β1- β3, etc.).[1-4] The pyrazoloquinolinone (PQ) ligands bind at the benzodiazepine (BZ) binding site (α+/γ- interface) and at the newly described α+/β- interface.[5] This compound class has proven to be a valuable tool to investigate the GABAAR function. Figure 1: Homology model of an α1β2γ2 GABAA receptor (top view) indicating different extracellular binding sites (α+/β- interface: red arrow).
Here, a small set of pyrazoloquinolinones were synthesized which show the following properties: high affinity to the BZ binding site and low- potency modulation at the α+/β- interface. In addition we report the first β - subtype selective compounds that even distinguish between all three beta isoforms. These findings provide more insights into the subtype- selective modulation of GABAARs. Further investigation could not only Figure 2: Pyrazoloquinolinone result in beneficial pharmacological tools, but also in selective ligands for scaffold containing different receptor pools that cannot be targeted with existing compounds. residues Rx.
[1] W Sieghart, Pharmacol. Rev.,1995, 47, 181. [2] E Siegl, Curr. Top. Med. Chem., 2002, 2, 833. [3] M. Ernst el at., Neuroscience, 2003, 119, 933. [4] Olsen RW and Sieghart W, Pharmacol. Rev., 2008, 6, 243. [5] Ramerstorfer J et al., J. Neurosci., 2011, 31, 870.
72 The 10th Joint Meeting on Medicinal Chemistry 2017
OP-14
SYNTHESIS OF TISSUE-SPECIFIC CONJUGATES FOR TARGETED DRUG DELIVERY INTO HEPATIC CELLS
S. Yu. Maklakova,[a],* V. V. Hapko,[a] R. A. Petrov,[a] T. S. Zatsepin,[a,b,c] T. O. Abakumova,[a] O. V. Sergeeva,[c] E. K. Beloglazkina,[a] N. V. Zyk,[a] V. E. Koteliansky[a,c] and A. G. Majouga[a,d]
[a] Lomonosov Moscow State University, Chemistry department, Leninskie Gory, 1/3, Moscow, 119991, Russia [b] Central Research Institute of Epidemiology, Novogireevskaya, 3a, Moscow 111123, Russia [c] Skolkovo Institute of Science and Technology, Novaya St., 100, Skolkovo, 143025, Russia [d] National University of Science and Technology MISiS, Leninskiy pr, 4, Moscow, 119049, Russia * [email protected]
Targeted delivery is a promising approach of medicinal chemistry that allows to improve efficiency of a drug and to diminish its toxicity. Particularly there is a desperate need for delivery systems of oligonucleotides and anticancer drugs due to abovementioned drawbacks.[1] The asialoglycoprotein receptor (ASGP-R) appears to be an appropriate target for the delivery into hepatic cells, in view of its abundant presence on parenchymal liver cells, selective binding to terminal D-galactose and N-acetylgalactosamine residues and ability to transport molecules through cell membrane. It was shown [2] that the best binding to the receptor could be achieved in case of using branched ligands containing three aforementioned carbohydrate moieties.
AHA1 mRNA levels relative to ACTB mRNA for groups treated with anti-AHA1 siRNA versus anti-Luciferase siRNA GalNAc conjugates (in vivo studies on mice)
We investigated synthetic approaches to conjugates of ligands for the ASGP-R with oligo- nucleotides,[3] anticancer therapeutics and fluorescent dyes. Biological testing of obtained compounds was conducted on human hepatocellular cell lines HepG2 and HuH7 with induced by biotin ASGP-R. In vivo studies were performed on C57BL/6 mice.
This work was supported by RSF, grant №17-14-01316.
[1] T. Zatsepin, Y. Kotelevtsev, V. Koteliansky, Int. J. Nanomedicine, 2016, 11, 3077. [2] X. Huang, J.-C. Leroux, B. Castanger, Bioconjugate Chem., 2017, 28, 283. [3] S.Yu. Maklakova, F.A. Kucherov, V.V. Gopko, G.A. Shipulin, T.S. Zatsepin, E.K. Beloglazkina, N.V. Zyk, A.G. Majouga, V.E. Koteliansky Russ. Chem. Bull., Int. Ed., 2015, 64, 1655.
73 The 10th Joint Meeting on Medicinal Chemistry 2017
OP-15
NOVEL POLYCYCLIC N-ACYLPYRROLIDINES AS 11β-HSD1 INHIBITORS
Rosana Leiva,[a],* Constantí Seira,[b] Andrew McBride,[c] Margaret Binnie,[c] Axel Bidon-Chanal,[b] F. Javier Luque,[b] Scott P. Webster[c] and Santiago Vázquez[a]
[a] Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and IBUB, Universitat de Barcelona, Av. Joan XXIII, 27-31, Barcelona, E-08028, Spain. [b] Department of Nutrition, Food Science and Gastronomy, Faculty of Pharmacy and IBUB, University of Barcelona, Av. Prat de la Riba, 171, 08921 Santa Coloma de Gramenet, Spain. [c] Endocrinology Unit, Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, EH16 4TJ, United Kingdom. * [email protected]
Glucocorticoids (GCs) are hormones that play a major role in the modulation of inflammatory and immune responses, metabolism regulation, cardiovascular homeostasis and our body response to stress.[1] It is now well accepted that the GC concentration in peripheral tissues where they perform their activity, not only depends on the adrenal secretion but also on the intracellular metabolism in these peripheral tissues. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the cortisol regeneration from its inactive form cortisone.[2] During the last years, both academia and industry have made great efforts to determine the role of this enzyme in several diseases and to develop potent inhibitors as potential drug candidates.[3] A polycyclic substituent optimization process from N-(2-adamantyl)amide 1[4] led us to identify the pyrrolidine-based amide 2 as a potent 11β-HSD1 inhibitor. However, 2 presented low microsomal stability and suboptimal selectivity. Herein, we report the exploration of different substituents in the right-hand side (RHS) of the molecule maintaining the pyrrolidine-based polycycle in order to address the abovementioned issues. Our endeavor started integrating different aromatic, heteroaromatic, heterocycloalkyl and branched alkyl substituents in order to generate diversity to build some structure-activity relationship (SAR) information. From this work we obtained again potent nanomolar inhibitors but still without the needed selectivity and stability properties. In light of these results, we focused our efforts on a rational design of new substitution patterns of the RHS group in order to establish additional interactions in the binding site that would deliver more potent and selective inhibitors.
[1] R. M. Sapolsky, L. M. Romero, A. U. Munck, Endocr. Rev., 2000, 21, 55. [2] J. R. Seckl, B. R. Walker, Endocrinology, 2001, 142, 1371. [3] M. Wamil, J. R. Seckl, Drug Discov. Today, 2007, 12, 504. [4] R. Leiva, C. Seira, A. McBride, M. Binnie, A. Bidon-Chanal, F. J. Luque, S. P. Webster, S. Vázquez, Bioorg. Med. Chem. Lett., 2015, 25, 4250. [5] R. Leiva, C. Griñan-Ferré, C. Seira, E. Valverde, A. McBride, M. Binnie, B. Pérez, F. J. Luque, M. Pallàs, A. Bidon-Chanal, S. P. Webster, S. Vázquez, manuscript in preparation.
74 The 10th Joint Meeting on Medicinal Chemistry 2017
OP-16
ENANTIOSPECIFIC MODULATION OF A2B ADENOSINE RECEPTOR
Maria Majellaro,[a,b] Jhonny Azuaje,[a] Carlos Carbajales,[a] Abel Crespo,[a] Angela Stefanachi,[b] Cosimo Altomare,[b] Saverio Cellamare,[b] María I. Loza,[c] José Brea,[c] María I. Cadavid,[c] Hugo Gutiérrez de Terán[d] and Eddy Sotelo[a],*
[a] Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS), University of Santiago de Compostela, 15782, Santiago de Compostela, Spain [b] Department of Pharmacy and Drug Sciences, University of Bari “A. Moro”, Via Orabona 4, 70125 Bari, Italy [c] Centro Singular de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), University of Santiago de Compostela, 15782, Santiago de Compostela, Spain [d] Department of Cell and Molecular Biology, Uppsala University, SE-75124 Uppsala, Sweden * [email protected]
A set of specific receptors, classified as A1, A2A, A2B and A3 adenosine receptors (ARs), mediate the plethora of physiological processes regulated by the purine nucleoside adenosine.[1] Accordingly, since their discovery ARs have been considered to be attractive targets in drug discovery.[1] Selective A2B antagonists have been claimed as anti-inflammatory agents or analgesics as well as to treat asthma.[1] We herein document the identification of novel, potent and selective non-xanthine ligands that enantiospecifically modulate the A2BAR. The reported ligands were assembled using a Biginelli- based multicomponent approach and its antagonistic behavior was confirmed through functional experiments. The optimization was assisted by a receptor-driven molecular modeling study and allowed valuable SARs to be established for this series. The scaffold documented herein contains a chiral center at the heterocyclic core. Accordingly, some representative ligands of the series were resolved into its two enantiomers by chiral HPLC and the absolute configuration of the enantiomers was established by circular dichroism. The biological evaluation of both enantiomers demonstrated enantiospecific recognition at A2BAR. This constitutes the first example of antagonistic enantioselective recognition at the A2B adenosine receptor and it opens new possibilities in the ligand design.
1200 Spectr um M ax Plot N s y1ja 167 5-2 AB 40 O 1000 800 (±) 16b O
O NH U 20 O 2 O A 600 K i hA 2B = 15.1 nM m + 400 H % hA (10 mM) = 2% 200 0 N O 1 Me CD O H O N 0 % hA (10 mM) = 4% 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 -20 2A Minutes (S)-16b N N Me
1500 Sp ectrum Max Plot sy1ja1675-2A (R)-16b H % hA3 (10 mM) = 4% 1250 -40 250 300 350 400 1000 (S)-16b O (R)-16b
U nm O A 750 m H 500 N O 250 N O 0 O % hA2B (10 mM) = 23% N N Me 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Sp ectrum Max Plot Minutes sy1ja1675-2B H H 1250 N O % hA 1 (10 mM =18% N 1000 (S)-16b (±)-16b % hA2A (10 mM) = 10% U 750
A N N Me K hA = 24.30 nM m i 2B 500 H % hA3 (10 mM) = 1% % hA 1 (10 mM) = 21% 250 % hA2A (10 mM) = 19 %, 0 (R)-16b 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 % hA3 (10 mM) = 4% Minutes
[1] B.B. Fredholm, A. Ijzerman, K.A. Jacobson, J. Linden, C. Muller, Pharmacol. Rev., 2011, 63, 1. [2] A. Crespo, A. El Maatougui, P. Biagini, J. Azuaje, A. Coelho, J. Brea, M.I. Loza, M. I. Cadavid, X. García- Mera, H. Gutiérrez-de-Terán, E. Sotelo, ACS Med. Chem. Lett., 2013, 4, 1031.; A. El Maatougui, J. Azuaje, M. González-Gómez, G. Miguez, A. Crespo, C. Carbajales, L. Escalante, H. Gutiérrez de Terán, E. Sotelo, J. Med. Chem., 2016, 59, 1967.
75 The 10th Joint Meeting on Medicinal Chemistry 2017
POSTER PRESENTATIONS
76 The 10th Joint Meeting on Medicinal Chemistry 2017
P-1
FREE RADICAL SCAVENGING POTENCY OF DIHYDROCAFFEIC ACID: THERMODYNAMICS OF 2H+/2e PROCESSES
Ana Amić,[a] Zoran Marković,[b] Jasmina Dimitrić Marković,[c] Bono Lučić[d] and Dragan Amić[e],*
[a] Department of Biology, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia [b] Department of Chemical-Technological Sciences, State University of Novi Pazar, Novi Pazar, Serbia [c] Faculty of Physical Chemistry, University of Belgrade, Belgrade, Serbia [d] Ruđer Bošković Institute, Zagreb, Croatia [e] Faculty of Agriculture, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia * [email protected]
Thermodynamics of 2H+/2e free radical scavenging mechanisms of dihydrocaffeic acid (3-(3’,4’- dihydroxyphenyl)propionic acid), an abundant colon catabolite of complex dietary (poly)phenols,[1] was studied by DFT method using the Gaussian 09 program package.[2] Geometry optimizations and frequency calculations were carried out using the M06-2X/6-311++G(d,p) level of theory, in conjunction with the SMD continuum solvation model. The role of catechol moiety (reaction path a) and carboxyl moiety (reaction path b) in free radical scavenging processes was investigated by considering double hydrogen atom transfer (dHAT), double electron transfer-proton transfer (dET-PT) and double sequential proton loss electron transfer (dSPLET) mechanisms.[3]
O O O H H O O O + 2H+/2e 2H /2e a H b O O O O O H H O o-quinone dihydrocaffeic acid dienone lactone
The Gibbs free energies of reactions (rG) indicate that dihydrocaffeic acid possesses potential for • • • • • • inactivating free radicals of different nature (HO , HOO , CH3O , CH3OO , CH2=CH–OO , PhO etc.) via dHAT and dSPLET mechanisms. 3’-Methylated, 3’-glucuronidated and 3’-sulfated conjugates of dihydrocaffeic acid may retain their appreciable activity via reaction path b. Because dihydrocaffeic acid is produced in colon in high concentrations (up to 90 mM),[1] and could be much more abundant in the circulation than its precursor molecules, it has potential to contribute to health benefits associated with regular intake of polyphenol-rich diet by direct scavenging of reactive oxygen species.
Acknowledgments: This work has been supported by The Foundation of the Croatian Academy of Sciences and Arts, under the project No. 10-102/244-1-2016. - “Investigations of the antioxidant mechanisms of polyphenols and their metabolites.”
[1] B. Halliwell, J. Rafter, A. Jenner, Am. J. Clin. Nutr., 2005, 81, 268S. [2] M. J. Frisch, G. W. Trucks et al., Gaussian 09. Revision A.02, Gaussian, Inc., Wallingford CT, 2009. [3] A. Amić, B. Lučić, V. Stepanić, Z. Marković, S. Marković, J. M. Dimitrić Marković, D. Amić, Food Chem., 2017, 218, 144.
77 The 10th Joint Meeting on Medicinal Chemistry 2017
P-2
RADICAL SCAVENGING AND COX-2 INHIBITION BY COLON METABOLITES OF POLYPHENOLS: A THEORETICAL APPROACH
Ana Amić,[a],* Zoran Marković,[b] Jasmina M. Dimitrić Marković,[c] Svetlana Jeremić,[b] Bono Lučić[d] and Dragan Amić[e]
[a] Department of Chemistry, Josip Juraj Strossmayer University, Cara Hadrijana 8A, 31000 Osijek, Croatia [b] Department of Chemical-Technological Sciences, State University of Novi Pazar, Vuka Karadžića bb, 36300 Novi Pazar, Serbia [c] Faculty of Physical Chemistry, University of Belgrade, Studentski trg 12-16, 11000, Belgrade, Serbia [d] NMR Center, Ruđer Bošković Institute, P.O. Box 180, 10002 Zagreb, Croatia [e] Faculty of Agriculture, Josip Juraj Strossmayer University, Vladimira Preloga 1, 31000 Osijek, Croatia * [email protected]
Colon polyphenolic metabolites can reduce activity of enzymes involved in human carcinogenesis,[1] for instance by inhibition of COX-2.[2] Recent studies have shown the importance of selective inhibition of COX-2 for the anti-inflammatory and anticancer therapy,[3] indicating COX-2 as a valid molecular target for cancer prevention and treatment.[4] Theoretical investigations of active site of COX-2 affirmed some natural phenolic antioxidants as potential inhibitors of this enzyme.[5] Radical scavenging mechanisms of selected polyphenolic metabolites were studied in water and pentyl ethanoate as a solvent, by DFT method using Gaussian 09 package.[6] Geometry optimizations and frequency calculations were carried out using the M06-2X/6-311++G(d,p) level of theory, in conjunction with the SMD continuum solvation model. Inhibitory potency against COX-2 by colon polyphenolic metabolites and their mono- and di-anionic forms, were theoretically studied. Free energy of binding and inhibition constant for these ligands at the most favourable binding positions were estimated. Hydrogen atom transfer and sequential proton loss electron transfer mechanisms were found to be thermodynamically probable and competitive processes in both media. The Gibbs free energy change for reaction of inactivation of radicals indicate selected metabolites as potent scavengers. Docking analysis with structural forms of selected metabolites indicates dianionic ligands as potent inhibitors of COX-2. Obtained results indicate that, because polyphenolic metabolites are produced in high mM concentrations and are usually better absorbed than their precursor molecules, they may contribute to health benefits associated with regular intake of polyphenol-rich diet.
Acknowledgments: We gratefully acknowledge the financial support to this work from The Foundation of the Croatian Academy of Sciences and Arts, under the project No. 10-102/244-1-2016. - “Investigations of the antioxidant mechanisms of polyphenols and their metabolites.”
[1] C. Miene, A. Weise, M. Glei, Nutr. Cancer, 2011, 63, 653. [2] P.C. Karlsson, U. Huss, A. Jenner, B. Halliwell, L. Bohlin, J.J. Rafter, J. Nutr., 2005, 135, 2343. [3] G. Dannhardt, W. Kiefer, Eur. J. Med. Chem., 2001, 36, 109. [4] R.A. Gupta, R.N. DuBois, Nat. Rev. Cancer, 2001, 1, 11. [5] M. Amaravani, N.K. Prasad, V. Ramakrishna, Springerplus, 2012, 1, 58. [6] M.J. Frisch, G.W. Trucks, H.B. Schlegel et al., GAUSSIAN 09, Wallingford, CT, 2009.
78 The 10th Joint Meeting on Medicinal Chemistry 2017
P-3
CYTOTOXICITY OF A KOJIC ACID DERIVATIVE ON A375 HUMAN MALIGNANT MELANOMA AND HGF1 FIBROBLAST CELLS
M. D. Aytemir,[a],* G. Karakaya,[a] A. Ercan[b] and S. Öncül[b]
[a] Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100, Sıhhiye, Ankara, Turkey. [b] Department of Biochemistry, Faculty of Pharmacy, Hacettepe University, 06100, Sıhhiye, Ankara, Turkey. * [email protected]
Malignant melanoma contributes to the majority of skin cancer related to deaths and shows an increasing incidence every year. It can occur at any age and in any region of the skin. According to the WHO, the incidence of melanoma is increasing worldwide faster than any other cancer type, with the exception of nonHodgkin’s lymphoma, lung cancer and testicular cancer, especially where fair- skinned people receive excessive sun exposure.[1] Despite improved treatment options, patients with advanced malignant melanoma still have poor prognosis as measured by progression-free and overall survival.[2,3] In our laboratory, kojic acid derivatives were synthesized and their extensive bioactivities were determined including anticonvulsant, antibacterial, antifungal, anti-mycobacterium and antiviral activities.4-7 In this study, we will present the results of the cytotoxicity activity of the Mannich base of kojic acid carrying substituted benzyl piperazine moiety. This compound is covered by the Turkish Patent (23.06.2015-TR2015/07653-WO2016/209180) and International Patent (17.05.2016- PCT/TR2016/000070). Viability of A375 malign melanoma and HGF1 fibroblast cells exposed to the compound was assessed by sulforhodamine B (SRB) assay. SRB is an aminoxanthene dye that binds to the basic amino acid residues of cellular proteins under mild acidic conditions. SRB assay is a colorimetric method based on measurement of cellular protein content and used for the determination of cytotoxicity.[8] A375 human malignant melanoma cell line was purchased from American Type Culture Collection (ATCC-CRL-1619). Vemurafenib, dacarbazine, temozolomide, lenalidomide and fotemustine currently used in the treatment of malign melanoma were utilized as control agents. It was found that the cytotoxicity effect of the Compound was higher when compared to all of the control agents, accept vemurafenib.
Acknowledgments: This research is funded as a project by TÜBİTAK. Project no: SBAG-315S067.
[1] R.M. MacKie, A. Hauschild, A.M.M. Eggermont, Ann. Oncol., 2009, 20 (Suppl. 6):1. [2] T.L. Diepgen, V. Mahler, Brit. J. Dermatol., 2002, 146 (Suppl. 61): 1. [3] S.A. Weiss, D. Hanniford, E.Hernando, I. Osman, Cancer, 2015, 121, 4108. [4] M.D. Aytemir, Ü. Çalış, M. Özal, Arch. Pharm. Pharm. Med. Chem., 2004, 337, 281. [5] M.D. Aytemir, B. Özçelik, Med. Chem. Res., 2011, 20, 443. [6] G. Karakaya, M.D. Aytemir, B. Özçelik, Ü. Çalış, J. Enz. Inh. Med. Chem., 2013, 28, 627. [7] M.D. Aytemir, B. Özçelik, G. Karakaya, Bioorg. Med. Chem. Lett., 2013, 23, 3646. [8] V. Vichai, K. Kirtikara, Nat. Protoc., 2006, 1, 1112.
79 The 10th Joint Meeting on Medicinal Chemistry 2017
P-4
DESIGN AND SYNTHESIS OF NOVEL TARGETED CHEMICAL CHAPERONES AS A BASIS FOR AMYOTROPHIC LATERAL SCLEROSIS (ALS) TREATMENT
Salome Azoulay-Ginsburg,* Tamar Getter, Edward Korshin and Arie Gruzman
Department of Chemistry, Bar-Ilan University, Ramat-Gan, Israel * [email protected]
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective degeneration of motor neurons in the brain and spinal cord, which leads to progressive paralysis and death. ALS is mostly acquired spontaneously (sALS), with inherited disease accounting for only 10-15% of all cases (fALS).[1] One of the most common mutations found in fALS is a mutation in the gene of SOD1.[1] Recent studies provide compelling evidence that the formation of the toxic aggregates of SOD1 is the primary cause of this type of fALS and the formation of protein aggregates in general, is underlie both types of ALS.[2] Chemical chaperones, which include polyols, trimethyl N-oxide (TMAO), phenylbutyric acid (PBA), and different amino acid derivatives, have been shown to reverse the mislocalization and aggregation of proteins associated with many human diseases.[3-4] However, using chemical chaperones as drugs is limited by the very high active concentrations (mM range) required for their efficacy. We propose to overcome this obstacle by coupling known chemical chaperones to organelle-targeted moieties, such as lysosomes, ER, Golgi, and mitochondria, where aggregation takes place. Based on this observation, we hypothesize that refolding of Superoxide Dismutase 1 (SOD1) by chemical chaperones in lysosomes will allow lysosome proteolytic enzymes and proteosome systems to cleave the refolded proteins and prevent SOD1 aggregates and as a result cell death. We have synthesized several ester- and amide- based TMAO chemical chaperones. The leading compound, 3-((5-((4,6-dimethylpyridin-2-yl)methoxy)-5-oxopentanoyl)oxy)-N,N dimethyl propan-1- amine oxide (Figure), has displayed both neuronal and astrocyte-protective effects in vitro in a micromolar concentration range,[5] and in daily doses of 10 mg/kg has dramatically improved the neurological functions and has delayed the body weight loss in ALS mice. In addition, the compound significantly increased the survival rate of Drosophila flies. Now, we have synthesized a series of novel compounds using FDA-approved chemical chaperone: phenylbutyric acid (PBA) with different intracellular targeting moieties and linkers. We hope that these new compounds might serve as drug candidates for ALS disease treatment.
Figure: 3-((5-((4,6-dimethylpyridin-2-yl)methoxy)-5-oxopentanoyl)oxy)-N,N-dimethyl propan-1-amine oxide.
[1] Y. Sheng, M. Chattopadhyay, J. Whitelegge, J. Selverstone Valentine, Curr.Topics Med.Chem., 2012, 12, 2560. [2] L. I. Bruijn, M. K. Houseweart, S. Kato, K. L. Anderson, S. D. Anderson, E. Ohama, A. G. Reaume, R. W. Scott, D. W. Cleveland, Science, 1998, 281, 1851. [3] R. S Rajan, K. Tsumoto, M. Tokunaga, H. Tokunaga, Y. Kita, T. Arakawa, Curr. Med. Chem., 2011, 18, 1. [4] C. Bai, J. Biwersi, A. Verkman, M. A. Matthay, J. Pharm. Toxicol. Methods, 1998, 40, 39. [5] T. Getter, I. Zaks, T. Barhum, T. Ben-Zur, S. Böselt, S. Gregoire, O. Viskind, H. Gottlieb, T. Shani, O. Green, M. Shubely, H. Senderowitz, A. Israelson, I. Kwon, S. Petri, D. Offen, A. Gruzman, ChemMedChem, 2015, 10, 850.
80 The 10th Joint Meeting on Medicinal Chemistry 2017
P-5
MULTICOMPONENT SYNTHESIS OF NOVEL ANDROSTANO-PYRIMIDINES AND THEIR PHARMACOLOGICAL EVALUATION IN VITRO
Ádám Baji,[a],* Éva Frank[a] and Mónika Kiricsi[b]
[a] Department of Organic Chemistry, University of Szeged, Dóm tér 8. H-6720, Szeged, Hungary [b] Department of Biochemistry and Molecular Biology, University of Szeged, Közép fasor 52, H-6726 Szeged, Hungary * [email protected]
Semi-synthesized derivatives of natural sex hormones (e.g. dihydrotestosterone) often display biological activities other than the parent compounds. Structural modifications may involve the incorporation of different heterocycles into the sterane skeleton.[1-3] During our experiments, different ring A-condensed arylpyrimidines (2a, 2d-i and 3a, 3d-i, 5a-i) were synthesized from 17β-acetoxy-dihydrotestosterone (1) and its 2-hydroxymethylidene derivative (4) by two kinds of multi-component reactions. The microwave-assisted syntheses were carried out in closed vessels. The reactions were completed within 10-15 minutes under the applied conditions and the corresponding products were obtained in moderate to good yields. The structures of the synthesized arylpyrimidines were determined by NMR spectroscopy.
In vitro viability assays of the heterocyclic derivatives were performed in collaboration. According to the results compounds 5c and 5f seem to be promising leads for further investigations.
Acknowledgments: The work of Ádám Baji was supported by a PhD Fellowship of the Talentum Fund of Richter Gedeon Plc.
[1] R. M. Mohareb, F. Al-Omran, R. A. Azzam, Steroids, 2014, 84, 46. [2] É. Frank, Z. Mucsi, I. Zupkó, B. Réthy, G. Falkay, Gy. Schneider, J. Wölfling, J. Am. Chem. Soc., 2009, 131, 3894. [3] Á. Baji, A. Gyovai, J. Wölfling, R. Minorics, I. Ocsovszki, I. Zupkó, É. Frank, RSC Adv., 2016, 6, 27501.
81 The 10th Joint Meeting on Medicinal Chemistry 2017
P-6
A COMPARATIVE MOLECULAR MODELLING STUDY OF MAO-A, MAO-B AND SSAO INHIBITORS
Balázs Balogh,[a],* Michela Contu,[b] Elias Maccioni[b] and Péter Mátyus[a][c]
[a] Department of Organic Chemistry, Semmelweis University, Hőgyes E. u. 7, H-1092, Budapest, Hungary [b] Dipartimento Farmaco Chimico Tecnologico, University of Cagliari, Via Ospedale 72, 09124 Cagliari, Italy [c] Drug Discovery and Safety Centre, Semmelweis University, Hőgyes E. u. 7, H-1092, Budapest, Hungary * [email protected]
Monoamine oxidase enzymes (MAO) exist in two isoforms MAO-A and MAO-B and possess a 70% amino-acid sequence identity. These flavin adenine dinucleotide (FAD) containing enzymes metabolize a wide range of endogen amines and xenobiotics and they are involved in the pathomechanism of various diseases. Semicarbazide-sensitive amine oxidase (SSAO) enzyme also known as vascular adhesion protein-1 (VAP-1) is another metabolic enzyme of amines with potentially great medical importance. Unlike MAO-A and B this protein belongs to the family of copper containing amine oxidases (AOCs) and as the name (semicarbazide sensitive) indicates it has a partially different inhibitor selectivity. The aim of our investigation was to study and compare the enzyme-inhibitor interactions within these enzyme classes on an atomic level via binding site analyses and computational dockings. As a continuation of our studies in the field,[1] we also aimed to investigate whether docking can discriminate compounds differing in their activities (based on docking scores) and in enzyme selectivity. Over 40 human MAO-B X-ray structures co-crystalized with various inhibitors (both reversible and covalent) have been published. We narrowed our studies to highly and moderately active reversible compounds including diphenylbutene (1OJ9), farnesol (2BK3), safinamide (2V5Z), coumarine analogues (2V60 and 2V61), zonisamide (3PO7), pioglitazone (4A79) and rosiglitazone (4A7A). A few covalent inhibitors, namely selegiline (aka deprenyl, 2BYB), rasagiline both R- (1S2Q) and S- forms (1S2Y) and mofegiline (2VZ2) were also involved. A few human MAO-A X-ray structures have only been published so far. We used in our study the only available harmine (2Z5X, reversible) and clorgiline (2BXR, covalent) containing structures. Human SSAO/VAP-1 structures were also hardly available; a covalent inhibitor, 2-hydrazinopyridine (2C11) and some reversible pyridazinone (4BTW, 4BTX and 4BTY) containing X-ray structures were selected for our modeling studies. Schrödinger’s prime module was used for protein structure modeling and Glide was applied to docking. In case of irreversible inhibitors, Schrödinger’s covalent docking protocol was utilized. The procedures were validated via re-dockings, the docking poses were compared with the ligand conformers of X-ray structures by calculating the RMSD values whereas ranking of docking scores was compared with that of biological activities. The docking studies were extended to a novel series of highly active MAO inhibitors of arylalkenylpropargylamines designed and synthesized by our research group.[2] In our conclusion, a detailed comparison of structural features required for inhibition of different classes of amine oxidases will be made.
[1] R. Meleddu, S. Distinto, R. Cirilli, S. Alcaro, M. Yanez, M. L. Sanna, A. Corona, C. Melis, G. Bianco, P. Matyus, F. Cottiglia and E. Maccioni, J. Enzyme Inhib. Med. Chem., 2017, 32, 264. [2] P. B. Huleatt, M. L. Khoo, Y. Y. Chua, T. W. Tan, R. S. Liew, B. Balogh, R. Deme, F. Goloncser, K. Magyar, D. P. Sheela, H. K. Ho, B. Sperlagh, P. Matyus, C. L. L. Chai, J. Med. Chem. 2015, 58, 1400.
82 The 10th Joint Meeting on Medicinal Chemistry 2017
P-7
IDENTIFICATION OF NEW KDM4 INHIBITORS THROUGH A HTS AND HIT REFINEMENT STRATEGY
A. L. Balzano,[a],* F. Sarno,[b] C. Milite,[a] G. Franci,[b,c] I. Forné,[d] L. Altucci,[b,e] A. Ihmof,[d] S. Castellano[a,f] and G. Sbardella[a]
[a] Department of Pharmacy, University of Salerno, Fisciano, Italy [b] Department of Biochemistry, Biophysics and General Pathology, University of Campania “Luigi Vanvitelli”, Naples, Italy [c] Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, University of Naples “Federico II”, Naples, Italy [d] Adolf-Butenandt-Institute and Center for Integrated Protein Science Munich, Ludwig-Maximilians- University, Munich, Germany [e] Istituto di Genetica e Biofisica, IGB “Adriano Buzzati Traverso”, Naples, Italy [f] Department of Medicine and Surgery, University of Salerno, Fisciano, Italy * [email protected]
JHDMs (JmjC-domain-containing histone demethylases) are the largest class of demethylase enzymes, contain a Jumonji C (JmjC) domain and catalyze lysine demethylation of histones through an oxidative reaction that requires Fe(II) ion and α-ketoglutarate (αkG) as cofactors. The misregulation of these enzymes, in particular JMJD2 subfamily, has being significantly implicated in cancer initiation and progression.[1] Potent and specific inhibitors of these enzymes have not been identified yet. Moreover, most of the reported ones show a good affinity to many other Fe(II)/αkG dependent oxygenases, are non-specific for the different isoforms or are affected by undesirable characteristics.[2] By means of an high throughput screening (HTS) campaign, we selected a pool of interesting hit compounds and then, to refine the results, filtered out poor quality scaffolds not suitable for future optimization. The use of a multiple combined approach of different in vitro techniques led us to select EML586 as scaffold for further derivatization. From a series of EML586 analogues we were able to derive a pharmacophore hypothesis and structure-activity relationships (hit-to-lead), and to select 3-hydroxy-2,3-dihydroquinazolinone moiety as starting point for the development of novel optimized derivatives. The substitution of quinoxaline ring with more aliphatic portions gave derivatives such as EML678 and EML684, which demonstrate a better activity against hKDM4A compared to the starting hit compound. Furthermore, they induced a marked reduction in methylation of lysines H3K9 and H3K27 in a cell-based assay together with an arrest in the S-phase of cell cycle. O OH N
N H O
CF3
EML678
O OH N Cl N H Cl
EML684 Figure: SARs of EML586 and most potent derivatives.
[1] D. Rotili, A. Mai, Genes & Cancer, 2011, 2, 663. [2] U. Leurs, R. P. Clausen, J. L. Kristensen, B. Lohse, Bioorg. Med. Chem. Lett., 2012, 22, 5811.
83 The 10th Joint Meeting on Medicinal Chemistry 2017
P-8
SYNTHESIS AND ANTIOXIDATIVE ACTIVITY OF SOME QUATERNARY 3- HYDROXYQUINUCLIDINIUM SALTS DETERMINED BY DPPH METHOD
Linda Bazina, Matilda Šprung, Barbara Soldo and Renata Odžak*
Department of Chemistry, Faculty of Science, University of Split, R. Boškovića 33, Split, Croatia * [email protected]
Antioxidants play an important role as health protecting factors. Scientific evidence suggests that antioxidants reduce the risk for chronic diseases including cancer and heart disease. Primary sources of naturally occurring antioxidants are whole grains, fruits and vegetables. Plant sourced antioxidants like vitamin C, vitamin E, carotenes, phenolic acids etc. have been recognized as agents having the potential to reduce the risk for disease development. Most antioxidants from a typical diet are derived from the plant sources and belong to various classes of chemical compounds with a wide variety of physical and chemical properties.[1] However, recent studies have shown that some synthetic organic compounds could also exhibit a strong antioxidative potential with a possible application in food and pharmaceutical industries.[2] In this study, we have synthesized the quaternary 3-hydroxyquinuclidinium salts (Figure 1) bearing different long alkyl chains (C8, C10, C12 and C14). All compounds were obtained in very good yields and characterized.
Figure 1 Figure 2
A rapid, simple and inexpensive method to measure antioxidant capacity involving the free radical, 2, 2-diphenyl-1-picrylhydrazyl (DPPH) was utilized in order to test the ability of the synthesized compounds to act as free radical scavengers or hydrogen donors and to evaluate their antioxidant activity. Our preliminary results suggest that the compounds displaying the higher antioxidative activities are those with the longer alkyl chains. Evaluation of the biological potential including the DNA protecting ability of the newly synthesized compounds is currently underway (Figure 2).
[1] T. Sravani, P.M. Paarakh, Indian J. Nat. Products Res,. 2016, 3, 354. [2] A. Augustyniak et al., Free Radic. Res., 2010, 44, 1216.
84 The 10th Joint Meeting on Medicinal Chemistry 2017
P-9
PHYTOCHEMICAL COMPOSITION AND BIOLOGICAL ACTIVITY OF THE EXTRACTS OF SATUREJA SUBSPICATA VIS. GROWING IN BOSNIA AND HERZEGOVINA
Mejra Bektašević,[a],* Ivana Carev,[b] Marin Roje,[c] Mladenka Jurin[c] and Olivera Politeo[b]
[a] Department of Biochemistry, Biotechnical Faculty, Bihać, BiH [b] Department of Biochemistry, Faculty of Chemistry and Technology, Split, Croatia [c] Department of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Zagreb, Croatia * [email protected]
Satureja subspicata Vis. (mountain savory) is a rare, endemic species distributed in the eastern Mediterranean area.[1] In traditional medicine of Bosnia and Herzegovina (BiH) S. subspicata is in ethnobotany used to treat leukemia and syndromes of lymphatic nodes. In this area preparations of S. montana and S. subspicata have been used with excellent results for different cardiovascular disorders, especially arrhythmia, heart fibrillation and the diseases of blood vessels.[2] There are only a few studies about the chemical composition and biological activity of non-volatile extracts of S. subspicata growing in Croatia and none report on the extracts from BiH. In this work we investigated the phytochemical composition of methanolic and hot aqueous extracts of S. subspicata collected in BiH, total phenols and flavonoids. In addition, the aim of this work was to determine the antioxidant potential and inhibition of cholinesterases of aqueous extracts. Chemical composition of extracts was assessed using HPLC/DAD technique. Antioxidant capacity was determined using DPPH, FRAP methods[3,4] and by determining activity of extracts in linoleic acid emulsion.[5] Ellman method was used to determine inhibition of acetilcholinesterase and butyrylcholinesterase.[6] The major compounds found in methanolic extract where: rosmarinic acid, eriodictyol and kaempferol, while in hot aqueous extract major compounds where: rosmarinic acid, myricetin and ferulic acid. Obtained results for content of total phenols and total flavonoids indicate considerable amount of these compounds. In concentration of 1 g/L in stock solution extracts showed low inhibition of both cholinesterases and good antioxidant potential.
[1] Č. Šilić, Endemične biljke, Svjetlost, Sarajevo, 1990. [2] S. Redžić, J. Medicinal Plants Res., 2010, 4, 1003. [3] I.F. Benzie, J.J. Strain, Anal. Biochem., 1996, 239, 70. [4] W. Brand-Williams, M.E. Cuvelier, C. Berset, Food Sci. Technol., 1995, 28, 25. [5] G.C. Yen and C.L. Hsieh, J. Agric. Food Chem., 1998, 46, 3952. [6] K.D. Ellman, V. Andres, R.M. Featherstone, Biochem. Pharmacology, 1961, 7, 88.
85 The 10th Joint Meeting on Medicinal Chemistry 2017
P-10
NOVEL ANTICANCER DRUGS DISPIRO-OXINDOLE SERIES BASED ON VARIOUS TYPES OF HETEROCYCLES: SYNTHESIS AND BIOLOGICAL TESTING
A. A. Beloglazkina,[a],* A. A.Barashkin,[a] G. A. Kotovskii,[a] M. A. Kunin,[a] N. A. Karpov,[a] M. E. Kukushkin,[a] E. K. Beloglazkina,[a] N. V. Zyk[a] D. A. Skvortsov,[a] N. A. Vorobyeva[b] and A. G. Majouga[a,b]
[a] Chemistry Dept, Moscow State University, 119991, Moscow, Leninskie gory, 1/3, Russia [b] National University of Science and Technology, 119049, Moscow, Leninskiy prospect, 4, Russia * [email protected]
Prostate cancer is one of the leading cancer type in the world: for example, in Russia about 14,000 cases are registered per year. Prostate cancer causes almost 10% of cancer deaths in men and it is one of the main causes of death for older men. In the USA, prostate cancer is the third most common cause of death from cancer.[1] MDM2 inhibitors, containing in its structure spiro-oxindole core are relatively new class of biologically active compounds, it has been reported that these compounds could effectively block the interaction of MDM2 and p53 protein-protein interaction (PPI).[2] Previously in our group the «hit»-compound with the promising anticancer activity 2,1 µM was found.[3] For this compound the enantioselective separation of two diastereoisomers was made and it was shown, that only one isomer had selectivity and cytotoxic effect for p53. In this work, we describe the synthesis of dispiro-compounds shown below on the base of different types of heterocyclic compounds as substrates for 1,3-cycloaddition:
The biological activity of synthesized compounds were studied using MTT assay on HCT p53(+, +), HCT p53(-, -) , LNCap and PC3 cell lines.
Acknowledgments: This work was supported by the Russian Foundation for Basic Research (grant № 16-33-60166).
[1] K. Ding, Y. Lu, Z. Nikolovska-Coleska, G. Wang, S. Oiu, S. Shangary, W. Gao, D. Oin, J. Stuckey, K. Krajewski, P. P. Roller, S. Wang., J. Med. Chem., 2006, 49, 3432. [2] Y. Zhao, L. Liu, W. Sun, J. Lu, D. McEachern, X. Li, S. Yu, D. Bernard, P. Ochsenbein, V. Ferey, J. Carry, D. Sun, S. Wang J. Am. Chem. Soc., 2013, 135, 7223. [3] Y. Ivanenkov, S. Vasilevski, E. Beloglazkina, M. Kukushkin, A. Machulkin, M. Veselov, N. Chufarova, A. Vanzcool, N. Zyk, D. Skvortsov, A. Khutornenko, A. Rusanov, A. Tonevitsky, O. Dontsova, A. Majouga, Med. Chem. Lett., 2015, 25, 404.
86 The 10th Joint Meeting on Medicinal Chemistry 2017
P-11
OSTEOBLASTIC CELL BEHAVIOUR ON DIFFERENT TITANIUM - SURFACE ANALYSIS
M. Lukaszewska-Kuska,[a] R. Majchrowski[b] and B. Dorocka-Bockowska[a],*
[a] Department of Oral Pathology and Medicine, Poznan University of Medical Sciences, Bukowska 70, Poland [b] Faculty of Chemistry, Institute of Mechanical Technology, Poznan University of Technology, Piotrowo 3, Poland * [email protected]
The surfaces of endoosseous dental implants have been subjected to numerous modifications which results in changes to the chemical composition and topography of the surfaces.[1,2] The aim of this study was to evaluate the surface topography and chemistry of various modified titanium surfaces prior to in vitro evaluation with human osteoblast cells. Five such groups were investigated: machined surface (MA), alumina-blasted (Al2O3), alumina-blasted and acid-etched (Al2O3 DE), hydroxyapatite/tricalcium phosphate grit-blasted (HA/TCP) and hydroxyapatite/tricalcium phosphate grit-blasted and acid-etched (HA/TCP DE). Materials and methods: Commercially pure titanium class 4b discs measuring 1mm thick and 8 mm radius were used. Five different surfaces modifications were evaluated. The surfaces were subject to topographic analysis by SEM, roughness analysis by optical profilometry and chemical composition evaluation by means of EDS analysis.[3-5] Results: The SEM surface images of the machined samples revealed regular, linear, parallel grooves created during machining. Al2O3 and HA/TCP sandblasted samples presented topographies with numerous irregular cavities, and clearly defined sharp-edged rims. In the case of the HA/TCP blasted and etched samples, the surfaces seemed to be slightly more irregular than the Al2O3 blasted and etched samples. Roughness analysis revealed two types of surfaces: the smoother surface with MA sample Sa=181,91nm, and the rougher surfaces on the remaining samples with Sa ranging from 507,48nm (HADE) to 748,45nm (Al2O3 DE). The sample surface chemical composition revealed titanium and oxygen as the main components present in all samples with minor quantities of aluminium appearing on the surfaces of the Al2O3 and Al2O3 DE samples while calcium and phosphorus were found on the surfaces of the HA samples. Conclusions: Blasted sampled along with blasted and etched samples were isotropic and rough. The grit-blasting procedure resulted in the incorporation of minor quantities of the grit medium into titanium surface.
[1] A. Wennerberg, T. Albrektsson, Clin. Oral Implants. Res., 2009, 20, 172. [2] A. Ponche, M. Bigerelle, K. Anselme, Proc. Inst. Mech. Eng. H, 2010, 224, 1471. [3] A. Canabarro, C.G. Paiva, H.T. Ferreira, B. Tholt-de-Vasconcellos, G. De-Deus, R. Prioli, A.B. Linhares, G.G. Alves, J.M. Granjeiro, Scanning, 2012, 34, 378. [4] K. Anselme, M. Bigerelle, J. Mater. Sci. Mater. Med., 2006, 17, 471. [5] A. Zareidoost, M. Yousefpour, B. Ghaseme, A. Amanzadeh, J. Mater. Sci. Mater. Med., 2012, 23, 1479.
87 The 10th Joint Meeting on Medicinal Chemistry 2017
P-12
A NOVEL CLASS OF HIGHLY POTENT SMALL MOLECULE INHIBITORS OF RHINOVIRUS REPLICATION: 6-{[2-(METHYLCARBAMOYL)PYRIDIN- 4-YL]OXY}BENZO[B]THIOPHENE-2-CARBOXYLIC ESTER DERIVATIVES
S. B. Han,* J. W. Kim, U.-K. Jung, J. Y. Lee, C. Kim and Y.-S. Jung
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology * [email protected]
Human rhinovirus (hRVs) is the cause of common colds and infections. The respiratory symptoms that are associated with these illnesses exacerbate asthma and chronic obstructive pulmonary diseases (COPD). The large number of serotypes of hRV that exist has complicated the development of rhinovirus replication inhibitors that can be employed to treat these maladies. In the current investigation, we developed a novel series of 6-{[2-(methylcarbamoyl)pyridin-4- yl]oxy}benzo[b]thiophene-2-carboxylic ester derivatives that potently inhibit replication of both hRV- A and hRV-B strains. One member of this group was observed to inhibit replication of a group of hRVs, including hRV-B14, hRV-A21 and hRV-A71, with respective EC50 values of 0.053, 0.08 and 0.016 μM. The results of a time-of-addition study revealed that it acts at an entry stage of the viral replication process. In addition, virus variants that are resistant to the compound were shown to possess a mutation at L25 of the viral capsid protein VP3. The results of a computational study suggested that it displays a capsid-binding mode that is similar to that of pleconaril, which involves a key interaction with the VP3 side chain located nearby the capsid canyon. Finally, the 6-{[2- (methylcarbamoyl)pyridin-4-yl]oxy}benzo[b]thiophene-2-carboxylic ester derivatives were observed to also significantly inhibit replication of poliovirus 3 (PV3), implying that these substances might show potentially general inhibitory activities against other enterovirus species.
[1] A. Muehlenbachs, J. Bhatnagar, S. R. Zaki, J. Pathol., 2015, 235, 217. [2] N. G. Papadopoulos, G. Sanderson, J. Hunter, S. L. Johnston, J. Med. Virol., 1999, 58, 100. [3] S. E. Jacobs, D. M. Lamson, K. St. George, J. T. Walsh, Clin. Microbiol. Rev., 2013, 26, 135. [4] A. C. Palmenberg, D. Spiro, R. Kuzmickas, S. Wang, A. Djikeng, J. A. Rathe, C. M. Fraser-Liggett, S. B. Liggett, Science, 2009, 324, 55.
88 The 10th Joint Meeting on Medicinal Chemistry 2017
P-13
SYNTHESIS, DOCKING AND ANTI-CANDIDA ACTIVITY OF SOME NEW 1,4-PHENYLENE-BISTHIAZOLES AS INHIBITORS OF LANOSTEROL 14α- DEMETHYLASE
Anca-Maria Borcea,[a],* Ilioara Oniga,[b] Gabriel Marc,[a] Dan C. Vodnar,[c] Adrian Pîrnău,[d] Laurian Vlase,[e] Andreea Pricopie,[a] Brîndușa Tiperciuc[a] and Ovidiu Oniga[a]
[a] Department of Pharmaceutical Chemistry, “Iuliu Haţieganu” University of Medicine and Pharmacy, 41 Victor Babeş Street, 400012 Cluj-Napoca, Romania [b] Department of Pharmacognosy, “Iuliu Haţieganu” University of Medicine and Pharmacy, 41 Victor Babeş Street, 400012 Cluj-Napoca, Romania [c] Department of Food Science and Technology, University of Agricultural Sciences and Veterinary Medicine, 3-5 Mănăştur Street, 400372 Cluj-Napoca, Romania [d] National Institute for Research and Development of Isotopic and Molecular Technologies, 67-103 Donath Street, 400293 Cluj-Napoca, Romania [e] Department of Pharmaceutical Technology and Biopharmaceutics, “Iuliu Haţieganu” University of Medicine and Pharmacy, 41 Victor Babeş Street, 400012 Cluj-Napoca, Romania * [email protected]
The incidence of systemic opportunistic infections caused by fungi in immunocompromised patients (treatment with chemotherapy, corticosteroids, immunosuppresive agents, patients with AIDS) is increasing. Furthermore, the resistance strains of Candida spp. have become a major cause of human morbidity and mortality worldwide. In order to reduce the development of resistance phenomenon it is necessary to discover new bioactive compounds.[1,2] In the context highlighted above, eighteen new molecules with a 1,4-phenylene-bisthiazole scaffold were synthesized and evaluated as anti-Candida agents. 1,4-phenylene-bisthiazole derivatives were obtained in good yields through a Hantzsch condensation reaction between the thioamide intermediary and various alfa-haloketones or alfa-haloesters. The purity of the newly synthesized compounds was confirmed by thin layer chromatography. The proposed structure of the compounds was confirmed by quantitative elemental analysis and spectral data: infrared spectroscopy, mass spectrometry and 1H-NMR. Compounds were screened in vitro for their ability to inhibit the growth of the patogenic Candida spp. In order to elucidate the mechanism of action, the synthesized compounds were docked into the active site of lanosterol 14α-demethylase isolated from Saccharomyces cerevisiae. The results of the in vitro antifungal evaluation and the molecular docking study showed that the new compounds have potential anti-Candida activity.
[1] F. Chimenti, B. Bizzarri, A. Bolasco, D. Secci, P. Chimenti, A. Granese, S. Carradori, M. D'Ascenzio, D. Lilli, D. Rivanera, Eur. J. Med. Chem., 2011, 46, 378. [2] L.T. Maillard, S. Bertout, O. Quinonéro, G. Akalin, G. Turan-Zitouni, P. Fulcrand, F. Demirci, J. Martinez, N. Masurier. Bioorg. Med. Chem. Lett., 2013, 23, 1803.
89 The 10th Joint Meeting on Medicinal Chemistry 2017
P-14
SCREENING OF BIOLOGICAL ACTIVITY OF CENTAUREA SPECIES AQUEOUS EXTRACTS
Ivana Carev,[a],* Anja Golemac,[b] Sanda Raić,[b] Jelena Žarković,[a] Ana Kelavić,[a] Maria Šarić,[a] François-Xavier Pellay[b] and Olivera Politeo[a]
[a] Faculty of Chemistry and Technology, Split, Croatia [b] NAOS group/Jean-Noël Thorel, 13855 Aix-en-Provence, France & MedILS, Split Croatia * [email protected]
Centaurea species are used as medical plants or as a food in eastern Mediterranean area.[1-3] The aim of our study was to make a screening of biological activity of twelve different aqueous extracts from seven Croatian Centaurea species: toxicity, antioxidant potential and inhibition of cholinesterases. The antioxidant and toxic properties of plant extracts and their constituents may be used in pharmaceutical, cosmetic and food industry. The inhibition of both cholinesterases by plant extracts may lead to a discovery of a potential chemical compound used in Alzheimer disease treatment.[4] Antioxidant capacity of extracts was determined using DPPH and FRAP methods.[5,6] Inhibition of both acetilcholinesterase and butyrylcholinesterase was determined using Ellman method.[7] Toxicity of Centaurea extracts was measured on primary fibroblasts through the MTT assay.[8] Aqueous extracts (AE) were prepared from wild growing Centaurea ragusina, C. scabiosa, C. solstitialis, C. rupestris, C. alba, C. jacea and C. salonitana. Among the tested aqueous extracts highest acetilcholinesterase inhibition exhibited C. solstitialis already known having chemical compounds responsible for fatal neurological disease in horses.[9] All of the tested Centaurea species aqueous extracts did not show inhibition on butyrylcholinesterase. Centaurea species show low to moderate antioxidant activity of AE. All of 3 AE of C. ragusina presented a higher toxicity than any other species with survival ranging from 10 to 50% at 0.5 g/L. Both AE of C. salonitana showed a slightly less toxic profile with 20 to 30% survival at 1 g/L of extracts. Every other AE showed low toxicity and C. scabiosa, wild edible species, showed no toxicity even at 1g/L of extract. Future investigation of chemical composition should highlight the main compounds in these extracts responsible for those biological activities. As far as previous research showed it is expected that some of the main groups of compounds could be sesquiterpene lactones, phenolic compounds and organic acids. Phenolics in plant extracts are usually responsible for a good in vitro antioxidant potential.[10] Sesquiterpene lactones are usually connected with a toxic properties of Centaurea extracts.[11]
[1] B. Ozcelik, I. Gurbuz, T. Karaoglu, E Yesilada, Microbiology Res., 2009, 165, 545. [2] L. Luczaj, K. Dolina, N. Fressel, S. Perković, Ethnobotany and Biocultural Diversities in the Balkans: Perspectives on Sustainable Rural Development and Reconciliation. 2014. [3] F. Bakkali, S. Averbeck, D. Averbeck, M. Idaomar, Food Chem. Toxicol., 2008, 46, 446. [4] P.J. Houghton, Y. Ren, M.J. Howes, Nat. Prod. Rep., 2006, 23,181. [5] I.F. Benzie, J.J. Strain, Anal. Biochem., 1996, 239, 70. [6] W. Brand-Williams, M.E. Cuvelier, C. Berset. Food Sci. Technol., 1995, 28, 25. [7] K.D. Ellman, V. Andres, R.M. Featherstone, Biochem. Pharmacol., 1961, 7, 88. [8] D. Gerlier, N. Thomasset, J. Immun. Meth., 1986, 94, 1. [9] H.T. Chang, W.K. Rumbeiha, J.S. Patterson, B. Puschner, A.P. Knight, Veterinary Pathology, 2012. [10] O. Kenny, T.J. Smyth, D. Walsh, C. T. Kelleher, C. M. Hewage, N. P. Brunton, Food Chem., 2014, 161, 79. [11] J. Y. Cho, A. R. Kim, J. H. Jung, T. Chun, M. H. Rhee, E. S. Yoo, Eur. J. Pharmacol., 2004, 492, 85.
90 The 10th Joint Meeting on Medicinal Chemistry 2017
P-15
ANTIOXIDANT ACTIVITY AND LIPOPHILICITY EVALUATION OF SOME NEW THIAZOLYL-TRIAZOLE SCHIFF BASES
Cezar Login,[a] Daniela Benedec,[b] Ioana Ionuţ,[c] Cristina Nastasă,[c] Anca Stana,[c] Ovidiu Oniga[c] and Brîndușa Tiperciuc[c],*
[a] Physiology Department, Iuliu Haţieganu University of Medicine and Pharmacy, 41 Victor Babeş Street, 400012 Cluj-Napoca, Romania [b] Pharmacognosie Department, Iuliu Haţieganu University of Medicine and Pharmacy, 41 Victor Babeş Street, 400012 Cluj-Napoca, Romania [c] Pharmaceutical Chemistry Department, Iuliu Haţieganu University of Medicine and Pharmacy, 41 Victor Babeş Street, 400012 Cluj-Napoca, Romania * [email protected]
Schiff bases have also been shown to exhibit a broad range of biological activities, including antifungal, antibacterial, antiproliferative, anti-inflammatory, antioxidant and antipyretic properties.[1- 5] Thiazoles, triazoles and their derivatives play an important part in heterocyclic chemistry due to their biological activity.[6] The ample evidence reported in the literature on the biological potential of Schiff bases containing thiazolo-triazole moieties in their structure led us to the synthesis, characterization and biological activity evaluation of 15 new Schiff bases of 4-amino-5-(4-methyl-2- phenylthiazol-5-yl)-4H-1,2,4-triazole-3-thiol, that combine the bioactive potential of the two heterocycles or bring new biological properties. These compounds were previously reported for their anti-Candida activity.[7] The lipophilicity study has been done in order to establish how the chemical structure and the hydrophobicity of these compounds influence their biological activity.[8] The antioxidant activity of the Schiff bases was evaluated using several assays: the DPPH, autooxidation rate of hemoglobin method, hemoglobin ascorbate peroxidase activity inhibition (HAPX) and ABTS assay. In the DPPH assay all the compounds shown antioxidant activities similar or superieur to Trolox used as reference.The ABTS based assay demonstrated the ability of all compounds to quench the ABTS•+ radical. The ascorbate peroxidase activity of hemoglobin was slowly affected by the presence of these compounds, the positive values obtained in suggesting an antioxidant effect. The lipophilicity has been determined by using PCA based on reversed-phase thin layer chromatography data. Data analysis showed that halogen-substituted-thiazolyl-triazoles Schiff bases were the most lipophilic, proving thus the importance of halogen atoms for the modulation of the lipophilic character of a certain molecule
[1] Y. Li, C.P. Zhao, H.P. Ma, M.Y. Zhao, Y.R. Xue, X.M. Wang, Bioorg. Med. Chem., 2013, 21, 3120. [2] E.L. Chazin, P.S. Sanches, E.B. Lindgren, W.T. Vellasco, et all, Molecules, 2015, 2, 1968. [3] A. Pandey, D. Dewangan, S. Verma, A. Mishra, R.D. Dubey, Int. J. ChemTech Res., 2011, 3, 178. [4] P. Przybylski, A. Huczynski, K. Pyta, B. Brzezinski, F. Bartl, Curr. Org. Chem., 2009, 13, 124 [5] S. Arulmurugan, P.H. Kavitha, R.P. Venkatraman, Rasayan. J. Chem., 2010, 3, 385. [6] M. Hanif, Z.H. Chohan, Spectrochim. Acta Part A, Mol. Biomol. Spectros., 2013, 104, 468. [7] A. Stana, A. Enache, D.Vodnar, C.Nastasă, D.Benedec, I.Ionuț, C.Login, G.Marc, O.Oniga, B.Tiperciuc, Molecules, 2016, 21, 1595. [8] R.Tamaian, A Moţ, R. Silaghi-Dumitrescu, I. Ionuţ, A. Stana, O. Oniga, C. Nastasă, D. Benedec, B.Tiperciuc, Molecules, 2015, 20, 22188.
91 The 10th Joint Meeting on Medicinal Chemistry 2017
P-16
NOVEL 2,4-DIAMINOPYRIMIDINE BEARING FUSED TRICYCLIC RING MOIETY FOR ANAPLASTIC LYMPHOMA KINASE (ALK) INHIBITOR
Chang-Soo Yun,[a] Chong Ock Lee,[b] Hyoung Rae Kim,[b] Chi Hoon Park,[b] Pilho Kim[b] and Jong Yeon Hwang[b],*
[a] Center for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea [b] Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea * [email protected]
Anaplastic lymphoma kinase (ALK) is one of the receptor tyrosine kinases and has been implicated in a variety of tumors including anaplastic large-cell lymphoma (ALCL), diffuse large B-cell lymphoma (DLBCL), inflammatory myofibroblastic tumors (IMT), and solid tumors.[1,2] Since ALK gene is fused with various partner genes, such as NMP, EML4, and KIF5 genes, the resulting fusion protein is constitutively activated, leading to a state of oncogenic addition. The constitutive kinase activity associated with ALK fusions seems to play an essential role in the growth and survival of cancer cells. Several drugs targeting ALK, such as crizotinib, ceritinib, and alectinib have been approved for the treatment of ALK-driven non-small cell lung cancer (NSCLC) patients. Brigatinib and lorlantinib are currently undergoing evaluation in clinical trials. In our previous efforts to discover potent ALK inhibitors,[3,4] we synthesized LDK378 and CEP-37440 with hybridized structures, thereby leading to a novel structure, which is a 2,4-diaminopyrimidine bearing tetrahydronaphthalenyl moiety.[5] Several compounds showed promising pharmacological results in in vivo, ex vivo, and pharmacokinetic studies. Also, in vivo efficacy study demonstrated highly potent inhibitory activity in H3122 tumor xenograft model in mice. In this study, a series of novel 2,4-diaminopyrimidines bearing fused tricyclic ring moiety was described for ALK inhibitor.[6] The pyrazole, imidazole, 1,2,4-triazole, piperazine and phenanthridine moieties were employed at the 2-position of pyrimidine in ceritinib. A few compounds showed promising activities in both enzymatic-and cell-based assays. Also, an in vivo efficacy study against H3122 tumor xenograft model in mice demonstrated highly potent inhibitory activity without body changes, similar to ceritinib, suggesting that it might be used for a novel ALK inhibitor development.
[1] A.V. Galkin, J.B. Melnick, S. Kim et al, Proc. Natl. Acad. Sci. USA, 2007, 104, 270. [2] T. Sasaki, S.J. Rodig, L.R. Chirieac et al. Eur. J. Cancer, 2010, 46, 1773. [3] C.H. Park, H. Choe, I.Y. Jang, S.Y. Kwon et al, Bioorg. Med. Chem. Lett., 2013, 23, 6192. [4] J.I. Yun, E.H. Yang, M. Latif, H.J. Lee et al, Arch. Pharm. Res, 2014, 37, 873. [5] D. Song, M. Lee, C.H. Park, S. Ahn et al, Bioorg. Med. Chem. Lett., 2016, 26, 1720. [6] R. Achary, G.R. Mathi, D.H. Lee, C.S. Yun et al, Bioorg. Med. Chem. Lett., 2017, in press.
92 The 10th Joint Meeting on Medicinal Chemistry 2017
P-17
TARGETED DELIVERY OF CYTOTOXIC AGENTS VIA cRGD PEPTIDE IN CANCER THERAPY AND THERANOSTICS
Theodora Chatzisideri,[a] Savvas Thysiadis,[a] Sotirios Katsamakas,[b] Theodore Lazarides[a] and Vasiliki Sarli[a],*
[a] Department of Chemistry, Aristotle University of Thessaloniki [b] School of Pharmacy, Aristotle University of Thessaloniki * [email protected]
In the fight against cancer the traditionally employed therapeutic approach is chemotherapy. However, as with any other non-selective delivery method of cytotoxic drugs, chemotherapy cannot differentiate between healthy and cancer cells, destroying both. Highly potent anti-cancer drugs suffer of poor bioavailability due to off-target toxicity and lack tumour specificity, requiring higher doses of the chemotherapeutic agent, resulting in severe side-effects.[1] Targeted delivery systems offer a more sophisticated and efficient approach, minimising side effects during the course of the treatment. In this work, targeted delivery systems are presented, which takes advantage of the synergistic effect of cycloRGD (Arg-Gly-Asp) peptide, which selectively recognizes integrins overexpressed at tumour sites,[2] with a cytotoxic drug, which destroys cancer cells. Natural products and known chemotherapeutic agents were employed as cytotoxic agents. Another important advantage of these flexible conjugated systems is that they can be combined with various dyes, in order to control and simultaneously detect the drug in tumor cells.[3] Thus, treatment and diagnosis can be combine, hence the name of the general approach, theragnostics. Release of the parent drug is also very important for efficacy and toxicity of the conjugate. The cytotoxic agent is coupled with the peptide via a linker. The ideal linker should be stable in the blood stream and labile at the cancer site to allow release of the cytotoxic drug. Amide linkers, are non- cleavable linkers, which were found to have improved stability in the bloodstream. In this case, release of the cytotoxic agent depends solely on the process of lysosomal degradation. On the other hand, disulphide linkers, which are cleavable linkers, take advantage of the reducing environment within cancer cells due to the elevated concentration of thiol molecules (e.g. glutathione).[4] Conjugates containing both amide and disulphide linkers have been synthesised. The mode of action of each one will be investigated in biological studies. Due to the significant difference of the acidity between the normal tissues (pH≈7.4) and the intracellular organelles such as lysosome and endosome (pH≈5.6), stability of the conjugates under these conditions are examined. The stability of the conjugate, as well as that of the linker, under physiological or slightly acidic conditions, along with their biological activity against various cell lines, will be discussed and be taken under consideration, for the selection of the most potent conjugate.
[1] C. Landen, T. Kim, Neoplasia, 2008, 10, 1259. [2] J. Desgrosellier, D. Cheresh, Nat. Rev. Cancer, 2010, 10, 9. [3] M. Lee,J. Kim, J. Am. Chem. Soc., 2012, 134, 12668. [4] C. Peters, S. Brown, Biosci. Rep, 2015, 35, e00225.
93 The 10th Joint Meeting on Medicinal Chemistry 2017
P-18
METHODS OF SYNTHESIS OF BIOLOGICALLY ACTIVE ANALOGUES AND HOMOLOGUES AMINOPHOSPHONATES AND AMINOBISHOSPHONATES
Ewa Chmielewska,[a],* Joanna Wietrzyk[b] and Paweł Kafarski[a]
[a] Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland [b] Laboratory of Experimental Anticancer Therapy, Institute of Immunology and Experimental Therapy, ul. Rudolfa Weigla 12, 53-114 Wroclaw, Poland * [email protected]
Bisphosphonates are class of drug molecules, used to treat osteoporosis, Paget’s disease, and hypercalcemia due to malignancy because they are powerful inhibitors of bone resorption.[1] They act by inhibiting the enzyme farnesyl diphosphate synthase (FPPS).[2] Bisphosphonates have been found to have antibacterial[3] and anticancer[4] properties and to stimulate γ, δ,T cells of immune drawing interest in cancer immunotherapy.[5] The aim of our studies is synthesis the aminomethylenebisphosphonic acids, analogs of cycloheptylaminomethylenebisphosphonate (commercialized as incadronate, the latest generation of antiosteoporotic drugs) as potential antiosteoporosis drugs. The simplest procedure for preparation of aminomethylenebisphosphonates relays on three-component reaction between amine, triethyl orthoformate and diethyl phosphite, followed by acid hydrolysis (Figure 1).[6] H N PO H H2O/HCl R 3 2 R-NH2 + HC(OEt)3 + 2 HP(O)(OEt)2 PO3H2 Figure 1: Synthesis of aminomethylenebisphosphonates
There is substantial evidence that aminobisphosphonates have a direct effect on osteoclasts by mechanisms that may lead to osteoclast cell death by apoptosis. They inhibit proliferation and cause cell death in macrophages in vitro. We present the studies of the preselection in vitro in the model mouse macrophage-like cell line J774E to choose potent compounds[6] and also influence of proliferation of two cancer cell lines: of human breast cancer MCF-7 and of prostate cancer PC-3. Heteroaromatic phosphonic acids have been scarcely studied and only selected examples of potentially useful compounds have been described so far. We synthesized aminophosphonates in a single-step procedure Kabachnik–Fields. It involves the condensation of three components: a primary or secondary amine, aldehyde (or ketone) and dialkyl phosphite (Figure 2). The influence of proliferation of two cancer cell lines: of human breast cancer MCF-7 and of prostate cancer PC-3 has been determinated for selected phosphonates. O RO O RO O NH + P P C + - H2O N RO H RO C Figure 2: The synthesis of aminophosphonates in Kabachnik – Fields reaction
[1] R. G. G Russell, Ann. N. Y. Acad. Sci., 2006, 1068, 367. [2] J. Sanders, A. O. Gomez, J. Mao, G. A. Meints, E. M. Van Brussel, A. Burzynska, P. Kafarski, D. Gonzalez- Pacanowska, E. Oldfield, J. Med. Chem., 2004, 46, 5171. [3] A. Leon, L. Liu, Y. Yang, C. T. Morita, E. Oldfield, J. Med. Chem.,. 2006, 49, 7331. [4] A. J. Roelofs, F. H. Ebetino. R. G. G. Russell C. M. Shipman, Int. J. Cancer, 2006, 119,1254. [5]. J. M. Sanders, A. Burzynska, P. Kafarski, E. Oldfield, J. Med. Chem., 2004, 47, 375. [6] E. Chmielewska, K. Kempińska, J. Wietrzyk, A. Piątek, J. J. Kuryszko, Z. Kiełbowicz, P. Kafarski, P. Novel bisphosphonates and their use. Int Pat Appl WO2015159153 (A1) ― 2015-10-22.
94 The 10th Joint Meeting on Medicinal Chemistry 2017
P-19
MOLECULAR MODELING AND DYNAMICS STUDIES OF LIGAND- DEPENDENT CONFORMATIONAL MACROSTATES OF A2A ADENOSINE RECEPTOR
Yoonji Lee,[a] Changbong Hyeon[b] and Sun Choi[a],*
[a] College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea [b] School of Computational Sciences, Korea Institute for Advanced Study, Seoul 02455, Korea * [email protected]
G-protein coupled receptor (GPCR) is a class of membrane protein that mediates the extracellular stimuli to the downstream signaling. Dynamics and functions of GPCRs are finely regulated depending on the type of bound ligands. While it is well understood that the binding of an agonist activates GPCR by reorganizing the transmembrane helices and recruiting a G-protein, the underlying mechanism of such allosteric signaling in presence of the agonist still remain elusive. To explore the allosteric mechanism of GPCRs, we generated each of 1 microsec molecular dynamics simulations of A2A adenosine receptor (A2AAR) in its apo, antagonist-bound, and agonist- bound forms. We investigated GPCR dynamics in terms of 10 on-off switch states defined by the micro-switches, which are highly conserved in class A GPCRs. Statistical analysis of the 10 binary switches, we clearly showed that the apo, antagonist-bound, and agonist-bound forms retain distinct dynamic properties. The antagonist- and agonist-bound forms explore quite different conformational space, and the apo form lies between them. Also, the correlation map among the 10 binary switches suggested that the direct sensing of the agonist by W246 residue derives the rest of intra-molecular signaling. The conformational features captured in our statistical representation of 10 binary switches confirmed the existing knowledge on the receptor and also made the specific predictions amenable to a further experimental study.
95 The 10th Joint Meeting on Medicinal Chemistry 2017
P-20
NEW DICARBOXIMIDE DERIVATIVES – ANTICANCER ACTIVITY AND MECHANISM OF ACTION
Julia Kaźmierczak-Barańska,[a] Karolina Królewska,[a] Marcin J. Cieślak,[a] Milena Sobczak,[a] Bożena Kuran,[b] Mariola Napiórkowska,[c] Jerzy Kossakowski[b] and Barbara Nawrot[a]
[a] Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Department of Bioorganic Chemistry, 112 Sienkiewicza Str., 90-363 Lodz, Poland [b] Chair and Department of Biochemistry, Medical University of Warsaw, 1 Banacha Str., 02-097 Warsaw, Poland [c] Department of Medical Chemistry, Medical University of Warsaw, 3 Oczki Str., 02-007 Warsaw, Poland
There is a permanent need for new anticancer drugs with improved pharmacological profiles. We have screened new derivatives of dicarboximides developed and synthesized in Department of Medical Chemistry of Warsaw Medical University. Among them, several entities exhibited interesting cytotoxic properties, i.e. displayed toxicity towards human leukemia cells (K562, HL-60, MOLT-4) and were non-toxic to adherent cancer cells (HeLa, CFPAC) neither to normal endothelial cells (HUVEC). We have shown that in leukemia cells these compounds induce programmed cell death (apoptosis) via receptor and mitochondrial pathways. This is evidenced by increase in activity of caspases 3, 7, 8 and 9 and enhanced annexin V staining. Based on the structural similarity between test dicarboximides and thalidomide, a known immunomodulatory drug (IMiD),[1,2] we hypothesized that their mechanism of action could be analogous. We tested whether incubation of leukemia cells with dicarboximides resulted in changes the level of transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). K562 and MOLT4 cells treated with dicarboximides expressed lower levels of Ikaros and Aiolos. PASS (Prediction of Activity Spectra for biologically active Substances) suggested that dicarboximides might inhibit the activity of proteasomal ATPase. Therefore, we studied the activity of proteasome in leukemia cells treated with dicarboximides and found that one derivative of dicarboximides inhibits proteasomal activity in MOLT4 cells.
Acknowledgments: The financial support from Polish Ministry of Science, project NCN OPUS UMO-2014/15/B/NZ7/00966 is acknowledged.
[1] T. Ito, Science, 2010, 327, 1345. [2] K. Stewart, Science, 2014, 343, 256.
96 The 10th Joint Meeting on Medicinal Chemistry 2017
P-21
ANTIPROLIFERATIVE ACTIVITY OF QUINONE METHIDES WITH BODIPY CHROMOPHORE
Matej Cindrić,[a],* Nikola Basarić,[a] Irena Martin Kleiner,[b] Lidija Uzelac[b] and Marijeta Kralj[b]
[a] Department of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia [b] Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia * [email protected]
BODIPY is a trade name for the well known fluorescent dyes comprising different 4,4-difluoro-4- bora-3a,4a-diaza-s-indacene derivatives.[1] These chromophores absorb in the visible region of spectrum and have excellent photophysical and spectral properties characterized by sharp fluorescence peaks with high fluorescence quantum yields.2 Small modifications of molecular structure lead to fine-tuning of their spectroscopic and photophysical properties.3 Therefore, a large number of different BODIPY derivatives has been synthesized and their spectroscopic properties have been investigated. We have become interested in the photochemistry of appropriately substituted phenols that undergo photodehydration and deliver quinone methides (QMs).[4] The interest in the chemistry of QMs has been initiated due to their biological properties. It has been demonstrated that QMs react with amino acids, proteins, nucleotides and DNA. Moreover, ability of QMs to cross-link DNA has been associated to biological action of some anticancer antibiotics such as Mitomycin C. Consequently, QMs represent potential new class of anticancer drugs. However, QMs are reactive intermediates that cannot be stored, they have to be generated in situ. The best method for the generation of QMs is photodehydration of phenol derivatives. To have molecules applicable as drugs in human medicine it is of pivotal importance to make QM precursors on the chromophoric system absorbing in the visible part of the spectrum (at > 600 nm) to assure penetration of light through tissue. Herein we present synthesis of QM precursors that bear BODIPY chromophore, investigation of their photochemical reactivity and aptitude to deliver QMs, as well as antiproliferative activity of photogenerated QMs. To test the effect of irradiation, the antiproliferative activity is tested on human cancer cell lines that are treated with compounds and kept in dark or irradiated with visible light.
[1] https://www.thermofisher.com/hr/en/home/brands/molecular-probes.html [2] A. Loudet, K. Burgess, Chem. Rev., 2007, 107, 4891. 3] N. Boens, V. Leen, Chem. Soc. Rev., 2012, 41, 1130. 4 N. Basarić, K. Mlinarić-Majerski, M. Kralj, Curr. Org. Chem., 2014, 18, 3.
97 The 10th Joint Meeting on Medicinal Chemistry 2017
P-22
MEPHEDRONE METABOLITES AND DERIVATIVES
Daniela Cintulova,[a] Laurin Wimmer,[a] Harald H. Sitte[b] and Marko D. Mihovilovic[a],*
[a] Vienna University of Technology, Institute of Applied Synthetic Chemistry, Getreidemarkt 9/163-OC, 1060, Vienna, Austria [b] Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Währingerstrasse 13A, 1090 Vienna, Austria * [email protected]
The endogenous monoamines dopamine, serotonin and norepinephrine are essential neurotransmitters in the mammalian system. They have been the focus of considerable research because their interaction at monoamine transporters has profound effects upon many pharmacological outcomes,[1] One diverse class of chemical compounds - the amphetamines, acts as inhibitors of monoamine transporter system and thus elicits strong psychostimulant effect which renders them liable for recreational abuse.[2]
Mephedrone
One frequently occurring recreational drug of this group is mephedrone - a derivative of naturally occurring alkaloids - cathinones. Mephedrone has been linked to a number of fatalities and seizure incidents across Europe. Despite its short time in blood plasma this compound has a long lasting effect in humans.[3] Within this contribution we present the enantioselective synthesis of Phase I mephedrone metabolites to better understand the mode of action of mephedrone itself and to investigate the activity of single enantiomers of its metabolites.
REDUCT ION
OXIDATI DEMETHYL ATION ON
[1] P. C. Meltzer, D.Butler, J. R. Deschamps, B. K. Madras, J. Med. Chem., 2006, 49, 1420. [2] H. H. Sitte, M. Freissmuth, Trends iPharmacol. Sci., 2015, 36, 41. [3] A. J. Pedersen, L. A. Reotzel, S. S. Johansen, K. Linnet, Drug Test. Analysis, 2012, 5, 313.
98 The 10th Joint Meeting on Medicinal Chemistry 2017
P-23
NOVEL SOLUBLE EPOXIDE HYDROLASE INHIBITORS FEATURING A 2- OXAADAMANTANE MOIETY I: PIPERIDINE DERIVATIVES
Sandra Codony,[a],* Javier Pizarro,[b] Elena Valverde,[a] Eugènia Pujol,[a] M. Isabel Loza,[c][d] J. Manuel Brea,[c][d] Elena Sáez,[e] Julen Oyarzábal,[e] Belén Pérez,[f] Rosana Leiva,[a] Manuel Vázquez-Carrera[b] and Santiago Vázquez[a]
[a] Laboratori de Química Farmacèutica (Unitat Associada al CSIC), and [b]Laboratori de Farmacologia, Departament de Farmacologia, Toxicologia i Química Terapèutica, Facultat de Farmàcia and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, 08028, Barcelona [c] Drug Screening Platform/Biofarma Research Group. CIMUS Research Center. University of Santiago de Compostela (USC) [d] Health Research Institute of Santiago de Compostela (IDIS) [e] Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), University of Navarra, Avenida Pio XII 55, E-31008 Pamplona, Spain [f] Departament de Farmacologia, Terapèutica i Toxicologia, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain * [email protected]
Soluble epoxide hydrolase (sEH) converts epoxyeicosatrienoic acids (EETs), endogenous chemical mediators derived from arachidonic acid (AA), to their corresponding dihydroxyeicosatrienoic acids (DHETs). Taking into account that EETs show anti-inflammatory, antihypertensive, analgesic, angiogenic, and antiatherosclerotic effects, it has been proposed that inhibition of sEH may have therapeutic effects in various inflammatory diseases.[1] A number of very potent sEH inhibitors (sEHI) have been developed, several of them featuring an adamantane moiety, that may account for the low solubility and poor pharmacokinetic profile that have hampered their progress into clinics.[2] Recently, we have found that the replacement of a methylene unit in the adamantane moiety of known AR9281 by an oxygen atom leads to a more soluble compound with retention of the inhibitory activity (analog 1). In this work, we report the synthesis and evaluation of several analogs of 1, featuring different substituent on the piperidine ring, in order to improve their potency and pharmacokinetic profiles.
[1] C. Morisseau, B. D. Hammock, Annu. Rev. Pharmacol. Toxicol., 2013, 53, 37. [2] H. C. Shen, B. D. Hammock, J. Med. Chem., 2012, 55, 1789.
99 The 10th Joint Meeting on Medicinal Chemistry 2017
P-24
NOVEL SOLUBLE EPOXIDE HYDROLASE INHIBITORS FEATURING A 2- OXAADAMANTANE MOIETY II: AROMATIC DERIVATIVES
Eugènia Pujol,[a],* Javier Pizarro,[b] Elena Valverde,[a] Sandra Codony,[a] Tiziana Ginex,[c] M. Isabel Loza,[d,e] J. Manuel Brea,[d,e] Belén Pérez,[f] Elena Sáez,[g] Julen Oyarzábal,[g] F. Javier Luque,[c] Rosana Leiva,[a] Manuel Vázquez-Carrera[b] and Santiago Vázquez [a]
[a] Laboratori de Química Farmacèutica (Unitat Associada al CSIC) [b] Laboratori de Farmacologia, Departament de Farmacologia, Toxicologia i Química Terapèutica, Facultat de Farmàcia and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, 08028, Barcelona, Spain [c] Departament de Nutrició, Ciències de l’Alimentació i Gastronomia, Facultat de Farmàcia, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Avda. Prat de la Riba 171, 08921 Santa Coloma de Gramenet [d] Drug Screening Platform/BioFarma Research Group. CIMUS Research Center, University of Santiago de Compostela (USC) [e] Health Research Institute of Santiago de Compostela (IDIS) [f] Departament de Farmacologia, Terapèutica i Toxicologia, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain [g] Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), University of Navarra, Av. Pío XII 55, 31008 Pamplona, Spain. * [email protected]
The soluble epoxide hydrolase (sEH) is an enzyme implicated in the metabolism of epoxyeicosatrienoic acids (EETs), endogenous lipid mediators involved in the regulation of inflammation.[1] Therefore, sEH appears to be a potential therapeutic target for the treatment of diverse diseases with an important inflammatory component.[2] Although several compounds targeting sEH have been developed, yet none has reached the market, mainly because of poor drug- like physicochemical properties. In this regard, our research group has developed new 2-oxaadamantylureas as sEH inhibitors (sEHI), displaying not only high potency but also improved physicochemical properties. Herein we report structure-activity relationship studies around the replacement of the trifluorophenyl group of our recently discovered lead sEHI 1 by a variety of aromatic and heteroaromatic rings.
[1] C. Morisseau, B.D. Hammock, Annu. Rev. Pharmacol. Toxicol., 2013, 53, 37. [2] J. He, C. Wang, Y. Zhu, D. Ai, J. Diabetes, 2016, 8, 305.
100 The 10th Joint Meeting on Medicinal Chemistry 2017
P-25
BIOLOGICAL ACTIVITIES OF EXTRACTS FROM THYME (THYMUS VULGARIS) LEAVES
Biljana Damjanović-Vratnica,[a],* Slađana Krivokapić,[b] Snežana Pantović[c] and Svetlana Perović[b]
[a] Faculty of Metallurgy and Technology, University of Montenegro, Dz. Vasingtona bb, Podgorica, Montenegro [b] Department of Biology, Faculty of Natural Science and Mathematics, Dz. Vasingtona bb, Podgorica, Montenegro [c] Faculty of Medicine, University of Montenegro, Krusevac bb, Podgorica, Montenegro * [email protected]
The genus Thymus, member of the Lamiaceae family, contains about 400 species of perennial aromatic, evergreen or semi-evergreen herbaceous plants with many subspecies, varieties, subvarieties and forms.[1] Thymus species are commonly used as herbal tea, flavoring agents (condiments and spices) and for medicinal purposes. In the Mediterranean environment, there are several ecotypes of wild-growing thyme, which differ in morphological characteristics, distinguished by a strong and penetrating odor and sometimes a very evident balsamic and spicy flavor.[2] Thyme (T. vulgaris) is used mainly as a food seasoning, but also as a source of essential oils that are used in perfumery and as a worming and bactericidal agent in medicine.[3] The aim of this study is to determine biological activities of extracts from Thymus vulgaris leaves from Montenegro. Fresh leaves of cultivated T. vulgaris were collected manually from the cultivation site (near Danilovgrad) in June 2016. Dried herb material was milled and extracted with different polarity solvents (hexane, acetone, methyl-alcohol and ethyl-alcohol). For antimicrobial activity of extracts of Thymus vulgaris from Montenegro microdilution method was used and minimal inhibitory concentration (MIC) was determined. Ability of the extracts to scavenge the stable free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH• ) was determined. Ascorbic acid solution was used as a reference standard. The absorbance of samples was compared to that of ascorbic acid standards and the results were expressed as the number of equivalents of ascorbic acid. The results revealed that thyme extracts exhibited antimicrobial activity against Gram (+) and Gram (-) bacteria. All examined extracts of thyme leaves cultivated in Montenegro showed rather good antioxidant capacity. Obtained results revealed that highest antioxidative potential has thyme ethanolic extract.
Acknowledgements: Financial support of this work to Montenegrian Ministry of Science (Project E!9906) is gratefully acknowledged.
[1] L. De Martino, M. Bruno, C. Formisano, V. De Feo, F. Napolitano, S. Rosselli, F. Senatore, Molecules, 2009, 14, 4614. [2] A. De Lisi, L. Tedone, V. Montesano, G. Sarli, D. Negro, Food Chem., 2011, 125, 1284. [3] AI. Dawidowicz, E. Rado, D. Wianowska, M. Mardarowicz, J. Gawdzik, Talanta, 2008, 76, 878.
101 The 10th Joint Meeting on Medicinal Chemistry 2017
P-26
SYNTHESIS, ANTICANCER ACTIVITY AND DOCKING STUDIES OF NEW PHENYLAMINOPYRIMIDINE DERIVATIVES
Aslı Demirci,[a] İrem Durmaz,[b] Rengül Çetin Atalay[b] and İlkay Küçükgüzel[a],*
[a] Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, 34668 İstanbul, Turkey [b] Graduate School of Informatics, Cancer Systems Biology Laboratory, Middle East Technical University, 06800 Ankara, Turkey * [email protected]
Cancer chemotherapy has showed a major progress for the last few decades. Since the launch of imatinib in 2001, kinase inhibitors in drug discovery remains to be one of the hot topics regarding cancer treatment in academia and in pharmaceutical industry.[1] The clinical success of imatinib has led to one or more new ‘tinib’ analogue small molecule kinase inhibitor has been discovered almost every year so that great majority of them have entered to the clinic. The number of kinase inhibitor drugs approved by FDA is currently over 30.[2] Kinases are established as important modulators of cells. Small molecule kinase inhibitor discovery remains to be one of the crucial interests of medicinal chemistry. Imatinib is the pioneering kinase inhibitor drug which has phenylaminopyrimidine core structure. In literature, there are various data indicating that phenylaminopyrimidine derivatives are straight candidates for anticancer drug discovery.[3,4] For this purpose, a series of novel phenylaminopyrimidine derivatives were designed and synthesized. Purity of the synthesized compounds was checked with TLC and HPLC. The structures of the final compounds were confirmed by FTIR, 1H-NMR, 13C-NMR and mass spectral data besides elemental analysis. Cytotoxic bioactivity of synthesized compounds was evaluated in vitro against breast (MCF-7), liver (Huh-7) and colon (HCT-116) cancer cell lines. Molecular modeling studies have been performed to simulate potential inhibition of different kinases by synthesized compounds. ABL2, SRC, VEGFR and AXL kinase proteins were rationally selected in accordance with biological studies. Docking studies on ABL2 and SRC kinases were run with inactive states of proteins; while docking studies on VEGFR kinase were run with both active and inactive state. In addition, docking studies on AXL kinase were run with its active form. Possible binding conformations of each ligand were evaluated. Interactions with hinge region and interactions with DFG motif of the kinase proteins which are both crucial for kinase inhibition were visualized after docking processes. Binding energies and conformations were re-evaluated in the light of biological study results. Further in silico and in vitro studies associated with synthesized compounds are in progress and the results will be discussed in detail.
[1] P. Wu, Drug Discov. Today, 2016, 21, 1. [2] P. Fisher, Med. Res. Rev., 2016, 0, 0, 1. [3] I. M. El-Deeb, S. H. Lee, Bioorg. Med. Chem., 2010, 18, 11. [4] J. Dietrich, C. Hulme, Bioorg. Med. Chem., 2010, 18, 15.
102 The 10th Joint Meeting on Medicinal Chemistry 2017
P-27
RADIOLABELED 1,2,4,5-TETRAZINES AS BIOORTHOGONAL IMAGING TOOLS
Christoph Denk,[a],* Martin Wilkovitsch,[a] Thomas Wanek,[b] Claudia Kuntner-Hannes,[b] Dennis Svatunek[a] and Hannes Mikula[a]
[a] Vienna University of Technology, Institute of Applied Synthetic Chemistry, Vienna, Austria [b] Austrian Institute of Technology, Biomedical Systems, Austria * [email protected]
Labeled antibodies are highly specific imaging probes that are incompatible with short-lived radionuclides due to their slow accumulation. This dilemma can be circumvented by pretargeting using bioorthogonal reactions (Figure).[1,2] These fast and biocompatible “click” type ligations are capable of forming a covalent linkage between a pre-administered marker compound and a labeled pull down reagent (PDR) in vivo.[2] Due to particularly high ligation rates the inverse electron demand Diels-Alder reaction (IEDDA) of strained dienophiles with 1,2,4,5-tetrazines (Tz) is especially suited for in vivo application.[1-3]
Figure: Comparison of “traditional” immuno-imaging vs a bioorthogonal approach.
In addition to fast ligation rates PDRs must exhibit homogenous biodistribution, good in vivo stability and fast excretion. Within this contribution the development and application of several radiolabeled tetrazines, serving as small molecule imaging agents, will be presented. 1,2,4,5-Tetrazines labeled with the positron emitter fluorine-18 were thought to be inaccessible due to reported degradation during radiolabeling.[4] In 2014 our group was able to prepare the first 18F-tetrazine by trading increased stability for reduced IEDDA reactivity.[5] This initial development our 18F-tetrazines were constantly improved. The newest developments include 18F-Tz derivatives with ~200-fold elevated ligation rate that still possess excellent in vivo stability, thus showing great promise as secondary imaging agent. Tetrazines for therapeutic application bearing radionuclides of iodine or the α-emitter astatine-211 were furthermore synthesized and evaluated. We are convinced that radiolabeled tetrazines can overcome problems associated with slow- accumulating vectors (such as antibodies and other nanomedicines), and should allow for many applications in the field of medicine, medicinal chemistry and drug development.
[1] R. Rossin et. al., J. Nucl. Med., 2013, 54, 1989. [2] B.M.Zeglis et. al., J. Nucl. Med., 2013, 54, 1389. [3] J.P. Meyer et. al., Bioconjugate Chem., 2016, 27, 2791. [4] Z. Li et. al., Chem. Comm., 2010, 46, 8043. [5] C. Denk et. al., Angw. Chem. Int. Ed., 2014, 53, 9655.
103 The 10th Joint Meeting on Medicinal Chemistry 2017
P-28
IDENTIFICATION OF EXPANDED CAG REPEATS LIGANDS TO COUNTERACT HUNTINGTON’S DISEASE
Jenny Desantis,[a],* Kenji Schorp,[b] Serena Massari,[a] Anna Bochicchio,[c] Frank Matthes,[d] Judith Schilling,[d] Stephanie Weber,[d] Nina Offermann,[d] Paolo Carloni,[c] Kamyar Hadian,[b] Giulia Rossetti,[c] Oriana Tabarrini[a] and Sybille Krauss[d]
[a] Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06123, Perugia, Italy [b] Assay Development and Screening Platform, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München für Gesundheit und Umwelt, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany [c] Computational Biomedicine, Institute for Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich, Jülich, Germany [d] German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Str. 27, 53127, Bonn, Germany * [email protected]
Huntington’s disease (HD) is a fatal, devastating, and inherited neurodegenerative genetic disorder, for which there is currently no cure.[1] The disease is caused by an autosomal dominant mutation at the huntingtin (HTT) gene encoding for the ubiquitously expressed Huntingtin protein (Htt), which is essential for brain development.[2,3] Growing evidences emerged that HTT mRNA transcripts with expanded CAG repeats (n > 36) (i) contribute to the pathogenesis of HD;[4] (ii) aberrantly regulate several cellular mechanisms;[5] (iii) bind to proteins in repeat size-dependent manner to form pathological complexes.[6-9] In particular, the interaction between mRNA transcripts of pathogenic length and the Midline-1 protein (MID1) is involved in the overproduction of aberrant Htt protein.[10] Hence, the design of ligands with high affinity for expanded CAG mRNA transcripts able to inhibit the formation of pathological mRNA/proteins complexes represents a promising, although challenging, strategy to interfere with the neuronal derangement associated with HD. Until now, a few small molecules able to bind CAG repeats in RNA in vitro have been identified, but unfortunately none of them resulted to be selective for the pathogenic CAG repeats in HTT, when assayed in vivo.[11] Here, we are currently selecting small molecules that might bind to mutant HTT RNA in vitro and in turn could inhibit the MID1/HTT RNA complex formation.
[1] C.A. Ross, S.J. Tabrizi, Lancet Neurol., 2011, 10, 83. [2] M.E. MacDonald, C.M. Ambrose, M.P. Duyao, R.H. Myers, C. Lin, G. Barnes, S.A. Taylor, M. James, N. Groot, H. MacFarlane, B. Jenkins, M.A. Anderson, N.S. Wexler, J.F. Gusella, Cell, 1993, 72, 971. [3] A. Reiner, I. Dragatsis, S. Zeitlin, D. Goldowitz, Mol. Neurobiol., 2003, 28, 259. [4] M. Wojciechowska, W.J. Krzyzosiak, RNA Biol., 2011, 8, 565. [5] R. Nalavad, N. Griesche, D.P. Ryan, S. Hildebrand, S. Krauß, Cell Death Dis,. 2013, 4, e752. [6] A. Kiliszek, R. Kierzek, W.J. Krzyzosiak, W. Rypniewski, Nucleic Acids Res., 2010, 38, 8370. [7] M. de Mezer, M. Wojciechowska, M. Napierala, K. Sobczak, W.J. Krzyzosiak, Nucleic Acids Res., 2011, 39, 3852. [8] L.P. Ranum, T.A. Cooper, Annu. Rev. Neurosci., 2006, 29, 259. [9] A. Fiszer, W.J. Krzyzosiak, J. Mol. Med. (Berl.), 2013, 91, 683. [10] S. Krauss, N. Griesche, E. Jastrzebska, C. Chen, D. Rutschow, C. Achmüller, S. Dorn, S.M. Boesch, M. Lalowski, E. Wanker, R. Schneider, S. Schweiger, Nat. Commun., 2013, 4, 1511. [11] A. Kumar, R. Parkesh, L.J. Sznajder, J.L. Childs-Disney, K. Sobczak, M.D. Disney, ACS Chem. Biol., 2012, 7, 496.
104 The 10th Joint Meeting on Medicinal Chemistry 2017
P-29
SYNTHESIS OF SOME NEW BENZOTHIAZOLONE DERIVATIVES AND INVESTIGATION OF THEIR CHOLINESTERASE INHIBITOR ACTIVITIES
Deniz S. Doğruer,* Merve Erdoğan and Burcu Kılıç
Department of Pharmaceutical Chemistry, Gazi University Faculty of Pharmacy, 06330 Ankara, Turkey * [email protected]
Alzheimer's disease (AD) was first identified by Dr. Alois Alzheimer in 1906. Since then, the average life expectancy has been significantly extended, AD has become an important health problem all over the world especially in developed countries. Since the cause of disease are not fully elucidated, available treatments are insufficient. Pathophysiological changes of AD cover lack in cholinergic neurotransmission, faulty amyloid-β (Aβ) protein metabolism, formation of intracellular neurofibrillary tangles and the participation of inflammatory, oxidative and hormonal pathways. Based on these markers, several hypotheses have been proposed to explain the mechanism of AD, which are cholinergic, amyloid and tau hypotheses.[1] According to the cholinergic hypothesis, since the symptoms of Alzheimer’s disease (AD) was linked to a deficiency in the brain neurotransmitter acetylcholine (ACh) that mediates memory and learning functions, current treatment of AD focuses on increasing acetylcholine levels by inhibiting cholinesterase, the enzymes responsible for ACh hydrolysis. Because AChE is the main enzyme involved in the breakdown of ACh in the normal brain, cholinergic therapy for AD initially focused on AChE inhibition. Recently research shows that the enzyme has also non-cholinergic function in addition to catalytic activity of AChE.[2] On the other hand, as the disease progresses, AChE levels decrease while the levels of BuChE increase.[3] Therefore, concurrent inhibition of both enzymes should provide additional benefits in the treatment of AD. In the present study, we designed and synthesized eight new benzothiazolone derivatives in order to investigate their acetylcholinesterase/butyrylcholinesterase inhibitory activities. The chemical structures of synthesized compounds were confirmed by 1H-NMR, 13C-NMR, HRMS and elemental analysis.
[1] M. Singh, M. Kaur, H. Kukreja, R. Chugh, O. Silakari, D. Singh, Eur. J. Med. Chem., 2013, 70, 165. [2] G. Johnson, S.W. Moore, Current Pharmaceutical Design., 2006, 12, 217. [3] X. Sai-Sai, W. Xiao-Bing, L. Jiang-Yan, Y. Lei, K. Ling-Yi, Eur. J. Med. Chem., 2013, 64, 540.
105 The 10th Joint Meeting on Medicinal Chemistry 2017
P-30
LONG-CHAIN DERIVATIVES OF (TRIFLUOROMETHYLPHENYL)PIPERAZINES – SYNTHESIS AND EVALUATION OF THE ACTIVITY TOWARDS 5-HT RECEPTORS
Anna Drabczyk,[a] Jolanta Jaśkowska,[a],* Damian Kułaga,[a] Grzegorz Satała[b] and Magdalena Malinowska[a]
[a] Cracow University of Technology, Department of Chemical Engineering and Technology, Institute of Organic Chemistry and Technology, 24 Warszawska St., 31-155 Cracow, Poland [b] Department of Medicinal Chemistry, Institute of Pharmacology Polish Academy of Sciences, 12 Smetna St., 31-343 Cracow, Poland * [email protected]
Smart drugs (designer drugs) is common term for the single substances, the group of substances or mixtures thereof, which have psychoactive effects. This group include the arylpiperazines that are bioactive compunds, having affinity towards serotonin 5-HT receptors. Among the arylpiperazine derivatives (1-(3-trifluoromethyl)phenyl)piperazine (TFMPP) can be found – a substance that is a non-selective agonist of serotonin receptors 5-HT1B, 5-HT2A, 5-HT2C. TFMPP and other arylpiperazine derivatives can be obtained by synthesis of substituted aniline with bis(2- chloroethyl)amine hydrochloride in the presence of base. However, the disadvantage of this method is low yield of obtaining the products and a very long reaction time lasting several hours.[1,2] An interesting aspect is the aryl-piperazine modifications leading to the formation of long chain derivatives of these compounds (LCAPs - Long Chain Aryl Piperazines), that have an amide or imide in the terminal part. Compared to the arylpiperazines affecting only on the 5-HT receptors, LCAPs have a wider activity - not only towards serotonin receptors, but also towards dopamine receptors. The literature data show high bioactivity of popular substances belonging to the group of LCAPs, such as Buspirone or NAN-190, as well as derivatives of mentioned TFMPP with bromobutylphthalimide e.g. 4-[4-(2-phthalimido)butyl]-1-(3 -trifluoromethylphenyl) piperazine.[3] These ligands can be prepared in lasting many hours and requiring the use of large amounts of toxic solvents synthesis. Furthermore, the resulting products requires purification by using column chromatography.[4,5] The research began by performing the synthesis of (trifluoromethylphenyl)piperazine derivatives via method which fulfills the principle of "Green Chemistry". The impact of the proposed reaction conditions on the yield and purity of obtaining the desired product was tested. In the next stage of the study, received derivatives of (trifluoromethylphenyl)piperazine were used for the synthesis of a series of LCAPs, which contained alkyl chain terminated with imide or amide moiety. The syntheses were carried out under microwave irradiation in a new, eco-friendly way that allows the reduction of solvents used during the reaction. In addition, thus obtained ligands were characterized by high purity and good physico-chemical properties. The results received after carrying out an in vitro tests for all of the ligands obtained by this method, have confirmed high biological activity of newly synthesized compounds.
Acknowledgments: The study was financially supported by the National Centre for Research and Development, Project LIDER VI (No. LIDER/015/L-6/14/NCBR/2015).
[1] R. Perrone et al. J. Med. Chem., 1994, 37, 99. [2] E. Mishani et al. Tetrahedron Lett., 1996, 37, 319. [3] M. Paluchowska et al. Arch. Pharm. Chem. Life Sci., 2006, 339, 498. [4] P.Kowalski et al. Arch. Pharm., 2013, 346, 339. [5] P. Kowalski et al. Arch. Pharm. Chem. Life Sci., 2012, 345, 81.
106 The 10th Joint Meeting on Medicinal Chemistry 2017
P-31
SYNTHESIS AND EVALUATION OF THE ACTIVITY TOWARDS 5-HT RECEPTORS OF NEW LIGANDS FROM THE LCAPS GROUP
Anna Drabczyk,[a] Jolanta Jaśkowska,[a],* Damian Kułaga,[a] Grzegorz Satała[b] and Magdalena Malinowska[a]
[a] Cracow University of Technology, Department of Chemical Engineering and Technology, Institute of Organic Chemistry and Technology, 24 Warszawska St., 31-155 Cracow, Poland [b] Department of Medicinal Chemistry, Institute of Pharmacology Polish Academy of Sciences, 12 Smetna St., 31-343 Cracow, Poland * [email protected]
Long-chain arylpiperazines (LCAPs) are an interesting group of compounds which have activity towards the serotonin receptors.[1] These compounds contain in their structure arylpiperazine moiety which, through the flexible alkyl chain, is linked mostly to imide, amide, or sulfonamide moiety. These compounds are generally obtained by several hours’ long, multi-step synthesis which requires the use of large amounts of solvents. This method of carrying out the reactions also requires the removal of solvents from the reaction mixture and purification of the compounds by using Pressure Liquid Chromatography Column.[2-4] One of the best known compounds belonging to the group of LCAPs having activity against the serotonin 5-HT receptors is NAN-190 – 1-(2-methoxyphenyl)-4-(4-phthalimidobutyl)piperazine which has a methoxy substituent in the ortho position in the aromatic ring of arylpiperazine moiety.[5] Within the framework of the research, basing on the structure of NAN-190, it was decided to check the influence of lengthening the alkyl chain connecting the arylpiperazine group with the phthalimide, as well as the impact of the position of methoxy group in the aromatic ring of arylpiperazine moiety. The group of ligands was obtained by newly developed method of synthesis which follows the principles of “Green Chemistry”. The reactions were carried out within a few minutes under microwave irradiation, using small amounts of solvents. The performed reactions allow obtaining the desired products with high purity in a short time and with a high yield. All obtained ligands were evaluated in in vitro tests for their affinity with selected serotonin 5-HT receptors. The results from these studies confirm high biological activity of testing compounds.
Acknowledgments: The study was financially supported by the National Centre for Research and Development, Project LIDER VI (No. LIDER/015/L-6/14/NCBR/2015).
[1] G. Caliendo et al. Curr. Med. Chem., 2005, 12, 763. [2] P. Kowalski et al. Archiv der Pharm., 2013, 346, 339. [3] P. Kowalski et al. Arch. Pharm. Chem. Life Sci., 2012, 345, 81. [4] N. Cesari et al. J. Med. Chem., 2006, 49, 7826. [5] A. J. Bojarski et al. Bioorg. Med. Chem. Lett., 2004, 14, 5863.
107 The 10th Joint Meeting on Medicinal Chemistry 2017
P-32
SYNTHESIS OF PHOTOSWITCHABLE INHIBITORS FOR CNS APPLICATIONS
D. Dreier,[a] M. Holy,[b] K. Jäntsch,[b] H. H. Sitte[b] and M. D. Mihovilovic[a],*
[a] Institute of Applied Synthetic Chemistry, TU Wien, Getreidemarkt 9/163-OC, 1060 Vienna, Austria [b] Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Währinger Straße 13A, 1090 Vienna, Austria * [email protected]
Recent advances in the field of photo pharmacology[1] enabled photo control over a variety of proteins (e.g. ion channels). Photo switchable molecules can be switched between two isomers by irradiation with light. Ideally, the biological activity of the two isomers is largely different. Within this contribution we investigate the feasibility to apply this concept to key proteins of CNS networks. We present the synthesis of novel photo switchable analogs based on well-studied ligands. Photo switchable small molecules might alter the functionality of targeted proteins to be light dependent. These photo-sensitive proteins would allow to study them in greater detail and thereby provide a deeper understanding of their functionality. Azobenzene and Hemithioindigo[2] based photo switches (Figure) were utilized as two potential substance classes to achieve our goals. These two compound classes exhibit a wide range of thermal half-life times and different activation wavelengths. In addition, we report on preliminary biological data obtained from cell based assays.
Figure: Application of Azobenzenes and Hemithioindigos in photopharmacology.
[1] J. Broichhagen, J. A. Frank, D. Trauner, Acc. Chem. Res., 2015, 48, 1947. [2] S. Wiedbrauk, H. Dube, Tetrahedron Lett., 2015, 56, 4266.
108 The 10th Joint Meeting on Medicinal Chemistry 2017
P-33
AER METHOD: A GOOD WAY TO OBTAIN APIs AS IONIC LIQUIDS
E. Alcalde,[a] I. Fallon,[a] F. Roig,[b] J. Esquena,[c] M. J. García-Celma[b,c] and I. Dinarès[a],*
[a] Unitat de Química Orgànica, Dep. Farmacologia, Toxicologia i Química Terapèutica [§] [b] Unitat de Tecnologia Farmacèutica, Dep. Farmàcia, Tecnologia Farmacèutica i Fisicoquímica [§] [c] Institut de Química Avançada de Catalunya (IQAC) [ǂ] * [email protected]
Ion-exchange resins are widely used in different processes. Anion exchange resins (AER) have been employed as an efficient tool to perform the anion exchange and their application has been extended to a variety of chemical reactions. In recent years, our research group has developed a broad and efficient method to swap the halide ion in quaternary heteroaromatic and ammonium salts for a variety of anions using an AER in non-aqueous media.[1] This simple procedure involves the preparation of AER (A¯ form) with the selected anion (anion loading) and then the halide exchange (Figure). The choice of the solvents for loading and for exchange is critical to achieve the best results. Following the AER method halide-free ion pairs with ionic liquid (IL) properties can be obtained.
Figure: AER method applied to arylpropionic derivatives.
Both charged counterparts in ILs can be independently modified, providing tunability in the design of new functional materials such active pharmaceutical ingredients (APIs) modulating the properties with novel performance enhancement, bioavailability and delivery options. Poor water solubility of active pharmaceutical ingredients (API) is a major challenge in drug development impairing bioavailability and therapeutic benefit. Direct synthesis of ILs from weakly acidic or weakly basic drugs shows perhaps the most promise for significant alteration of drug properties, such to avoid the crystallinity or to promote aqueous solubility. As a part of our ongoing research, AER simple method was applied to the synthesis of several drug examples of arylpropionic acids (non-steroidal anti-inflamatory drugs) or bisphosphonates (osteoporosis treatment) with ILs properties. Moreover, toxicity and biocompatibility of cation should be taken into account. In addition, the study of the release from micro and nanogels as drug delivery systems was carried out.
Acknowledgments: AGAUR-Generalitat de Catalunya (2014SGR1655), MINECO (CTQ2016- 80645-R), and SCT-UB.
[§] Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, Av. Joan XXIII 27-31, 08028- Barcelona. [ǂ] CSIC i CIBER-BBN, Jordi Girona 18-26, 08034-Barcelona.
[1](a) I. Dinarès, C. Garcia de Miguel, A. Ibáñez, N. Mesquida, E. Alcalde. Green Chem., 2009, 11, 1507.; (b) E. Alcalde, I. Dinarès, A. Ibáñez, N. Mesquida Chem. Commun., 2011, 47, 3266.; (c) E. Alcalde, I. Dinarès, A. Ibáñez, N. Mesquida, Molecules, 2012, 17, 4007.
109 The 10th Joint Meeting on Medicinal Chemistry 2017
P-34
SYNTHESIS OF SOME NEW BENZOXAZOLONE DERIVATIVES AND EVALUATION OF THEIR CHOLINESTERASE INHIBITOR ACTIVITIES
Merve Erdoğan,* Burcu Kılıç and Deniz S. Doğruer
Department of Pharmaceutical Chemistry, Gazi University Faculty of Pharmacy, 06330 Ankara, Turkey * [email protected]
According to World Health Organization (WHO), Alzheimer’s disease (AD), most common age- related neurodegenerative disease, affects more than 30 million people around the world and number of AD patient expected to increase up 100 million by 2050.[1] AD is characterized by progressive cognitive impairments, learning problems and decrease language and motor skills.[2] Although extensive research has focused on pathogenetic mechanism of AD, exact cause is still uncertain. Several hypothesis has been explained as the cause of AD. One of them is cholinergic hypothesis, suggested that decreased level of neurotransmitter acetylcholine in some parts of the brain such as hippocampus related to learning and cognition is the typical pathological hallmarks of AD.[3] Thus, the acetylcholine level in the brain is enhanced by inhibition of cholinesterase enzymes. Recent approved cholinesterase inhibitors (ChEIs) donepezil, galantamine and rivastigmine have been used for this purpose. However, present cholinesterase inhibitor drugs are only effective in mild and moderate stages of AD, their effectiveness varies individually and they can cause peripheral side effects.[4] These restrictions motivate researchers to investigate for new alternatives. As a result, cholinesterase inhibitors keep their values for drug development studies. In the present study, we designed and synthesized eight new benzoxalone derivatives in order to investigate their acetylcholinesterase/butyrylcholinesterase inhibitory activities. The chemical structures of synthesized compounds were confirmed by 1H-NMR, 13C-NMR and HRMS.
[1] Alzheimer's Disease International, World Alzheimer Report. 2011, p. 1. [2] A. Wimo, B. Winblad, L. Jönsson, Alzheimers Dement., 2010, 6, 98. [3] N. Guzior, A. Wickowska, D. Panek, B. Malawska. Curr. Med. Chem., 2015, 22, 373. [4] H. B. Nygaard, Clin. Ther., 2013, 35, 1480.
110 The 10th Joint Meeting on Medicinal Chemistry 2017
P-35
DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NEW SERIES OF DIHYDROXYLATED 2,6-DIPHENYL-4-CHLOROPHENYLPYRIDINES: DNA NON-INTERCALATIVE CATALYTIC TOPOISOMERASE I & IIα DUAL INHIBITOR
Eung-Seok Lee,[a],* Ganesh Bist,[a] Til Bahadur Thapa Magar,[a] Aarajana Shrestha,[a] Pramila Katila[a] and Youngjoo Kwon[b]
[a] College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea [b] College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea * [email protected]
A novel series of eighteen dihydroxylated 2,6-diphenyl-4-chlorophenylpyridines were systematically designed, and investigated for their topoisomerase (topo) I and IIα inhibitory properties and antiproliferative effect in HCT15, T47D, and HeLa cancer cell lines. Compounds 22-30 which possess a meta- or para-phenol on 2-, or 6-position of central pyridine ring showed significant dual topo I and topo IIα inhibitory activities with strong antiproliferative activities against all the tested human cancer cell lines. However, compounds 13-21 which possess an ortho-phenol on 2-, or 6- position of central pyridine ring did not show significant topo I and topo IIα inhibitory activities but displayed moderate antiproliferative activities against all the tested human cancer cell lines. The structure-activity relationship study revealed that the para position of a hydroxyl group at 2-and 6- phenyl ring and chlorine atom at the para position of 4-phenyl ring of the central pyridine exhibited the most significant topo I and topo IIα inhibition, which might indicate introduction of the chlorine atom at the phenyl ring of 4-pyridine have an important role in topo I & IIα dual inhibition. Compound 30 with the most potent dual topo I and topo IIα inhibition with strong antiproliferative activity in T47D cell line was selected to perform further study on the mechanism of action and was found to be functioning as a potent DNA non-intercalative catalytic topo I and IIα dual inhibitor.
111 The 10th Joint Meeting on Medicinal Chemistry 2017
P-36
SYNTHESIS OF RING A-FUSED PYRAZOLE REGIOISOMERS IN THE ANDROSTANE SERIES AND AN EVALUATION OF THEIR CELL- GROWTH INHIBITORY EFFECTS IN VITRO
Éva Frank,[a],* Ádám Baji,[a] Gergő Mótyán[a] and István Zupkó[b]
[a] Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary [b] Department of Pharmacodynamics and Biopharmacy, University of Szeged, Eötvös u. 6, H-6720 Szeged, Hungary * [email protected]
Pyrazoles represent an important class of five-membered N-containing heterocycles in view of the broad spectrum of their bioactivity.[1] The incorporation of a pyrazole moiety into the relatively rigid and planar backbone of natural sex hormones, either connected to[2] or condensed with one of the core-forming rings,[3] also deserves attention from pharmacological aspects. Some of these derivatives have been reported to exhibit direct antiproliferative effects on cancer cell lines of diverse origins in a hormone receptor independent manner.[4] Herein a rapid and simple synthesis of novel ring A-condensed steroidal pyrazoles from 2-hydroxymethylene-dihydrotestosterone (1) with different arylhydrazines (2a-h) is described. The Knorr-type transformations led to a 5:4 mixture of two regioisomeric arylpyrazoles (3 and 4) in good yields within 5 min using pyridine as solvent. However, strong electron-withdrawing groups (CN, NO2) attached to the phenylhydrazine ring (2g and 2h) were observed to affect the isomeric distribution ratio favoring the formation of 4 over 3, though the reaction rates were left unchanged. After separating the related isomers by column chromatography, they were subjected to in vitro pharmacological studies to explore their antiproliferative activities against three human breast malignant cell lines (MCF7, T47D, MDA-MB-231).
Overall Isomeric Arylhydrazine R yield ratio (3:4) (%) 2a H 5:4 89 2b CH3 5:4 82 2c OMe 5:4 82 2d F 4:3 79 2e Cl 4:3 85 2f Br 4:3 84
2g CN 1:2 78 2h NO2 1:2 84
[1] M.F. Khan, M.M. Alam, G. Verma, W. Akhtar, M. Akhter, M. Shaquiquzzaman, Eur. J. Med. Chem., 2016,120,170. [2] D. Kovács, J. Wölfling, N. Szabó, M. Szécsi, Zs. Schelz, I. Zupkó, É. Frank, Eur. J. Med. Chem., 2016,120, 284. [3] D.S. Fischer, G.M. Allan, C. Bubert, N. Vicker, A. Smith, H.J. Tutill, A. Purohit, L. Wood, G. Packham, M.F. Mahon, M.J. Reed, B.V.L..Potter, J. Med. Chem., 2005, 48, 5749. [4] É. Frank, Gy. Schneider, J. Steroid Biochem. Mol. Biol., 2013, 137, 301.
112 The 10th Joint Meeting on Medicinal Chemistry 2017
P-37
SYNTHESIS, CYTOSTATIC AND ANTIBACTERIAL EVALUATIONS OF N- 4-BENZOYLCYTOSINE–1,2,3-TRIAZOLE AND 7-DEAZAPURINE–1,2,3- TRIAZOLE HYBRIDES
Maja Stipković Babić,[a] Mande Miošić,[a] Moris Mihovilović,[a] Marijana Jukić,[b] Ljubica Glavaš-Obrovac,[b] Domagoj Drenjančević,[c,d] Silvana Raić-Malić[a] and Tatjana Gazivoda Kraljević[a],*
[a] Department of Organic Chemistry, Faculty of Chemical Engeneering and Technology, University of Zagreb, Marulićev trg 20, 10000 Zagreb, Croatia. [b] Department of Medicinal Chemistry, Biochemistry and Clinical Chemistry, Faculty of Medicine Osijek, J. J. Strossmayer University of Osijek, Huttlerova 4, HR-31000 Osijek, Croatia. [c] Department of Microbiology and Parasitology, Faculty of Medicine Osijek, J. J. Strossmayer University of Osijek, Huttlerova 4, HR-31000 Osijek, Croatia. [d] Department of Transfusion Medicine, University Hospital Centre Osijek, Huttlerova 4, HR-31000 Osijek, Croatia * [email protected]
Cytosine and 7-deazapurine (pyrrolo[2,3-d]pyrimidine) derivatives have a great role in medicinal chemistry and have shown rather marked antitumor, antiviral, antibacterial and antiinflammatory activities.[1-4] 7-deazapurines are an important class of compounds, structurally and chemically related to naturally nucleosides. In the last few years, several 7-deazapurine derivatives have been approved for the treatment of different diseases or are currently in phase I/II clinical trials.[1] As important pharmacophores, pyrrolo[2,3-d]pyrimidine scaffold is being extensively investigated and many of such compounds resulted active as kinase inhibitors.[5] Herein we present the synthesis of novel N-4-benzoylcytosine–1,2,3-triazole and pyrrolo[2,3-d]pyrimidine–1,2,3-triazole hybrides and their cytostatic and antibacterial evaluations. The novel N-1 propargylated and C-5 alkynylated N-4- benzoylcytosine derivatives were prepared by N-alkylation of pyrimidine bases and subsequent Pd- catalysed Sonogashira cross-coupling reaction, while C-6 substituted pyrrolo[2,3-d]pyrimidine derivatives were afforded by in situ N-heteroannulation of C-5 alkynylated cytosines. Cytosine- and 7-deazapurine–1,2,3-triazole hybrides were obtained by click reaction with corresponding azides in the pressence of CuI and base. The novel compounds were evaluated against tumor cell lines (HeLa, CaCo-2, Raji and K562) and on the growth of gram-positive and gram-negative bacterial strains.
[1] F. Musumeci et al, Eur. J. Med. Chem., 2017, 127, 369. [2] L. Wang et al, J. Med. Chem., 2015, 58, 6938. [3] V. P. Kumar et al, Bioorg. Med. Chem. Lett., 2013, 23, 5426. [4] K. M. H. Hilmy et al, J. Am. Sci., 2011, 7, 308. [5] T. Wang et al, Bioorg. Med. Chem. Lett., 2016, 26, 2936.
113 The 10th Joint Meeting on Medicinal Chemistry 2017
P-38
STERANE-FUSED PYRAZOLES: AN EFFICIENT MICROWAVE-ASSISTED SYTHESIS ON RING A
Gergő Mótyán,* Réka Kiss-Faludy, János Wölfling and Éva Frank
Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary * [email protected]
Pyrazole derivatives are important class of heterocycles, since they have been found to be a versatile element in numerous pharmacological and chemically remarkable compounds.[1] Five-membered N- containing heterocycles are known to have various activities and several compounds have been proven as, useful intermediates in the deduction of biological targets.[2] The introduction of a pyrazole moiety condensed to the steroidal skeleton may cause a significant change in the original biological activities, newly-synthesized derivatives were found to exert pronounced antiproliferative action on human malignant cell lines.[3,4]
A series of novel A-ring fused pyrazole derivatives containing differently substituted aryl group were designed and synthesized using efficient and rapid microwave-mediated approach. The newly gained compounds were subjected to in vitro bioassays and pharmacological investigations against different human malignant cell lines, further studies ‒ which are in progress ‒ may result in essential structure-activity relationships and permit the better understanding of the mode of action of the potent derivatives.
Acknowledgments: This work has been supported by the ÚNKP-ÚNKP-16-3 New National Excellence Program of the Ministry of Human Capacities.
[1] É. Frank, Z. Mucsi, I. Zupkó, B. Réthy, G. Falkay, G. Schneider, J. Wölfling, J. Am. Chem. Soc., 2009, 131, 3894. [2] A. W. Brown, M. Fisher, G. M. Tozer, C. Kanthouand, J. P. A. Harrity, J. Med. Chem., 2016, 59, 9473. [3] G. Mótyán, I. Zupkó, R. Minorics, G. Schneider, J. Wölfling, É. Frank, Mol. Div., 2015, 78, 69. [4] G. Mótyán, F. Kovács, J. Wölfling, A. Gyovai, I. Zupkó, É. Frank, Steroids, 2016, 112, 36.
114 The 10th Joint Meeting on Medicinal Chemistry 2017
P-39
BROADLY EFFECTIVE METAL CHELATORS, AS INFLUENZA PA ENDONUCLEASE AND HEPATITIS C VIRUS INHIBITORS
Erofili Giannakopoulou,[a] Annelies Stevaert,[b] Efseveia Frakolaki,[c] Vassilios Myrianthopoulos,[a] Emmanuel Mikros,[a] Ralf Bartenschlager,[d] Niki Vassilaki,[c] Lieve Naesens[b] and Grigoris Zoidis[a],*
[a] School of Health Sciences, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, 15771, Athens, Greece [b] Rega Institute for Medical Research, KU Leuven – University of Leuven, Herestraat 49, 3000, Leuven, Belgium [c] Molecular Virology Laboratory, Hellenic Pasteur Institute, Vas. Sofias Avenue, 11521, Athens, Greece [d] Department of Infectious Diseases, Molecular Virology, University of Heidelberg, Im Neuenheimer Feld 345, 69120, Heidelberg, Germany * [email protected]
Influenza viruses cause considerable morbidity and mortality whether in the context of seasonal epidemics or pandemic outbreaks which are associated with huge economic costs. Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, in approximately 170 million people worldwide, that often leads to cirrhosis and hepatocellular carcinoma. Since the efficacy of currently approved antivirals is threatened by emerging viral resistance and their cost remains high, new antiviral drugs are still required, as they are an indispensable component of the broad approach for the treatment and prevention of these infections. By utilizing a structure-based approach, novel substituted indole-flutimide heterocyclic derivatives were rationally designed, synthesized and evaluated as influenza PA endonuclease and HCV NS5B polymerase inhibitors.[1] The compounds were also tested for their antiviral effect against HCV and their cytotoxicity. The source of inspiration for the design of the new analogues was several compounds that bear a N-hydroxyimidic moiety, a metal chelating group, and especially the structurally related compound flutimide, the first identified natural product that is found to selectively inhibit the "cap-snatching" endonuclease reaction of Influenza A and B viruses.[2] All N- hydroxyimides were potent PA endonuclease inhibitors, while displaying low cytotoxicity. Some of them also showed additional significant anti-HCV activity and exhibited remarkable selectivity index.[1] The results of in vitro evaluation contribute in the clarification of the role of several structural characteristics in the Structure-Activity Relationships of the compounds with the active site of the enzymes. Our findings suggest that the novel pyrazino[1,2-α]indole-1,3(2H,4H)-dione framework, that we have developed, offers a promising motif for an ameliorated future design of novel antiviral agents with optimized properties.
[1] G. Zoidis, E. Giannakopoulou, A. Stevaert, E. Frakolaki, V. Myrianthopoulos, G. Fytas, P. Mavromara, E. Mikros, R. Bartenschlager, N. Vassilaki, L. Naesens, MedChemComm, 2016, 7, 447. [2] J.E. Tomassini, M.E. Davies, J.C. Hastings, R. Lingham, M. Mojena, S.L. Raghoobar, S.B. Singh, J.S. Tkacz, M.A. Goetz, Antimicrob. Agents Chemother., 1996, 40, 1189.
115 The 10th Joint Meeting on Medicinal Chemistry 2017
P-40
ORGANOCATALYSIS MEETS BETA LACTAMS
Thavendran Govender,[a] Tricia Naicker,[a] Hendrik G. Kruger[a] and Per I. Arvidsson[a,b]
[a] Catalysis and Peptide Research Unit, University of KwaZulu Natal, South Africa [b] Science for Life Laboratory, Drug Discovery and Development Platform, and Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
Compounds containing β-lactams are amongst the most important molecules in clinical use today.[1- 3] Most notably is their wide utility as antibacterial agents and as related β-lactamase inhibitors; however, β-lactams are also being explored in other therapeutic areas,[4] including HIV protease inhibition.[5] Given the global challenge of antibiotic resistance,[6] there is an urgent need for increased focus on the discovery and development of antibacterial agents. We have exploited the use of organocatalysis to make realized novel derivatives for medicinal chemistry.[7-10]
Figure: Novel HOMO rising strategies offering a mild and facile route to carbapenam derivatives.
[1] A. C. Rodloff, E. J. C. Goldstein, A. Torres, J. Antimicrob. Chemother., 2006, 58, 916. [2] R. P. Elander, Appl. Microbiol. Biotechnol., 2003, 61, 385. [3] F.-R. Schmidt, In Industrial Applications, ed. M. Hofrichter, Springer Berlin Heidelberg 2010; vol 10, pp 101. [4] J. M. T. Hamilton-Miller, J. Antimicrob. Chemother., 1999, 44, 729. [5] T. Sperka, J. Pitlik, P. Bagossi J. Tozser, Bioorg. Med. Chem. Lett., 2005, 15, 3086. [6] F. Rossi, Clin. Infect. Dis., 2011; 52:1138. [7] S. A. Pawar, S. Alapour, S. Khanyase, Z. E. D. Cele, S. Chitti, H. G. Kruger, T. Govender, P. I. Arvidsson, Org. Bio. Chem., 2013, 8294. [8] Z. E. D.Cele, S. A. Pawar, T. Naicker, G. E. M. Maguire, P. I. Arvidsson, H. G. Kruger, T. E. Govender, Eur. J. Org. Chem., 2014, 2253. [9] Z. E. D. Cele, P. I. Arvidsson, H. G. Kruger, T. Govender, T. Naicker, Eur. J. Org. Chem., 2015, 638. [10] S. Khanyase, T. Naicker, G. E. M. Maguire, H. G. Kruger, P. I. Arvidsson, T. Govender, Tetrahedron Asymmetry, 2014, 25, 969.
116 The 10th Joint Meeting on Medicinal Chemistry 2017
P-41
SEARCH FOR 5-HT6 RECEPTOR AGENTS AMONG TRIAZINE DERIVATIVES OF HYDANTOIN
Jadwiga Handzlik,[a],* Rafał Kurczab,[b] Dorota Łażewska,[a] Małgorzata Więcek,[a] Angelika Nowakowska,[a] Grzegorz Satała,[b] Andrzej J. Bojarski[b] and Katarzyna Kieć-Kononowicz[a]
[a] Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, ul. Medyczna 9, 30-688 Kraków, Poland [b] Department of Medicinal Chemistry Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland * [email protected]
The 5-HT6 receptors are a relatively new subgroup of serotonin receptors that are quite different from other members. The significant interest in 5-HT6 receptors is related to the therapeutic ability of their ligands as potential anti-dementia, antipsychotic, antidepressant or anti-obese drugs.[1] Several families of compounds displaying action on 5-HT6R found previously allowed to postulate pharmacophore features.[2] Reviewing the library of our compounds, we stumbled on two hydantoin 1,3,5-triazine derivatives that display some features corresponding to those of the pharmacophore of the 5-HT6R ligand and we decided to evaluate their affinities for 5-HT6R in the radioligand binding assay.The compounds differed in the co-position of both, triazine and benzyl moieties, in respect to the hydantoin core. Thus, the compound with 1,3,5-triazine at position 3 of hydantoin and benzyl at position 1 (1, Figure) had nanomolar 5-HT6R affinity, whereas the compound with triazine at 1 and the benzyl substitution at position 3 had weak micromolar activity.
Thus, the compound 1 was selected as a lead structure for further modifications to search for new 5-HT6R agents 2-10 (Figure). The new compounds were obtained within 3-step synthesis, including: (i) an intruduction of ester at position 3, (ii) an alkylation at position 1, and (iii) cyclic condensations with biguanide to give 1,3,5-triazine moiety. The compounds were examined on their affinities to 5- HT6R in the radioligand binding assay. Docking to the homology model of 5-HT6R was performed. The best compounds displayed significant affinities for the serotonin 5-HT6R (Ki < 200 nM). Docking studies provided new interesting information about poses of the hydantoin-triazines (1-10) within the ligand binding pocket of this important serotonin receptor.
Acknowledgments: Supported by the Polish National Science Centre (NCN) grant UMO- 2015/17/B/NZ7/02973.
[1] D. Marazziti, S. Baroni, F. Borsini, M. Picchetti, E. Vatteroni, V. Falaschi, M. Catena-Dell’Osso, Curr. Med. Chem., 2013, 20, 371. [2] B. Benhamú, M. Martín-Fontecha, H. Vázquez-Villa, L. Pardo, M.L. López-Rodríguez, J. Med. Chem., 2014, 57, 7160.
117 The 10th Joint Meeting on Medicinal Chemistry 2017
P-42
NOVEL SYNTHESIS OF (+)-DIENOMYCIN C AND ANALOGOUS COMPOUNDS WITH ANTIBACTERIAL ACTIVITY
Hajime Yokoyama, Yuko Hayashi, Hiromi Ejiri, Masahiro Miyazawa and Yoshiro Hirai*
Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan * [email protected]
The piperidine alkaloids (ex 1, 2), many of which have been isolated from the plant kingdom, have great potential as a source of new drugs. Dienomycin C (1) was isolated from the culture filtrate of the Streptomyces strain MC67-C1 by Umezawa in 1970.[1] This compound has a characteristic antibacterial activity against some strains of Mycobacterium tuberculosis. Hitherto, we have been studying the Pd(II)-catalyzed cyclization of urethane and its application to the total synthesis of natural products. Here, we describe the application of this cyclization to asymmetric synthesis of (+)-dienomycin C (1) and analogous compounds.
The key synthetic problem for (+)-dienomycin C (1) is the construction of three consecutive chiral centers on the piperidine ring. We planned to achieve this by using the combination of Sharpless asymmetric epoxidation, Pd-catalyzed hydrogenolysis with formic salt and Pd (II)-catalyzed cyclization of the urethane. Sharpless asymmetric epoxidation of the allyl alcohol 3 provided the epoxide 4 in 90% yield (78% ee). After conversion of 4 to the ester 5, hydrogenolysis of 5 gave the alcohol 6 as a single isomer in 90% yield. Treatment of the allyl alcohol 7, which was easily transformed from 6, with PdCl2(MeCN)2 in THF at rt gave the cyclized product 8 as a single isomer in 82% yield. Ozonolysis of 8 followerd by Wittig reaction and deprotection with concd HCl gave (+)-dienomycin C (1). We also synthesized some analogous compounds of (+)-dienomycin C using Pd(II)-catalyzed cyclization. Medicinal chemistry based on these compounds are currently under investigation in our laboratory.
[1] S. Umezawa, et al. J. Antibiot., 1970, 23, 20; J. Antibiot., 1970, 23, 28.
118 The 10th Joint Meeting on Medicinal Chemistry 2017
P-43
NOVEL para SUBSTITUTED N-ARYL 3-HYDROXYPYRIDIN-4-ONE MANNOSIDES: SYNTHESIS, HEMAGGLUTINATION INHIBITORY PROPERTIES AND MOLECULAR MODELING
V. Petrović Peroković,[a] Ž. Car,[a] K. Meglić,[a] R. Ribić,[a] T. Tandarić,[b] R. Vianello[b] and S. Tomić[a],*
[a] Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102 a, Zagreb, Croatia [b] Ruđer Bošković Institute, Bijenička cesta 54, Zagreb, Croatia * [email protected]
Adhesion of pathogenic organisms to host tissues is the initiation of the majority of infectious diseases. It is often mediated by lectins present on the surface of infectious organisms which then combine with complementary sugars on the host surface.[1] One of the best characterized bacterial lectin involved in receptor-ligand interaction is mannose-specific type 1 fimbrial FimH adhesin. For example, in uropathogenic E. coli (UPEC) mannose-specific adhesion is mediated by this lectin.[2] A large number of α-D-mannopyranosides with aromatic aglycon moiety were found to bind with high affinity to FimH and thus prevent agglutination of red blood cells. In our previous work we have explored the inhibitory potential of α-mannosides with meta and para substituted N-aryl 3-hydroxy- 2-methylpyridin-4-ones as aglycon parts of a molecule.[3,4] The hemagglutination assays revealed greater preference of FimH towards the para substituted pyridinone mannosides. In this work we report the synthesis of novel para substituted N-aryl 3-hydroxypyridin-4-ones without methyl group in position 2 of the pyridinone ring (Figure). Their inhibitory properties towards the adhesion of E. coli to quinea pig erythrocytes will be evaluated using hemagglutination assay. These results will be compared with inhibitory potencies of analogous para derivatives of N-aryl 3-hydroxy-2- methylpyridin-4-ones. Computational analysis complemented experimental results by elucidating specific interactions within Figure: Structure of N-aryl the FimH active site responsible for the binding and aided in substituted pyridinone the interpretation of the observed binding trends. mannosides
Acknowledgements: This research is financially supported by Croatian Science Foundation (project IP 2014-09-7899).
[1] N. Sharon, Biochim. Biophys. Acta, 2006, 1760, 527. [2] N. Firon, S. Ashkenazi, D. Mirelman, I. Ofek, N.Sharon, Infect. Immun., 1987, 55, 472. [3] Ž. Car, T. Hrenar, V. Petrović Peroković, R. Ribić, M. Seničar, S. Tomić, Chem. Biol. Drug Des., 2014, 84, 393. [4] V. Petrović Peroković, R. Ribić, Ž. Car, S. Tomić, Croat. Chem. Acta, 2016, 89, 237.
119 The 10th Joint Meeting on Medicinal Chemistry 2017
P-44
ANTIBACTERIAL AND ANTIPROLIFERATIVE ACTIVITY OF NOVEL 2- BENZIMIDAZOLYL AND 2-BENZOTHIAZOLYL SUBSTITUED BENZO[B]THIENO-2-CARBOXAMIDES
Maja Cindrić,[a] Mihaela Perić,[b] Marijeta Kralj,[c] Irena Martin Kleiner,[c] Hana Čipčić Paljetak,[b] Mario Matijašić,[b] Donatella Verbanac,[b] Grace Karminski-Zamola[a] and Marijana Hranjec[a],*
[a] Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, 10000 Zagreb, Croatia [b] Department for Intercellular Communication, University of Zagreb School of Medicine, Šalata 2, 10000 Zagreb, Croatia [c] Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia * [email protected]
Small heteroaromatic molecules, like nitrogen and sulphur-containing heterocycles play an extremely important role in medicinal chemistry due to variety of their possible chemical, pharmacological and industrial applications. These molecules are widely incorporated in the structure of numerous natural or synthetic medical and biochemical molecules.[1] Benzimidazoles and benzothiazoles, as one of the privileged sub-structures and an important bioactive heterocyclic building block in medicinal chemistry, while benzothiophene skeleton is incorporated in the structure of numerous therapeutic agents.[2] Herein, we present the synthesis and biological evaluation of novel nitro and amino substituted 2- benzimidazolyl and 2-benzothiazolyl benzo[b]thieno-2-carboxamides.[3] Antibacterial activity was assessed against Gram-positive and Gram-negative bacteria and the highest antibacterial activity was observed for the nitro and amino substituted benzimidazole derivatives with MICs in the range of 2-8 µg/mL. Additionally, the tested compounds not displaying promising antibacterial activity were further tested for the antiproliferative activity in vitro against three human cancer cell lines. The most pronounced and selective antiproliferative activity against MCF-7 cell line was demonstrated by amino substituted hydrochloride salt of benzothiazole derivative with an IC50 of 0.04 µM.
Cl O X S R1 NH N R2 + - 5b R1 = NH3 Cl ; R2 = H X = NH antibacterial activity
+ - 5d R1 = H; R2 = NH3 Cl X = S antiproliferative activity
Figure: Lead compounds for further optimization and biological evaluation.
[1] R. B. Silverman, The Organic Chemistry of Drug Design and Drug Action, Elsevier Academic Press, Second Edition, 2004. [2] a) N. Perin, R. Nhili, M. Cindrić, B. Bertoša, D. Vušak I. Martin-Kleiner, W. Laine, G. Karminski-Zamola, M. Kralj, M. H. David-Cordonnier, M. Hranjec, Eur. J. Med. Chem., 2016, 122, 530; b) L. Racane, R. Stojkovic, V. Tralić-Kulenović, H. Cerić, M. Ðakovic, K. Ester, A. Misir Krpan, M. Radic Stojkovic, Eur. J. Med. Chem., 2014, 86, 406. [3] M. Aleksić, B. Bertoša, R. Nhili, S. Depauw, I. Martin-Kleiner, M.-H. David-Cordonnier, S. Tomić, M. Kralj, G. Karminski-Zamola, Eur. J. Med. Chem., 2014, 71, 267.
120 The 10th Joint Meeting on Medicinal Chemistry 2017
P-45
SYNTHESIS OF DIPEPTIDES CONTAINING PHOTOCHEMICALLY REACTIVE MODIFIYED TYROSINE AND EVALUATION OF THEIR DNA BINDING
Antonija Husak,* Josipa Matić, Ivo Piantanida and Nikola Basarić
Department of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb * [email protected]
Quinone methides (QMs) are recative intermediates with a potential in the development of new leads for drugs owing to their reactivity with DNA, proteins and enzymes.[1] In particular, some anticancer antibiotics such as mitomycine base their action on metabolic formation of QMs and subsequent DNA cross-linking. Therefore, it is important to investigate different classes of simple QMs as potential anticancer agents. However, QM are reactive intermediates with short inherent lifetimes, so they have to be prepared in situ in the living cells. An excellent methodology for the generation of QMs in the biological systems are photochemical reactions of deamination or dehydration.[2] We have recently demonstrated that tyrosine derivatives can be modified into QM precursors and imbedded in proteins where they remain photochemically reactive.[3] Furthermore, it is known that photo-triggered DNA alkylation by QMs can be significantly enhanced by binding QM precursors to the DNA intercallators.[4]. Here we present synthesis of dipeptides 1 and 2 that contain two unnatural amino acids, photochemically reactive tyrosine derivative and amino acid bearing DNA intercalators- phenanthridine[5] or pyrene.[6] Their non-colvalent and photo-triggered covalent DNA binding ability will be investigated. NMe2 NMe2
OH OH
O O H O H O N N O O N N H O H O O O
N
1 2
[1] S. E. Rokita, Quinone Methides, Wiley, 2009. [2] N. Basarić, K. Mlinarić-Majerski, M. Kralj, Curr. Org. Chem., 2014, 18, 3. [3] A. Husak, B. P. Noichl, T. Šumanovac Ramljak, M. Sohora, Đ. Škalamera, N. Budiša, N. Basarić, Org. Biomol. Chem., 2016, 14, 10894. [4] W. F. Veldhuyzen, P. Pande, S. E. Rokita, J. Am. Chem. Soc., 2003, 125, 14005. [5] M. Dukši, D. Baretić, V. Čaplar, I. Piantanida, Eur. J. Med. Chem., 2010, 45, 2671. [6] M. Radić Stojković, P. Piotrowski, C. Schmuck, I. Piantanida, Org. Biomol. Chem., 2015, 13, 1629.
121 The 10th Joint Meeting on Medicinal Chemistry 2017
P-46
TARGETED DEGRADATION OF ANAPLASTIC LYMPHOMA KINASE (ALK) BY APPLYING THE PROTEOLYSIS TARGETING CHIMERAS (PROTAC)
Jong Yeon Hwang,* Chi-Hoon Park, Dong Ho Lee, Chung Hyo Kang, Chong Ock Lee and Jae Du Ha
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea * [email protected]
Recently, a new and powerful technology called “proteolysis targeting chimeras" (PROTAC) has been actively applied in the field of drug development. Treatment of PROTAC molecule, which contains a ligand for the targeted protein, a ligand for E3 ubiquitin ligase binding, and a linker for connection of two ligands, successfully induced targeted protein degradation, thereby inhibiting cancer growth in in vivo animal model study.[1-3] Anaplastic lymphoma kinase (ALK) gene fused to various partner genes are observed in 3–7% of non-small cell lung cancer (NSCLC) in humans. The constitutively activated ALK fusions play an essential role in cancer growth and survival. In this study we aimed to discover novel ALK target degraders (TDs) by applying PROTAC technology. LDK-378 (ceritinib) as an ALK ligand and VHL or CRBN as an E3 ubiquitin ligase were used. Hydroxyproline analogs (HP-7) and pomalidomide were used for VHL and CRBN E3 ligase ligands, respectively. All TDs synthesized in this study were evaluated in enzymatic- and cell-based assays. ALK degradation by TDs were confirmed by western blotting in SU-DHL-1 cell lines. In vivo antitumor activities were evaluated in xenograft mouse model with H3122 cell lines.
[1] D. P. Bondeson, A. Mares, and C. M. Crews, Nat. Chem. Biol., 2015, 11, 611. [2] G. E. Winter, D. L. Buckley, J. Paulk, J. M. Roberts, A. Souza, S. Dhe-Paganon, J. E. Bradner, Science, 2015, 348, 1376. [3] A. C. Lai, C. M. Crews, Nat. Rev. Drug Discov., 2017, 16, 101.
122 The 10th Joint Meeting on Medicinal Chemistry 2017
P-47
LIPOPHILICITY EVALUATION AND IN SILICO ADME-TOX STUDIES OF SOME NOVEL THIOSEMICARBAZONE AND 1,3,4-THIADIAZOLINE DERIVATIVES
Ioana Ionuţ,* Gabriel Marc, Ovidiu Oniga and Brîndușa Tiperciuc
Pharmaceutical Chemistry Department, Iuliu Haţieganu University of Medicine and Pharmacy, 41 Victor Babeş Street, 400012 Cluj-Napoca, Romania * [email protected]
The lipophilic character of a substance is considered as a vital component of drug discovery and development, because it influences basic steps of a drug pharmacokinetics and pharmacodynamics, such as absorbtion, distribution, metabolism, excretion and toxicity (ADME-Tox).[1-5] The lipophilicity of twenty compounds - derivatives of chromenyl-thiosemicarbazone (series 1) and chromenyl-thiadiazolines (series 2) – has been determined by reversed-phase thin layer chromatography, using i-propanol-water mixtures as eluents. These compounds were previously reported for their antiproliferative[6] and antimicrobial activities.[7] Principal component analysis (PCA) allowed an objective estimation of the retention behavior of the tested compounds and also afforded to obtain a 2D scatterplot, described by the first two principal components, which had the effect of separating the compounds from each other the most effectively. With the use of clustering methods (K-means clustering) based on PCA data, the studied compounds were finally grouped into two classes. Data analysis showed that, in general, thiosemicarbazones 1a- j were more lipophilic compared to their corresponding thiadiazolines 2a-j. In both series, the presence of a -CF3 group substantially increased the lipophilic character. The compounds were also virtually screened for their ADME-Tox properties. The results obtained showed good properties and good drug-likeness, all molecules being “accepted” after passing the ADME-Tox rules. Further optimization can be performed on these compounds, in order to achieve a better biological activity and better ADME-Tox properties.
[1] M. Janicka, M. Sztanke, K. Sztanke, J. Chromatogr. A., 2013, 1318, 92. [2] E. Rutkowska, K. Paja̧k, K. Jóźwiak, Acta Pol. Pharm. - Drug Res., 2013, 70, 3. [3] A. Toma, D. Hapău, D. Casoni, V. Zaharia, J. Chromatogr. Sci., 2014, 52,1302. [4] D. Casoni, A. Kot-Wasik, J. Namieśnik, C. Sârbu, J. Chromatogr. A., 2009, 1216, 2456. [5] D. Casoni, C. Sârbu, J. Sep. Sci., 2012, 35, 915. [6] I. Ionuţ, C. Nastasǎ, J.T. Ndongo, C. Bruyère, H. Leclercqz, B. Tiperciuc, F. Lefranc, A. Pîrnău, R. Kiss, O. Oniga, Dig. J. Nanomater. Biostructures., 2013, 8, 1509. [7] I.Ionuț, D.C. Vodnar, I. Oniga, O. Oniga, B.Tiperciuc, R. Tamaian, Pakistan J. Pharm. Sci., 2016, 29, 261.
123 The 10th Joint Meeting on Medicinal Chemistry 2017
P-48
SYNTHESIS OF NOVEL RING STRUCTURES AS GABAA RECEPTOR LIGANDS WITH FUNCTIONAL SELECTIVITY
Maria Teresa Iorio,[a] Laurin Wimmer,[a] Konstantina Bampali,[b] Margot Ernst[b] and Marko Mihovilovic[a],*
[a] TU Wien, Institute of Applied Synthetic Chemistry, Getreidemarkt 9/163-OC, 1060, Vienna, Austria [b] Medical University of Vienna, Center for Brain Research, Spitalgasse 4, 1090, Vienna, Austria * [email protected]
The GABAA receptors are pentameric channel proteins with an high subunit diversity. So far 19 subunits were identified: six α subunit, three β, three γ, one δ, one ε, one θ, one π and three ρ subunits. The different subunits can be combined in different ways to for the pentamer, but the most accepted structure presents two α-, two β- and one γ- subunits.[1] Upon the binding of two molecules of GABA to the receptor, the pore opens and allows the influx of chloride ions. While the benzodiazepines act as positive allosteric modulator via a binding site located at the α+γ- interface in the extracellular domain of GABAA receptors, the 2 GABA [2] binding sites are located at the two β+α-. Figure 1 The GABAA receptor is the target of many clinically relevant drugs such as benzodiazepine, barbiturates and steroids for the treatment of anxiety, depression and epilepsy. Eventhough, benzodiazepines are excellent anxiolytic drugs, they show sedative side effects and due to their addictive properties they cannot be used in long term treatment. For this reason and in order to develop tools for further studies of the GABAA receptor new compounds need to be investigated. Pyrazoloquinolinones were found to act as positive modulators at the α+β- interface, maintaining a high affinity for the benzodiazepine binding site of the receptor. In order to gain selectivity for the binding site at the α+β- interface some modifications of this scaffold are required. Therefore, a more stretched structure needs to be synthesized which may interact better with the β subunit of the receptor, giving as a result a loss in affinity for the binding site at the α+γ- interface.[3] Figure 2 For this purpose a series of indoles derivatives was synthesized (Figure 3). These compounds might maintain the same binding mode at the desired interface due to the analogy with the closed structure. Some preliminary results showed that compounds like these have low affinity for the benzodiazepine binding site, maintaining the modulation of the GABA induced current in receptor containing α and β subunits. Due to their interesting properties these compounds will be further investigated. Figure 3
[1] W. Sieghart, G. Sperk. Curr. Top. Med. Chem., 2002, 2, 795. [2] Z. Varagic, et al. British J. Pharmacol., 2013, 169, 371. [3] K.A. Wafford, B. Ebert, Curr. Opin. Pharm., 2006, 6, 30.
124 The 10th Joint Meeting on Medicinal Chemistry 2017
P-49
SYNTHESIS AND BIOLOGICAL EVALUATION OF CHALCONE DERIVATIVES AS NEUROPROTECTIVE AGENTS FOR PARKINSON’S DISEASE
Bo Ko Jang,[a] Ji Won Choi,[a,b] Jong-Hyun Park,[a] Seul Ki Yeon,[a,b] Si Won Kim,[a,c] Yerim Lee,[a,d] Su Jeong Shin,[a,b] Hyeon Jeong Kim,[a,b] Hyeon Ji Kim,[a] Yong Gu Kang,[a] Ae Nim Pae[a,d] and Ki Duk Park[a,c,d],*
[a] Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Institution, Korea Institute of Science and Technology, 5, Hwarang-ro 14-gil, Seongbuk-gu 02792, Seoul, Republic of Korea [b] Department of Biotechnology, Yonsei University, 50 Yonsei-ro Seodaemun-gu, Seoul, 03722, Republic of Korea [c] KHU-KIST Department of Conversing Science and Technology, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea [d] Department of Biological Chemistry, University of Science and Technology, Gajeong-ro, Yuseonggu, Daejeon, 34113, Republic of Korea * [email protected]
Although the etiology of Parkinson’s disease (PD) is unclear, recent reported studies suggest that oxidative stress contributes to the cascade leading to dopaminergic (DAergic) neurodegeneration. The Nrf2 signaling is the main pathway responsible for cellular defense system against oxidative stress. Nrf2 is a transcription factor that regulates environmental stress response by inducing expression of antioxidant enzyme genes. We have synthesized novel chalcone derivatives to improve their Nrf2 activity and ADME/Tox profiles. Among the derivatives, compound KIST-389 showed significant efficacy for activating Nrf2 and excellent profiles in ADME/Tox tests. In addition, compound KIST-389 effectively protected DAergic neurons and attenuated PD-associated behavioral deficits in the MPTP-induced mouse model.
[1] L.M. de Lau, M.M. Breteler, Lancet Neurol., 2006, 5, 525. [2] J.M. Han, Y.J. Lee, S.Y. Lee, E.M. Kim, Y. Moon, H.W. Kim, O. Hwang, J. Pharmacol. Exp. Ther., 2007, 321, 249. [3] J. Segura-Aguilar, I. Paris, P. Munoz, E. Ferrari, L. Zecca, F.A. Zucca, J. Neurochem., 2014, 129, 898. [4] S.H. Choi, D.Y. Lee, E.S. Chung, Y.B. Hong, S.U. Kim, B.K. Jin, J. Neurochem., 2005, 95, 1755. [5] Z.Q. Jia, H. Zhu, B.R. Misra, Y.B. Li, H.P. Misra, Neurochem. Res., 2008, 33, 2197. [6] I.M. Copple, C.E. Goldring, N.R. Kitteringham, B.K. Park, Toxicology, 2008, 246, 24. [7] K. Itoh, N. Wakabayashi, Y. Katoh, T. Ishii, K. Igarashi, J.D. Engel, M. Yamamoto, Genes Dev., 1999, 13, 76.
125 The 10th Joint Meeting on Medicinal Chemistry 2017
P-50
SYNTHESIS, STRUCTURE-ACTIVITY RELATIONSHIPS, AND MOLECULAR MODELING STUDIES OF NEW LONG-CHAIN CHLOROARYLPIPERAZINES DERIVATIVES AS 5-HT7 AND 5-HT1A RECEPTOR LIGANDS
Jolanta Jaśkowska,[a],* Paweł Śliwa,[a] Zbigniew Majka,[b] Anna K. Drabczyk,[a] Damian Kułaga,[a] Magdalena Malinowska[a] and Grzegorz Satała[b]
[a] Cracow University of Technology, Department of Chemical Engineering and Technology, Institute of Organic Chemistry and Technology, 24 Warszawska St., 31-155 Cracow, Poland [b] Adamed Ltd., Pieńkow 149, Czosnów 05-152, Poland [c] Department of Medicinal Chemistry, Institute of Pharmacology Polish Academy of Sciences, 12 Smetna St., 31-343 Cracow, Poland * [email protected]
Diversity in the variety of functions that serotonin plays in the human body is undoubtedly related to the fact that serotonin receptors have a number of connections with other neurotransmitter systems. However, the 5-HT1A receptors fulfill the key role because they are crucial in pathogenesis and treatment of depression and anxiety.[1-3] The research conducted in recent years has proved that the increased density of 5-HT7 receptors in limbic structure of CNS may be connected with the occurrence of affective disorders.[4,5] Numerous findings in the literature prove that the active ligands [6] of 5-HT7 receptors can play a crucial therapeutic role in treating depression and insomnia. Based on our previous studies of structure activity relationships on N-hexyl-arylpiperazine derivatives, in this work, we synthesized a new set of long-chain arylpiperazines in order to explain whether certain structural modifications involving substitution of hydrogen in arylpiperazine by chlorine may affect the binding affinity for the 5-HT7 receptors and 5-HT1A receptors. It is known that [7] hexyl-2-chloroarypiperazine shows high affinity for the 5-HT1A receptors 5-HT1A (Ki = 2.67 nM ), therefore we have started the synthesis of ligands from a group containing this moiety. In the terminal part of these ligands, we tested phtalimide and comparative amide fragment. All ligands were prepared by a new synthetic reaction in the presence of microwave radiation. Analysis of results from in vitro studies shows that the most active ligands for the 5-HT1A receptor in the group of hexyl- phtalimides are ligands which have a substituent 2-chloroarylpiperazine group, and binding decreases in a series of 2-chloro > 3-chloro > 4-chloro > 2,3-dichloro > 3,5-dichloro arylpiperazines. However, the most active ligands for the 5-HT7 have 3-chloroarylpiperazine moieties. In the case of conversion of the phtalimide on salicylamide moiety, we observed several-fold increase in the activity of both 5-HT1A and 5-HT7. For the most active ligands, we also performed an assessment of the bioactive conformation in the receptors binding site.
Acknowledgments:The study was financially supported by the National Centre for Research and Development, Project LIDER VI (No. LIDER/015/L-6/14/NCBR/2015).
[1] A. P. Front, Neurosci., 2010, 4, 35. [2] J. W. Richardson-Jones, Neuron, 2010, 65, 40. [3] M. Boldrini, Psychiatr. Res., 2008, 42, 433. [4] P.B. Hedlund, Trends Pharmacol. Sci., 2004, 25, 481. [5] D.R. Thomas, Curr. Drug Targets CNS Neurol. Disord., 2004, 3, 81. [6] A.J. Bojarski, Postępy Polskiej Medycyny i Farmacji 2012, 2, 61. [7] K. Tokarski, Postepy Hig. Med. Dosw., 2014, 68, 1104. [8] J.L. Mokrosz, J. Med. Chem., 1992, 35, 2369.
126 The 10th Joint Meeting on Medicinal Chemistry 2017
P-51
NEW METHODS FOR SYNTHESIS OF THE TRAZODONE ANTIDEPRESSANT
Przemysław Zaręba,[a] Jolanta Jaśkowska[a],* and Zbigniew Majka[b]
[a] Cracow University of Technology, Department of Chemical Engineering and Technology, Institute of Organic Chemistry and Technology, 24 Warszawska St., 31-155 Cracow, Poland [b] Adamed Ltd., Pieńkow 149, Czosnów 05-152, Poland * [email protected]
NH N
N N Cl[CH2]3Br Cl N NH N [CH ] Cl 2 3 N [CH2]3 NN N N N Cl O O O 1 2 3 4 5
Trazodone is an antidepressant of the serotonin antagonist and reuptake inhibitor (SARI) class. It is a LCAP (Long Chains Arylpiperazine) compound. It acts as an antagonist of serotonin receptors 5- [1] HT2. In the 1980’s, trazodone was the most frequently applied antidepressant in the United States. Later, it was superseded by selective serotonin reuptake inhibitors (SSRI). Today we see growing interest in SARI, including trazodone. It led to search for new, more efficient and faster synthesis methods.[2] The aim of the research was to develop the most advantageous method for synthesis of trazodone (5). 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one (1) was the substrate, which was subjected to N-alkylation of 1-bromo-3-chloropropane (2) in the presence of potassium carbonate and TBAB (Tetrabutylammonium bromide) as a PTC (Phase Transfer Catalyst). The reaction was carried out under conventional conditions, in the presence of microwave irradiation (MW) or in the presence of ultrasound ( ))) ). The influence of different factors was examined: used solvent, its amount, or the type of glass in which the reactions were carried out, and their impact on the reaction performance. In the next step, 2-(3-chloropropyl)-1,2,4-triazolo[4,3-a]pyridine-3(2H)-one (3) was condensed with 1-(3-chlorophenyl)piperazine (4) to give the product (5) under conventional conditions, in the presence of microwave irradiation (MW), ultrasound ( ))) ) and in tribochemistry variant, with changing the type and amount of used solvent. The study showed that in both stages of carrying out the reaction in the presence of MW or ))), they can significantly reduce the reaction time (45 sec in MW, 40min in )))) ) compared to the synthesis in conventional conditions, where reaction takes a few hours.[1,3,4] Moreover, these methods reduce the amount of used solvents, which is consistent with the principles of green chemistry. The described methods were also used for the preparation of trazodone derivatives with altered chain length and the revised arylpiperazine. The reaction progress was monitored using TLC (thin layer chromatography). The purity of the resulting products were analyzed using UPLC-MS and the received calls, and the structure was confirmed using 1H NMR and IR.
[1] L. Baiocchi, M. Giannangeli, Boll Chim Farm., 1974, 113, 152. [2] M. Jarema, D. Dudek, Psychiatria Polska, 2011, 750, 611. [3] T.G. Gant, S. Sarshar, US2009/209550 Auspex Pharmaceuticals Inc., 2009. [4] G. Palazzo, B. Silvestrini, US3381009, 1968.
127 The 10th Joint Meeting on Medicinal Chemistry 2017
P-52
PHENYLSULFONYL HYDRAZIDE DERIVATIVES AS NOVEL POTENT ANTI-INFLAMMATORY AGENTS
Hui Rak Jeong,[a] Sun Yeung Kim[a] and Jae Yeol Lee[a],*
[a] Department, Institution, Address Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, Republic of Korea * [email protected]
A novel series of phenylsulfonyl hydrazide derivatives were found to reduce LPS-induced PGE2 levels in RAW 264.7 macrophage cells via an inhibition of mPGES-1 enzyme. Recently, regioisomeric mixture of phenylsulfonyl hydrazide was formed depending on the reaction conditions. One regioisomer corresponds to a kinetic product (7a-c) and the other regioisomer corresponds to a thermodynamic product (8a-c). Among them, the structure of kinetic product 7b was confirmed by measuring single X-ray crystallography. In vitro PGE2 assay studies showed that the kinetic product (7a and 7b; IC50 = 0.69 and 0.55 μM against PGE2) is generally more potent than the thermodynamic product (8a and 8b; IC50 = > 10 and 0.79 μM against PGE2). A molecular docking study also exhibited that the kinetic product (7a) has a higher MolDock Score (-147.4) than that of 8a (-142.4), which is consistent with the PGE2 assay results. In vivo test was also carried out in two experimental edema models of rat, and the results clearly show that 7d has anti-inflammatory effects. A new potent phenylsulfonyl hydrazide (7d; IC50 = 0.06 μM against PGE2) without affecting COX-1 and COX-2 enzyme activities was identified based on these overall results.
128 The 10th Joint Meeting on Medicinal Chemistry 2017
P-53
DESIGN, SYNTHESIS AND EVALUATION OF INDOLE DERIVATIVES AS MULTIFUNCTIONAL AGENTS AGAINST ALZHEIMER’S DISEASE
Jacques Joubert, Ireen Denya and Sarel F. Malan
Pharmaceutical Chemistry, School of Pharmacy, University of the Western Cape, Bellville, South Africa
Alzheimer’s disease (AD) is one of many diseases that can be classified as a neurodegenerative disorder and is ranked as the leading cause of death among the elderly. The pathology of AD and other neurodegenerative disorders involves multiple steps leading to neuronal cell death. Current treatment options include cholinesterase- and monoamine oxidase-B inhibitors, calcium channel blockers and NMDA receptor antagonists. These treatment options, however, only alleviate the symptoms of these disorders and are devoid of any neuroprotective and/or neurorestorative properties that are needed for disease modifying effect. The result is a shift in research towards the design and discovery of multi-target compounds. This study is thus based on this one-drug-multiple- target paradigm and aims to produce a new series of indole derivatives with multifunctional activities. We hypothesize that these compounds will serve as dual cholinesterase and monoamine oxidase inhibitors and possess superior activity compared to existing anti-Alzheimer’s drugs. The novel indole derivatives were synthesized by means of nucleophilic substitution reactions. Structural elucidation was carried out using analytical techniques such as NMR, MS, and IR. Biological activity on MAO-A and MAO-B, acetyl- and butyrylcholinesterase enzymes were assessed and IC50 values were calculated. All compounds were successfully synthesized and confirmed. MAO-A and B inhibitory activities were tested at various concentrations with clorgyline and rasagiline as reference compounds. All the compounds showed satisfactory inhibition of both enzymes with some compounds showing low micromolar inhibitory activities. The compounds also showed promising cholinesterase inhibition sub-micromolar ranges. AD poses an enormous socio-economic burden on society and it is critical that research identifies compounds that are able to slow down or halt the progression of AD. This study identified novel multifunctional agents with potential neuroprotective properties that may be considered as new lead compounds/drug candidates against AD.
129 The 10th Joint Meeting on Medicinal Chemistry 2017
P-54
3,4-DIHYDROQUINAZOLINE DERIVATIVES AS NOVEL AND SELECTIVE BUTYRYLCHOLINESTERASE INHIBITORS
Da Woon Jung, Jin Han Kim, Hong Bin Yoon and Jae Yeol Lee*
Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, Republic of Korea * [email protected]
A series of 3,4-dihydroquinazoline derivatives consisting of the selected compounds from our chemical library on the diversity basis and the new synthetic compounds were in vitro tested for their inhibitory activities for both acetylcholinesterase (AChE, from electric eel) and butyrylcholinesterase (BChE, from equine serum) enzymes. It was discovered that most of the compounds displayed weak AChE and strong BuChE inhibitory activities. In particular, compound KYS05080F and KYS05090S were the most active compounds in the series against BChE with IC50 values of 45 nM and 62 nM, as well as 146- and 161-fold higher affinity to BChE, respectively. To understand the excellent activity of these compounds, molecular docking simulations were performed to get better insights into the mechanism of binding of 3,4-dihydroquinazoline derivatives. As expected, compound KYS05080F and KYS05090S bind to both catalytic anionic site (CAS) and peripheral site (PS) of BChE with better interaction energy values than AChE, in agreement with our experimental data. Furthermore, the non-competitive/mixed-type inhibitions of both compounds further confirmed their dual binding nature in kinetic studies.
130 The 10th Joint Meeting on Medicinal Chemistry 2017
P-55
HIGH-THROUGHPUT SCREENING FOR DIPEPTIDYL PEPTIDASE III-INTERACTING PROTEINS
Snježana Jurić,[a] Katarzyna Kliza,[b] Koraljka Husnjak[b] and Mihaela Matovina[a],*
[a] Ruđer Bošković Institute, Zagreb, Croatia [b] Goethe University School of Medicine, Institute of Biochemistry II, Frankfurt a/M, Germany * [email protected]
Dipeptidyl peptidase III (DPP III), the ubiquitously expressed member of the M49 family of metallopeptidases, cleaves dipeptides from the N-termini of 3 to 10 residues long peptides. Over the last decades, DPP III was primarily investigated at the biochemical and enzymatic levels, while its physiological roles remained largely unknown. Recent advances in DPP III research showed that direct binding of DPP III to Keap1 induces translocation of the transcription factor NRF2 from cytosol into the nucleus, thus initiating the transcription of oxidative stress protective genes. The possibility that DPP III interacts with other proteins in a similar fashion prompted us to investigate the DPP III interactome by using two high-throughput screening methods. Yeast two-hybrid screening of the universal standardized human cDNA library was set up to identify direct interactors of DPP III, whereas the SILAC-based immunoprecipitation of DPP III coupled to MS analysis was envisioned to identify the DPP III-containing protein complexes in the cell. We aim to discover the novel DPP III protein interactors and to confirm these interactions by several complementary approaches, such as pull-down assays and confocal microscopy techniques. Once confirmed, novel interactors might open new directions in the investigation of the DPP III physiological roles in the future.
131 The 10th Joint Meeting on Medicinal Chemistry 2017
P-56
IN VITRO, IN VIVO AND MOLECULAR MODELING STUDIES OF N-(3-{4- [3-(TRIFLUOROMETHYL)PHENYL]PIPERAZIN-1-YL}PROPYL)-1H- INDAZOLE-3-CARBOXAMIDE (D2AAK3) AS A POTENTIAL ANTIPSYCHOTIC
Agnieszka A. Kaczor,[a,b],* Katarzyna M. Targowska-Duda,[c] Marta Kruk-Słomka,[d] Andrea G. Silva,[e] Peter Kolb,[f] Antti Poso,[b] Grażyna Biała[d] and Marian Castro[e]
[a] Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Faculty of Pharmacy with Division for Medical Analytics, 4A Chodźki St., PL-20059 Lublin, Poland [b] School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, FI-70211 Kuopio, Finland [c] Department of Biopharmacy, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodzki St., PL-20093 Lublin, Poland [d] Department of Pharmacology and Pharmacodynamics, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodzki St., PL-20093 Lublin, Poland [e] Department of Pharmacology, Universidade de Santiago de Compostela, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Avda de Barcelona, E-15782 Santiago de Compostela, Spain [f] Department of Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, DE 35032 Marburg, Germany * [email protected]
Antipsychotics currently available to treat schizophrenia suffer several limitations: (1) they are efficient against positive but not negative and cognitive symptoms of the disease; (2) they help only a half of patients; (3) they have severe side effects including neurological and metabolic side effects. Thus, novel drugs to treat schizophrenia are highly demanded. We identified a novel dopamine D2 receptor antagonist, D2AAK3, with Ki of 115 nM using structure-based virtual screening. D2AAK3 possesses additional nanomolar or low micromolar affinity to D1, D3, 5-HT1A, 5-HT2A and 5-HT7 receptors, making it an ideal candidate for a multi-target drug. The compound has also some affinity to M1 and H1 receptors. Here we present homology modeling, molecular docking and molecular dynamics of D2AAK3 and its molecular targets and animal studies of D2AAK3 as a potential antipsychotic. The main contact of D2AAK3 and all the receptors studied is the electrostatic interaction between the protonatable nitrogen atom of the ligand and the conserved Asp(3.32) as typical for orthosteric ligands of aminergic GPCRs. We confirmed antagonistic/partial agonistic/agonistic properties of D2AAK3 towards the receptors in in vitro assays and in in silico studies as the ligand affects the ionic lock interaction. D2AAK3 decreases amphetamine-induced hyperactivity (when compared to the amphetamine-treated group) measured as spontaneous locomotor activity in mice. In addition, passive avoidance test demonstrated that D2AAK3 improves memory consolidation after acute treatment in mice. Elevated plus maze tests indicated that D2AAK3 induces anxiogenic activity 30 minutes after acute treatment, whereas this effect is reversed 60 minutes after administration of the studied compound in mice.
132 The 10th Joint Meeting on Medicinal Chemistry 2017
P-57
DIRECT PHOSPHONYLATION OF HETEROAROMATIC COMPOUNDS AS A MEAN TO SYNTHESIZE CYTOTOXIC AGENTS
Ewa Chmielewska,[a] Monika Prokopowicz,[a] Natalia Wojtowicz,[a] Joanna Wietrzyk,[b] Piotr Młynarz[a] and Paweł Kafarski[a],*
[a] Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland [b] Laboratory of Experimental Anticancer Therapy, Institute of Immunology and Experimental Therapy, ul. Rudolfa Weigla 12, 53-114 Wroclaw, Poland * [email protected]
The well-documented biological importance of heterocylic phosphonates has stimulated intensive efforts directed toward methods of their preparation.[1] Numerous studies have indicated that it is a challenging task, and quite frequently, yields of the applied procedures are moderate or even low.[2] In most cases the electron rich aromatic heterocycles easily undergo lithation in position 2 when alkyllithium was used. The formed salts are important intermediates in synthesis of many groups of organic compounds.[3] In this paper we describe elaboration of simple and almost one-pot procedure for the synthesis of heteroaromatic phosphonates by simple phosphonylation of lithium salts of corresponding heterocycles. A good example is procedure elaborated for lithiation of benzothiophene followed by diethyl chlorophosphite followed by oxidation of the resulting phosphinate (Figure 1).
Figure 1: Reaction of lithium benzothiophene with diethyl chlorophosphite
This reaction is of a general value and has been applied to a series of aromatic heterocycles. However, in some cases modification of this general procedure is required. This is well illustrated by phosphonylation of indole, which require specific protection of its amino moiety (Figure 2). Unfortunately hydrolysis of this product caused its decomposition.
Figure 2: Phosphonylation of indole
The obtained heteroaromatic phosphonates influence of proliferation of two cancer cell lines: of human breast cancer MCF-7 and of prostate cancer PC-3.
[1] K. Moonen, I. Laureyn, C. V. Stevens, Chem. Rev., 2004, 104, 6177. [2] S. Van der Jeught, C. Stevens, Chem. Rev., 2009, 109, 2672. [3] V. H. Gessner, C. Dächslein, C. Strohman, Chem. Eur. J., 2009, 15, 3320.
133 The 10th Joint Meeting on Medicinal Chemistry 2017
P-58
EVALUATION OF ANTIMYCOBACTERIAL ACTIVITY FOR A RANGE OF POLYCYCLIC AMANTADINE AND PENTACYCLOUNDECANE DERIVATIVES
Erika Kapp,[a] Jacques Joubert,[a] Samantha L. Sampson,[b] Margaretha de Vos[b] and Sarel F. Malan[a],*
[a] School of Pharmacy, Faculty of Natural Sciences, University of the Western Cape, Cape Town, South Africa [b] Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, University of Stellenbosch, Cape Town, South Africa * [email protected]
Ever-increasing levels of drug resistance in Mycobacterium tuberculosis necessitate novel approaches in the design of new antimycobacterials as well as the utilization of available treatment options. As part of a research project to evaluate modulating drug resistance in M. tuberculosis through strategies to increase intracellular accumulation of antimycobacterials, a range of compounds were selected from our compound library to be evaluated as possible efflux pump inhibitors in M. tuberculosis. The first phase of the research project was to determine the baseline antimycobacterial activity of the selected polycyclic amantadine and pentacycloundecane derivatives. A number of the compounds demonstrated significant antimycobacterial activity. This report describes the analysis of the antimycobacterial activity for the range of compounds with a preliminary investigation into possible mechanisms of action for the active molecules. Compounds were primarily selected based on their ability to inhibit voltage gated calcium channels and N-Methyl-D-Aspartate (NMDA) receptor channels as well as the recurrence of selected functional groups within the two classes. Consideration of previous data on resistance reversal in malaria was also factored into the selection. The structures of the selected compounds generally consisted of a cage moiety (oxa / aza-pentacycloundecane or adamantane) linked to an aromatic moiety (derivatives of benzyl, nitrobenzyl dansyl, quinoline, aniline and isoindole moieties) via various linkers. The 16 selected compounds were initially screened using the attenuated M. tuberculosis H37Rv leuD panCD strain (SAMMtb). SAMMtb was transformed with the fluorescent marker pCHERRY3 (Addgene). Mycobacterial growth was assessed over the course of 5 days through fluorescence measurement. Antimycobacterial activity was confirmed employing the same assay method in the standard laboratory strain, M. tuberculosis H37Rv. Good correlation was observed between levels of activity measured in SAMMTb and H37Rv. Repeat analyses were completed for the six most active compounds. Minimum inhibitory concentrations (MIC99) for all 16 compounds were determined independently and also showed good correlation to levels of activity observed in fluorescent assays. Six of the polycyclic compounds screened showed significant antimycobacterial activity (MIC99 ranging from 9.6 µM to 82.2 µM). Interestingly, during MIC determination only one compound, a benzyl-azapentacycloundecane, showed prominent activity in media where glycerol is the primary carbon source (Gaste Fe), whereas significant activity for the quinoline derivative was limited to standard 7H9 glucose rich media. The dansyl, 2,4-dintroaniline and cyanoisoindole structures showed comparable MIC values in both rich and poor media. Results confirm that SAMMtb is an appropriate model to identify compounds with possible activity against M. tuberculosis and point towards different mechanisms of antimycobacterial action, likely linked to the side chains of the compounds rather than the lipophilic scaffold.
134 The 10th Joint Meeting on Medicinal Chemistry 2017
P-59
DEVELOPMENT OF A DISINFECTANT PRODUCT CONTAINING THE ESSENTIAL OIL EXTRACTED FROM ROSMARINUS OFFICINALIS L.
Fetta Kessal,[a],* Amina Dahmoune,[b] Amina Azzam,[c] Boumrar Silia[d] and Boualem Samia[d]
[a] Laboratory of pharmaceutical industry, University Mouloud Mammeri of Tizi Ouzou, Algeria [b] Botanical Laboratory, University Mouloud Mammeri of Tizi Ouzou, Algeria [c] Laboratory of microbiology, University Mouloud Mammeri of Tizi Ouzou, CHU Nedir Mohamed Algeria [d] Department of pharmacy, University Mouloud Mammeri of Tizi Ouzou, Algeria. * [email protected]
Background and aim: Algeria, for its location, offers a rich and diverse vegetation. A big number of aromatic plants grow spontaneously. To this end, and as part of the valorization of the Algerian flora, we became interested in Rosemary (Rosmarinus officinalis L.) because of its wide availability at the University Mouloud Mammeri but especially of the antimicrobial effect of essential oil proved particularly against germs of mostly hand-transmitted infections. In the present study, an attempt was made to formulate a gel for hands’ hygiene in hospital, containing Rosmarinus officinalis L. essential oil and was evaluated for its antimicrobial activity. Methods: The Rosemary essential oil is extracted by hydrodistillation from its leaves with a yield of 1.45%. In parallel, a pharmaceutical gel was formulated and optimized basing on the results of the effected controls like pH, density, microbiological quality, skin irritation test and spreadability. The essential oil was analyzed by GC/MS then introduced into a gel which will be evaluated microbiologically. Results: The hydrodistillation gives a yield of 1.45%. GC/MS has shown a chemotype verbenone/camphor/α-pinene and has identified 65 components representing 97.86% of the essential oil. The evaluation of its antimicrobial activity has revealed a sensitivity of Staphylocococcus aureus, Enterococcus faecalis, Escherichia coli, Acinetobacter baumanii and Candida albicans, while Pseudomonas aeruginosa was resistant to this oil. The CMI (Inhibiting Microbial Concentration) were between 0.5% (v/v) and 1% (v/v), and the MBC (Microbial Bactericide Concentration) were ≥ 1% (v/v). The essential oil was incorporated at a concentration of 2%. The last step of our work will be to assess in vitro antimicrobial activity gel formulated with essential oil of Rosemary against the same pathogens. Conclusion: The gel showed promising antibacterial and antifungal activity against studied germs. Keywords: Essential oil, Rosemary, disinfectant gel, hands’ hygiene, antimicrobial activity.
[1] T. Lograda, M. Ramdani, P. Chalard, G. Figueredo, Global J. Res. Med. Plants & Indigen. Med., 2014, 3(6), 232. [2] N. Bousbia, Extraction des huiles essentielles riches en anti-oxydants à partir de produits naturels et de co-produits agroalimentaires. El Harrach: Ecole Nationale Supérieure Agronomique; Aix-Marseille : Université d’Avignon; 2011. [3] Z. Faixova, S. Faix, Folia vet., 2008, 52, 135. [4] A. Pandey, J.V. Jagtap, S.A. Polshettiwar, Int. J. Pharm. Pharm. Sci., 2011, 3, 234.
135 The 10th Joint Meeting on Medicinal Chemistry 2017
P-60
DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF D-RING OPENED 17-β ESTRADIOL ANALOGUES AS ESTROGEN RECEPTOR SUBTYPE-SELECTIVE LIGANDS
Sun Young Lee,[a] Yun Seon Song,[a] Minsun Chang[b] and Hee-Doo Kim[a],*
[a] College of Pharmacy, Sookmyung Women’s University, Yongsan-Ku, Seoul, 04310, Korea [b] Division of Biological Science, Sookmyung Women’s University, Seoul, 04310, Korea * [email protected]
Since the discovery of the estrogen receptor subtype beta (ER beta), the search for subtype selective estrogen receptor modulators (SERMs) has attracted attention in an attempt to achieve an advantage over non-subtype selective SERMs.[1] ER subtype-selective ligands could be valuable to manage various pathological conditions such as cancer, neuropathies, cardiovascular disease, osteoporosis, and metabolic disorders.[2] Although the ligand binding domains of ER alpha and ER beta share only modest homology (58% identity), their ligand binding cavities are highly conserved, differing by only two amino acid residues.[3] While this slight difference in the binding cavities poses a great challenge in developing ER subtype-selective ligands, medicinal chemistry efforts in recent years have yielded a number of structural motifs with impressive subtype selective SERMs.[4] As a part of our program to develop novel subtype-selective SERMs, we present here the ER subtype-selective ligands with a novel oxime scaffold that resembles 17 beta-estradiol (E2), but with the D-ring opened. Because scaffold hopping is one of the important approaches in discovering structurally new compounds by starting from known compounds, we planned to deconstruct the D- ring of E2 to make it jump into different chemical space of E2-related ER ligands. We also envisioned that conformational flexibility resulting from the D-ring opening might enhance the ligand’s ability to recognize the slight difference in the binding cavities between the two receptors subtypes. The biological activities and the selectivity for the receptor subtype of new oxime analogues as well as their prototype D-ring opened E2 analogue have been studied by radioligand competitive binding assay and cell-based transcription assays. In summary, our approach is successful to generate the novel and promising scaffold with subnanomolar concentrations range of EC50 and higher subtype-selectivity than E2 and we propose that they may serve the lead structure to develop subtype-selective ER ligands useful in treating ER and/or estrogen-associated diseases.
[1] S. Mosselman, J. Polman, R. Dijkema, FEBS Lett., 1996, 392, 49. [2] G. G. Kuiper, J. A. Gustafsson, FEBS Lett., 1997, 410, 87. [3] A. C. Pike, A. M. Brzozowski, R. E. Hubbard, T. Bonn, A. G. Thorsell, O. Engstrom, J. Ljunggren, J. A. Gustafsson, and M. Carlquist, EMBO J., 1999, 18, 4608. [4] G. H. Veeneman, Curr. Med. Chem., 2005, 12, 1077.
136 The 10th Joint Meeting on Medicinal Chemistry 2017
P-61
SYNERGISTIC ANTICANCER EFFECT OF T-TYPE CALCIUM CHANNEL BLOCKER AND CHEMOTHERAPEUTIC AGENTS IN HUMAN LUNG CANCER
Jin Han Kim, Hong Bin Yoon, Da Woon Jung and Jae Yeol Lee*
Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, Republic of Korea * [email protected]
We synthesized new 3,4-dihydroquinazoline derivative containing ureido group, KCP10043F and evaluated for T-type calcium channel inhibitory activity, cytotoxicity, and cell cycle arrest against human lung cancer (A549) cells. KCP10043F showed both weaker T-type Ca2+ channel inhibitory activity and less cytotoxicity against A549 cells than parent compound KYS05090S [4- (benzylcarbamoylmethyl)-3-(4-biphenylyl)-2-(N,N’,N’-trimethyl-1,5-pentanediamino)-3,4- dihydroquinazoline 2 hydrochloride], but it exhibited more potent G1-phase arrest than KYS05090S in A549 cells. This was found to be accompanied by the downregulations of cyclin-dependent kinase (CDK) 2, CDK4, CDK6, cyclin D2, cyclin D3, and cyclin E at the protein levels. However, p27KIP1 as a CDK inhibitor was gradually upregulated at the protein levels and increased recruitment to CDK2, CDK4 and CDK6 after KCP10043F treatment. Based on the strong G1-phase cell cycle arrest of KCP10043F in A549 cells, the combination of KCP10043F with etoposide (or cisplatin) resulted in a synergistic cell death (combination index = 0.2–0.8) via the induction of apoptosis compared with either agent alone. Taken together with these overall results and the favorable in vitro ADME (absorption, distribution, metabolism, and excretion) profiles of KCP10043F, therefore, it could be used as a potential agent for the combination therapy on human lung cancer.
Figure: Structures of T-type Ca2+ channel inhibitor and chemotherapeutic drug.
137 The 10th Joint Meeting on Medicinal Chemistry 2017
P-62
DISCOVERY OF PHENYLSULFONYL HYDRAZIDE DERIVATIVES AS NOVEL AND SELECTIVE mPGES-1 INHIBITORS
Sun Young Kim, Hui Rak Jeong and Jae Yeol Lee*
Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, Republic of Korea * [email protected]
A novel series of phenylsulfonyl hydrazide derivatives, which were derived from the high throughput screening hit compound 1 (IC50 = 5700 nM against PGE2 production), for a potent inhibitor of mPGES-1 is described. Compound 8n turned out to be most potent lead compound with IC50 value of 4.5 nM and 6.9 nM , respectively, against LPS-1 induced PGE2 and NO production in RAW 264.6 macrophage cells. In addition, 8n was about 30- and > 150-fold more potent against mPGES-1 enzyme in a cell-free assay (IC50 = 70 nM) than MK-886 and hit compound 1, respectively. Molecular docking suggests that compound 8n could inhibit PGE2 production by blocking the PGH2 binding site of human mPGES-1 enzyme.
138 The 10th Joint Meeting on Medicinal Chemistry 2017
P-63
RUTHENIUM-BASED CATALYSTS FOR ASYMMETRIC TRANSFER HYDROGENATION
Andrea Kišić,[a] Michel Stephan,[b] Barbara Mohar,[a],* Andrej Emanuel Cotman[a] and Dominique Cahard[c]
[a] National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, Slovenia [b] PhosPhoenix SARL, 115, rue de l’Abbé Groult, 75015 Paris, France [c] Université de Rouen, F-76821 Mont Saint Aignan, France * [email protected]
The importance of asymmetry in medicinal chemistry can be understood when we know that 80% of all pharmaceuticals on the market (2006) are chiral molecules among which 75% are single enantiomers. Many biologically active compounds or organic building-blocks used by the pharmaceutical industry consist of chiral secondary alcohols wherein the stereogenic carbon bears a hydrogen atom and a hydroxyl group. A convenient asymmetric chemical transformation for obtaining chiral secondary alcohols is the enantioselective reduction of their corresponding prochiral ketones which are widely available or easy to synthesize. Such reduction can be catalytically performed by the use of metal complexes of enantiopure organic ligand molecules. 6 ansa-Ru(II) complex wherein the -arene is alkylene-tethered to R2NSO2DPEN from the N'-terminal (Figure 1), and their asymmetric transfer hydrogenation (ATH) results against various types of prostereogenic aryl ketones is presented (Figure 2).[1,2]
Me (CH2)n N SO2NR2 O2S Ph N H Ph N Ru R' Ru Rn NR = NMe , N NPh 2 2 Ph N Cl n = 2, 3 H n = 3, 4 H2 n Rn = H, Me, iPr R' = H, Me, iPr ansa-Ru(II) complex I ansa-Ru(II) complex II
Figure 1: Ansa-ruthenium(II) complexes of multidentate ligands.
Figure 2: Various classes of aryl ketones and stereoarrayed CF3-substituted 1,3-diols evaluated in Ru(II) catalyzed ATH.
[1] A. Kišić, M. Stephan, B. Mohar, Adv. Synth. Catal., 2015, 357, 2540. [2] A. E. Cotman, D. Cahard, B. Mohar, Angew. Chem. Int. Ed., 2016, 55, 5294.
139 The 10th Joint Meeting on Medicinal Chemistry 2017
P-64
THE PREPARATION OF THE FOUR STEREOISOMERS OF 16- HYDROXYMETHYL-13-EPI-ESTRA-1,3,5(10)-TRIEN-17-OL-3-METHYL-, AND 3-BENZYLETHERS
Anita Kiss,* János Wölfling and Gyula Schneider
Department of Organic Chemistry, University of Szeged, Dóm tér 8., Szeged, Hungary, H-6720 * [email protected]
In connection with our earlier investigations,[1,2] we are interested in compounds with an inverted configuration at C-13, i.e. derivatives of 16-hydroxymethyl-13-epi-estra-1,3,5(10)-trien-17-one-3- methyl, and 3-benzylether containing a cis junction of rings C and D. The natural estrone and its derivatives have hormonal effect, which could be a disadvantage during the development of new anticancer drug candidates, while the epi-estrone and its derivatives show no estrogen properties at all. Treatment of 2 and 4 with sodium methoxide and ethyl formate on Claisen condensation gave 5 and 6. The formyl compounds 5a and 6a were reduced with potassium borohydride in methanol to give 7a, 8a and 9a, 10a, respectively. Two new chiral centers were formed in this reaction, but only the two trans isomers of the possible four isomers could be obtained, in 6:1 ratio. After selective acetylation and Jones oxidation of the separated isomers resulted the 16α-hydroxymethyl-17-keto-, and the 16β-hydroxymethyl-17-keto compounds (11, 12 and 13, 14). The Luche reduction of 11 and 13 gave the 16-hydroxymethyl-17α -hydroxy isomers 15 and 17. The reduction of 12 and 14 with potassium borohydride in methanol resulted the 16β-hydroxymethyl-17β-hydroxy isomers (16 and 18). For confirmation of the configurations assumed for 15, 17 and 16, 18 transformation were carried out with the individual isomers. The O O O OR2 isomers resulted the corresponding 16-bromo-, and 16-iodomethyl H H H H H H H H H derivatives in Appel reaction. On 1 1 1 R O R O R O 2 1 5, 6 R 1 R1=Me 2 R =Me 5 R1=Me alkaline methanolysis of 19a,b; 21a,b 1 a H 3 R1=Bn 4 R =Bn 6 R1=Bn and 20a,b; 22a,b the β oxetanes 23, b Ac
25 and 24, 26 condensed to the D-ring OH OAc OH OAc O OAc O OAc in the sterane were formed. The + process can be regarded as a 6 : 1 H H H H 1 1 1 neighbouring group participation 7 R1=Me 8 R =Me 11 R =Me 12 R =Me 1 1 14 R1=Bn characterized by the general symbol 9 R1=Bn 10 R =Bn 13 R =Bn – (O 4). Despite to the trans isomers 7, 8, 9, 10 R2 R3 a H H OR3 OR2 OR3 OR2 (7a-10a), the cis isomers gave the b Ac H c Ac Ac corresponding acetonides (15c-18c) H H and phenylboronate esters (15d-18d) 15, 16, 17, 18 R2 R3 H H H H 1 1 a H H R O R O 1 too. The investigations of b Ac Ac 15 R1=Me 16 R =Me 1 17 R1=Bn 18 R =Bn antiproliferative activites of the c H3C CH3 C structurally related compounds are in Ph O O progress. d B CH2 1 CH2 23 R1=Me 24 R =Me 2 3 1 19, 20, 21, 22 X = R , R = H 25 R1=Bn 26 R =Bn a Br H H b I
[1] E. Mernyák, J. Wölfling, G. Bunkóczi, L. Luo, T. R. Schneider, Gy. Schneider, Chech. Chem. Comm., 2003, 68, 1141. [2] J. Wölfling, E. Mernyák, É. Frank, G. Falkay, Á. Márki, R. Minorics, Gy. Schneider, Steroids, 2003, 68, 277.
140 The 10th Joint Meeting on Medicinal Chemistry 2017
P-65
DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF CXCR3 AND CXCR4 MODULATORS WITH PYRAZOLOPYRIDINE SCAFFOLD
Anja Kolarič,[a,b] Urban Švajger,[c] Tihomir Tomašič,[b] Nikola Minovski,[a] Nuška Tschammer[d] and Marko Anderluh[b]
[a] Department of Cheminformatics, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia [b] Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia [c] Blood Transfusion Center of Slovenia, Šlajmerjeva 6, 1000 Ljubljana, Slovenia [d] Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany * [email protected]
The overexpression of chemokine receptors CXCR3 and CXCR4 was linked to severe diseases such as inflammation, autoimmune diseases, transplant rejection, cancer and HIV.[1] These receptors are found to be natural allosteric proteins, where small molecule modulators can modify the binding and function of chemokines.[2] Based on the previously published dual negative allosteric modulator of chemokine receptors CXCR3 and CXCR4 (Figure),[3] we designed, synthesized and biologically characterized a set of novel negative allosteric modulators with preserved pyrazolopyridine scaffold, connected with lipophilic moiety of the molecule through three different linkers. The ability of negative modulation has been evaluated by three biological assays (β-arrestin 2 recruitment assay, BRET-based cAMP assay and the transwell migration assay) on both chemokine receptors. We have successfully identified dual binders (27), as well as compounds selective for either one of the receptors (Figure), able to negatively modify chemokine-mediated signaling. Furthermore, initial structure-based calculations were performed in order to predict binding mode and identify crucial interactions for establishment of structure-activity relationship, which will help in the on-going drug discovery research of chemokine receptor small molecules.
Figure: Formula of previously published dual negative CXCR3 and CXCR4 allosteric modulator with structure fragmented into 3 building blocks that constitute a focused library of novel pyrazolopyridine CXCR3 and CXCR4 modulators.
[1] F. Balkwill, Nat. Rev. Cancer, 2004, 4, 540. [2] D. Wootten, A. Christopoulos, P. M. Sexton, Nat. Rev. Drug Discov., 2013, 12, 630. [3] D. Schmidt, V. Bernat, R. Brox, N. Tschammer, P. Kolb, ACS Chem. Biol., 2014, 10, 715.
141 The 10th Joint Meeting on Medicinal Chemistry 2017
P-66
CHEMICAL PROTEOMICS IN THE EVALUATION OF THE EGFRI LAPATINIB PHARMACOLOGY
Tatjana Kovačević,* Krunoslav Nujić and Milan Mesić
Fidelta Ltd. Prilaz baruna Filipovića 29, 10000 Zagreb, Croatia * [email protected]
Understanding drug interaction with a biological target and the mechanism of action is important in modern drug discovery. However, testing all unknown-targets is challenging as either target prediction is poor or vast off-target screening campaigns are expensive. This work is focused on the identification of potential anti/off-targets of lapatinib, inhibitor of EGFR and ErbB2.[1,2] In this chemical proteomics approach lapatinib was modified with specific tags that can be used for identification of proteins in cell lysate.[3]
Scheme 1: Proposed tagged analogue of an EGFRi based on protein-ligand x-ray structure.
The poster will show analogues of lapatinib with various linkers and functionalities (amino group, click chemistry motifs and finally the dual tags with photoaffinity labelling group) that were prepared (Scheme 1). These inhibitors were used in the protein fishing experiments using SKBR3, T47D and A431 cell lysates. Initially, the lapatinib dual tag was linked to a matrix using click chemistry. Proteins from the lysate that has the highest affinity to the tagged lapatinib are covalently bound to it using UV illumination (Scheme 2) and unbound are washed out. Finally, captured proteins are identified using MALDI-TOF after in-gel or in-solution tryptic digestion.
PRG PRG PRG UV =365 MATRIX MATRIX P MATRIX P ligand ligand
ligand
Scheme 2: The two step process of link dual tagged lapatinib to unknown proteins.
We will report the finding that modified lapatinib (dual tag) identified the expected EGFR protein in cell lysates. We will also report four putative protein targets that bound our modified ligand. Interestingly, these proteins are not kinases. Future work will involve validation of those proteins as new potential targets or anti-targets of lapatinib with various biochemical and cellular assays.
[1] K. Petrov et al., Bioorg. Med. Chem. Lett., 2006, 16, 4686. [2] C. Yewale et al., Biomaterials, 2013, 34, 8690. [3] J. Wang et al., Pharmacol. Ther., 2016, 162,10.
142 The 10th Joint Meeting on Medicinal Chemistry 2017
P-67
MEDICAL CHEMICAL DEFENCE AGAINST CHEMICAL NERVE AGENT THREATS
Zrinka Kovarik, Nikolina Maček-Hrvat and Tamara Zorbaz
Institute for Medical Research and Occupational Health, Ksaverska cesta 2, Zagreb, Croatia * [email protected]
The high toxicity of organophosphorus compounds (OP; tabun, sarin, VX, cyclosarin and soman) originates from the irreversible inhibition of acetylcholinesterase (AChE), an essential enzyme in cholinergic neurotransmission. Poisonings that lead to life-threatening toxic manifestations call for immediate treatment, which usually consists of a combined administration of anticholinergic drugs and an aldoxime as the reactivator of AChE. Finding an optimal reactivator for prophylaxis against and post-treatment of OP toxicity is a continuing challenge. We identified several oximes with significantly improved human AChE reactivating efficacy against several OP and antidotal efficacy in mice when compared to standard reactivators. Further ex vivo testing of selected oximes and AChE mutants confirmed efficient oxime-assisted catalytic bioscavenging and neutralizing of OP exposure in whole blood. Therefore, our findings offer a platform for further antidote and scavenger development for nerve agents exposure.
Acknowledgments: Supported by the Croatian Science Foundation (4307).
143 The 10th Joint Meeting on Medicinal Chemistry 2017
P-68
ANTITUMOR ACTIVITY OF ANTHROLS THAT PHOTOCHEMICALLY GENERATE QUINONE METHIDES OR REACTIVE OXYGEN SPECIES AND THEIR SELECTIVITY TOWARDS CANCER STEM CELLS
Lidija Uzelac,[a] Đani Škalamera,[b] Kata Mlinarić-Majerski,[b] Nikola Basarić[b] and Marijeta Kralj[a],*
[a] Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia [b] Department of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, 10000 Zagreb, Croatia * [email protected]
Cancer stem cells (CSCs) are a subpopulation of cancer cells that share properties of embryonic stem cells like pluripotency and self-renewal. They are responsible for tumor formation, relapse and metastasis and also exhibit resistance to a whole range of drugs with different cellular targets. Mechanisms of resistance include enhanced survival pathways, increased activation of drug efflux pumps and enhanced capability for reactive oxygen species (ROS) defense. Targeting CSC, rather than cancer cells in general, is a novel and highly promising strategy for cancer treatment.[1,2] As a result of current treatments failing to target CSCs, novel therapies such as photodynamic therapy (PDT) are being investigated. PDT involves the treatment of cancer cells with an inactive and nontoxic photosensitizer (PS), which is activated by light with specific wavelength, matching its absorbance spectrum. This leads to reactive oxygen species (ROS) generation, which causes cancer cell death. Further development of cancer treatment approaches and search for new targets and compound leads, requires discovery and elucidation of novel phototherapy mechanisms on molecular level. A promising group of phototherapeutic agents are reactive intermediates - quinone methides (QMs). One of the methods for the generation of QMs is photodehydration or phototautomerization of phenol derivatives.[3,4] The objective of the proposed research is to test anticancer potential of anthracene derivatives 1-4 that can generate either QMs, or ROS upon the irradiation with near visible light at λ > 400 nm. Special attention was put to demonstrate the potential selectivity of these compounds towards the cells with CSC-like properties. We performed a detailed photochemical and photobiological investigation on anthrol derivatives 1-4. While upon the excitation 1-2 can give QMs, 3-4 cannot undergo photodehydration and deliver QM, but lead to the singlet oxygen formation. Their activity was tested on a panel of human tumor cell lines (HCT116, MCF-7, H460 and SUM 159), as well as on a unique transgenic CSC model (HMLEshEcad/HMLEshGFP).[2] The antiproliferative ability was tested by MTT assay, colony formation assay, and cell cycle analysis. Confocal microscopy was used to demonstrate the localization of compounds in the cells, and ROS measurements were conducted to evaluate the ability of 3 and 4 to induce oxidative stress. We demonstrated an intriguing cytotoxic activity of 1 R = OH, R = CH OH R1 1 2 2 anthrols, and selectivity towards CSC cell model of those 2 R1 = OH, R2 = CPh2OH 3 R1 = OH, R2 = H that produced ROS. This study forms the basis for R 2 4 R1 = H, R2 = CH2OH further research on cancer phototherapy, as well as for the elucidation of CSC selectivity based on oxidative stress activation.
[1] L.V. Nguyen, R. Vanner, P. Dirks, C.J. Eaves, Nat. Rev. Cancer, 2012, 12,133. [2] P.B. Gupta, T.T. Onder, G. Jiang, K. Tao, C. Kuperwasser, R.A. Weinberg, E.S. Lander, Cell, 2009, 138, 645. [3] N. Basarić, K. Mlinarić-Majerski, M. Kralj, Curr. Org. Chem., 2014, 18, 3. [4] M. Kralj, L. Uzelac, Y-H. Wang, P. Wan, M. Tireli, K. Mlinarić-Majerski, I. Piantanida, N. Basarić, Photochem. Photobiol. Sci., 2015, 14, 1082.
144 The 10th Joint Meeting on Medicinal Chemistry 2017
P-69
SURFACE INTERACTIONS BETWEEN OLIGOPEPTIDE DERIVATIVES OF SALICYLIC ACID AND CALCITE AS A MODEL OF AN INORGANIC DRUG DELIVERY SYSTEM
Marko Ukrainczyk,[a] Lara Štajner,[a] Zlatko Brkljača,[a,b] Robert Stepić,[c] David Smith,[a] Ana Sunčana Smith,[a,c] Matija Gredičak,[a] Ivanka Jerić,[a] Andreja Jakas[a] and Damir Kralj[a],*
[a] Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia [b] University of Zagreb, Croatia [c] FA University, Erlangen, Germany * [email protected]
Targeted or sustained drug delivery is a promising strategy for improving the therapeutic efficiency of existing active pharmaceutical molecules. Typically, liposomal, micellar or biodegradable polymeric matrices are used for encapsulation of model drug molecules and/or design of new drug delivery systems. Recently, however, porous inorganic materials have been proposed as suitable carriers. Calcium carbonate is a rather common mineral, which has been considered as a mineral drug carrier due to recognized biocompatibility, nontoxicity and biodegradability. Indeed, it has been suggested that CaCO3 may significantly improve drug stability and bioavailability, as well as to control the release of active compounds by influencing their desorption and/or dissolution rates. However, the understanding of the basic molecular interactions of model pharmaceutical compounds with mineral surfaces is a critical step in the development of efficient CaCO3 based hybrid materials that could be used as biocompatible carriers in drug delivery systems. Previously, we studied the molecular interactions between well defined calcite surfaces and salicylic acid (Sal), as well as its derivatives, which were selected as a simple models of anti-inflammatory drug substances.[1,2] The inspiration for derivatization of salicylic acid molecules with glutamic acid (Glu) or aspartic acid (Asp) is taken from the process of biomineralization, in which organic-inorganic hybrid materials are composed of CaCO3 polymorphs (calcite or aragonite) and Asp-rich acidic glycoproteins. The synthesized amino acid adducts with Sal exerted significantly enhanced binding to specific calcite surfaces, in comparison to free Sal. The aim of this study is to design new salicylic acid adducts, which should be biocompatible and water-soluble. The adducts should also enable stronger Sal binding by means of multiple carboxylic groups, while the linkers should be easily cleaved after binding to CaCO3 surface. Thus, we designed and synthesized 6 tripeptides (L-Asp-L-Asp-L-Asp; D-Asp-D-Asp-D-Asp; L-Asp-D-Asp-L-Asp; L-Asp- Gly-L-Asp; L-Asp--Ala-L-Asp and L-Asp-Gly-D-Asp), as well as the respective adducts with salicylic acid (Sal-Gly-L-Asp-D-Asp-L-Asp; Sal-L-Asp-D-Asp-L-Asp; Sal-Gly-L-Asp-L-Asp-L-Asp and Sal-L- Asp-L-Asp-L-Asp) in order to test the efficiency of their binding with rhombohedral calcite crystals bounded by the stable {1 0 4} faces. The efficiency has been correlated with the number of carboxylic groups, their orientation in space, charge separation effect and chirality of α-carbon atom. The qualitative compliance of the results of molecular dynamics calculations (MD) of binding energies -1 3 -1 (Eb = -755 kJ mol ) and the Langmuir adsorption constants (Kad = 0.56 dm mmol ), determined from the crystal growth kinetics of calcite crystals in the presence of respective adducts, indicated the strongest interactions of L-Asp-D-Asp-L-Asp. Similarly, the MD and the crystal growth kinetic data 3 –1 showed the strongest surface interactions of Sal-Gly-L-Asp-D-Asp-L-Asp (Kad = 1.58 dm μmol ). The obtained results and proposed systematic approach (MD and crystal growth kinetics) can contribute to a better understanding of molecular interactions between model drug derivatives containing carboxylic functional groups with mineral surfaces, thus being the basis for the design of efficient mineral drug delivery systems.
[1] M. Ukrainczyk, M. Gredičak, I. Jerić, D. Kralj, J. Colloid Interface Sci., 2012, 365, 296. [2] M. Ukrainczyk, M. Gredičak, I. Jerić, D. Kralj, Cryst. Growth Des., 2014, 14, 4335.
145 The 10th Joint Meeting on Medicinal Chemistry 2017
P-70
OLIGOTUFTSIN-BASED CARRIERS FOR NOVEL ANTIMYCO- BACTERIAL ACTIVE AGENTS AND THEIR CONJUGATES
Martin Krátký,[a],* Zsuzsa Baranyai,[b] Szilvia Bősze,[b] Nóra Szabó[c] and Jarmila Vinšová[a]
[a] Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic [b] MTA-ELTE Research Group of Peptide Chemistry, Pázmány Péter Sétány 1/A, Budapest, H-1117, Hungary, P.O. Box 32, 1518 Budapest 112, Hungary [c] Laboratory of Bacteriology, Korányi National Institute for Tuberculosis and Respiratory Medicine, Pihenő út 1, Budapest, H-1122, Hungary * [email protected]
The global tuberculosis epidemic and increasing emergence of drug-resistant Mycobacterium tuberculosis (Mtb.) strains as well as non-tuberculous mycobacteria (NTM) call for intensive research on novel therapeutic interventions. Drug delivery systems (DDS) may help to overcome inconvenient properties of bioactive molecules, e.g., poor solubility, bioavailability or selectivity. Additionally, they are useful in targeted drug delivery.[1] We selected tuftsin-based oligopeptides as potential carriers for small antimycobacterial active molecules. Tuftsin derivatives are non-toxic, non-immunogenic and biodegradable. They also enhance immune response and target macrophages specifically, thus increasing cellular uptake, activity and reducing toxicity.[2,3] A pilot study with isoniazid indicates that this concept is viable.[2] Salicylanilides (2-hydroxy-N-phenylbenzamides) have exhibited interesting antimicrobial properties including drug-resistant Mtb. and NTM (MIC ≥ 0.5 µM), but their potential use is prevented due to limited solubility and comparatively higher toxicity.[4] These obstacles can be overcome, i.a., by employment of DDS. That is why salicylanilides bearing a carbonyl group were selected as model compounds for the evaluation of oligotuftsine carriers. Oligotuftsin-based carriers ([TKPKG]n, n=1-4) were synthesized by solid-phase synthesis (Fmoc/tBu strategy, rink amide MBHA resin, diisopropylcarbodiimide/HOBt, NMP). N-Terminus and/or side chain lysine ε-amino group(s) were substituted to obtain carriers with various properties. Carboxylic acids (acetic, succinic, palmitic etc.) modify lipophilicity, short peptide spacers (G5, GFLG cleavable by cathepsin B) were used to control the cellular site where the drug is released, whereas fluorescein enables to determine cellular uptake by flow cytometry and fluorescent microscopy. One or more aminooxyacetic acid molecule(s) were coupled with peptides to provide a reactive group for the attachment of active molecules. After these modifications, peptide carriers were cleaved from the resin TFA and purified. Then, carriers were coupled with salicylanilide derivatives to form acid stable oxime bond. Novel conjugates were purified and characterised.[3] Generally, salicylanilide-oligotuftsin conjugates exhibited a significant extracellular antimyco- bacterial activity including against drug-resistant Mtb. Moreover, they are more effective against intracellular mycobacteria than parent salicylanilides. Cellular uptake was enhanced substantially, too, together with decreased cytostatic and cytotoxic effects on mammalian cells. In conclusion, our tuftsine peptides are perspective carriers for antimycobacterial agents.
Acknowledgments: This work was supported by the Czech Science Foundation project No. 17- 27514Y.
[1] G. Tiwari, R. Tiwari, et al., Int. J. Pharm. Invest., 2012, 2, 2. [2] K. Horvati, G. Mezo, et al., J. Pept. Sci., 2009, 15, 385. [3] Z. Baranyai, M. Krátký, et al., Eur. J. Med. Chem., 2017, under revision. [4] Z. Baranyai, M. Krátký, J. Vinšová, et al., Eur. J. Med. Chem., 2015, 101, 692.
146 The 10th Joint Meeting on Medicinal Chemistry 2017
P-71
NOVEL 1,2,3-TRIAZOLYL-7-SUBSTITUTED COUMARINS AND BIS(COUMARIN-TRIAZOLYL)BENZENES: SYNTHESIS, PHOTOPHYSICAL PROPERTIES AND CYTOSTATIC EVALUATION
Kristina Bobanović,[a] Ema Horak,[a] Lidija Furač,[a] Marijeta Kralj,[b] Lidija Uzelac,[b] Ivana Murković Steinberg[a] and Svjetlana Krištafor[a],*
[a] Department of General and Inorganic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, 10000 Zagreb, Croatia [b] Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia * [email protected]
Coumarins, with the structure of benzopyrone, are widely studied heterocyclic structures in the fields of biology, medicine, perfumes, cosmetics and environmental chemistry. The favourable photophysical properties validated coumarin derivatives as fluorescent probes in cellular imaging and as good chemosensors of some transition metal ions essential for human health. In addition, “click”-derived 1,2,3-triazole has become a very common motif from the biological fields to the material sciences. It can interact with biological molecules, organic and inorganic surfaces and materials. Triazole rings have been used as components of fluorogenic probes and as chelating ligands in fluorescent metal sensors.[1] Herein, we report the synthesis, spectroscopic study and cytostatic evaluation of some novel coumarin-triazole conjugated heterocycles as well as 1,3- and 1,4-bis(coumarin-triazolyl)benzenes based on Cu(I)-catalyzed azide-alkyne cycloaddition reaction (Figure).
Figure: 1,2,3-Triazolyl-substituted coumarins (1) and 1,3- and 1,4-bis(coumarin-triazolyl)benzenes (2).
All synthesised compounds are tested against human carcinoma cell lines. Interaction of some representatives with ct-DNA is also studied by UV-vis and fluorescence spectroscopy. In order to reveal the influence of substitutions at position 7 of coumarin probes on their pH and metal ion sensing properties, detailed spectroscopic titrations are performed and fluorescence intensity changes are discussed as part of our ongoing research.[2]
[1] a) C. Le Droumaguet, C. Wang, Q. Wang, Chem. Soc. Rev., 2010, 39, 1233.; b) Y. H. Lau, P. J Rutledge, M. Watkinson, M. H. Todd, Chem. Soc. Rev., 2011, 40, 2848. [2] M. Hranjec, E. Horak, D. Babić, S. Plavljanin, Z. Srdović, I. Murković Steinberg, R. Vianello, N. Perin, N. J. Chem., 2017, 41, 358.
147 The 10th Joint Meeting on Medicinal Chemistry 2017
P-72
DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL POTENT MDM2/P53 SMALL MOLECULE INHIBITORS
M. E. Kukushkin,[a],* V. K. Novotortsev,[a] V. E. Filatov,[a] A. A. Beloglazkina,[a] N. A. Vorobyeva,[b] D. A. Skvortsov,[a] E. K. Beloglazkina,[a] N. V. Zyk[a] and A. G. Majouga[a,b]
[a] Moscow State University, Chemistry Dept., 119991 Moscow, Leninskie Gory, Building 1/3, GSP-1, Russian Federation [b] National University of Science and Technology MISiS, Moscow 119049, Leninskiy prosp. 4, Russian Federation * [email protected]
The search of non-peptide small-molecules that block protein-protein p53-MDM2 interaction is being actual problem and appears as a new strategy for anticancer drug design. The first is tumor suppressor plays a key role in controlling cell cycle progression and apoptosis. Another is endogenous oncoprotein cellular inhibitor of p53. This referred small-molecular inhibitors binds to MDM2 whereby released p53 activating the process of destruction of the tumor cells. Compounds inhibitors of MDM2 containing spiro-oxindole core in structure is relatively new class biological active materials which has been proven ability to effectively block the interaction p53-MDM2.[1] We developed synthetic approaches to the spiro-oxindoles of two structural types from commercially available reagents through 1,3-dipolar cycloaddition:[2,3]
To elucidate the possible binding affinity of the synthesized compounds towards MDM2, a static 3D molecular docking study was performed in ICM-Pro software based on several X-Ray data of known oxindoles. Although the cell-based assay that was carried out in this work did not elucidate the underlying mechanism of action for the evaluated compounds, this scaffold brings novelty and possesses the 3D-pharmacophore elements crucial for binding as compared to the reported MDM2/p53 PPI inhibitors, including spiroindolinones. After biogical testing more than 100 obtained compounds on the HCT116 p53(+/+) and HCT116 p53(- /-) as well as LNCap and PC3 cell lines the leader was determined. Then, thаt compound was tested on HCT116 Nude mice model that showed 93% inhibition compared with the control group.
Acknowledgments: The work was supported by the Russian Foundation for Basic Research, grant number 16-33-60166.
[1] K. Ding, et al. JACS, 2005, 127, 10130. [2] Y.A. Ivanenkov, et al. Bioorg. Med. Chem. Lett., 2015, 25, 404. [3] Y.A. Ivanenkov, et al. Bioorg. Med. Chem., 2016, 24, 802.
148 The 10th Joint Meeting on Medicinal Chemistry 2017
P-73
SYNTHESIS AND BIOLOGICAL ACTIVITY OF NOVEL LONG CHAIN ARYLOPIPERAZINES (LACPs) WITH PYRIDYL MOIETY AS LIGANDS FOR SEROTONIN RECEPTORS
Damian Kułaga,[a] Jolanta Jaśkowska,[a],* Anna Drabczyk,[a] Grzegorz Satała[b] and Magdalena Malinowska[a]
[a] Cracow University of Technology, Department of Chemical Engineering and Technology, Institute of Organic Chemistry and Technology, 24 Warszawska St. 31-155 Cracow, Poland [b] Department of Medicinal Chemistry , Institute of Pharmacology Polish Academy of Science, 12 Smetna St., 31-343 Cracow, Poland * [email protected]
Buspiron is a typical anxiolytic drug that contains long-chain arylopiperazine (LACPs) moiety and exhibits binding with 5HT receptor.[1] Other drugs with a very similar activity to Buspiron are Gepiron or Ipsapiron and they have the same moiety. LACPs contain a long flexible carbon chain (C2-and more) connected with e.g. imid, amide, sulphonamide moiety at the one side of the chain and with arylopiperazine on the other side.[3,4] One of the most characteristic features for these ligands is binding with serotonin receptors.[2] In recent study, a few compounds were synthesized with pyridyl moiety in LACPs, which are an analogue of Buspiron. Molecules were examined toward binding with serotonin receptors 5HT in in vitro assay. Novel long chain arylopiperazines were obtained in a three-step reaction. At the beginning, LACPs were obtained with imide moiety. The compounds were obtained in the reaction between bromoalkylphtalimide and 1-(2-pyridyl)piperazine. It is a new, eco-friendly method, supported under microwave irradiation. At this stage, the compounds were transformed into HCl salts and examined in in vitro. The rest of the free base was used in the next step - Gabriel’s reaction to obtain amine. The third step is coupling amine with 1- and 2-naphthalenesulfonyl chloride or benzoyl chloride to yield LACPs with sulphonamide and amide moiety. The final compound was transformed into HCl salt and examined in in vitro assay. The preliminary results showed high affinity to 5HT-1a. The more preferable result is LACPs with imide moiety, and in terms of sulphonamides, more preferable is 2-naphtalenesulfonyl.
Acknowledgments: The study was financially supported by the National Centre for Research and Development, Project LIDER VI (No. LIDER/015/L-6/14/NCBR/2015).
[1] J. Malmkvist, S.W. Hansen, B.M. Damgaard, Physiol. Behav., 2003, 78, 229. [2] R. Perrone,F. Berardi, et al., J. Pharm. Pharmacol., 2005, 57, 1319. [3] G. Caliendo, et al., Curr. Med. Chem., 2005, 12, 1721. [4] P. Kowalski, et al., Arch. Pharm., 2013, 346, 339.
149 The 10th Joint Meeting on Medicinal Chemistry 2017
P-74
DIFFERENT ROLES OF HALOGEN SUBSTITUENTS IN LIGAND- RECEPTOR INTERACTIONS – A CLASS A GPCRS CASE STUDY
Rafał Kurczab
Department of Medicinal Chemistry, Institute of Pharmacology Polish Academy of Sciences, 12 Smętna Street, 31-343 Krakow, Poland * [email protected]
Substitution of halogen atoms is a common and frequently used strategy in hit and/or lead optimization since many years.[1,2] Moreover, the incorporation of halogen atoms is usually used to increase membrane permeability and hence, improve the oral absorption,[3] to enhance the blood- brain barrier permeability, what is a requirement for the CNS drugs.[4] However, the applicability of halogen atoms in drug design is still far from been completely explored, e.g. the most SAR discussions of halogenated compounds have only considered the classical steric parameters, ignoring other contributions and effects of such atoms. In recent years the role of halogen atoms in protein–ligand complexes has been attributed to the formation of specific and direct interactions called halogen bonding.[6,7] Herein, the different roles of halogen atoms were studied regarding the influence of: the type of halogen atom used (Cl, Br and I), the position of substitution in aromatic ring and the number of halogen atoms used, on the biological activity. The all crystalized GPCRs A were used as a testing set. For a given target, sets containing halogenated and unsubstituted derivatives were extracted from ChEMBL database using in-house scripts. The sets were next docked and analyzed by using previously tested QM/MM-GBSA procedure.[5] The results showed that, in majority of cases, increasing the size of halogen atom (Cl < Br < I) substituted in the same position of aromatic ring increased the compound’s activity, however, a sort of plateau effect was observed, where the most active derivative contained chlorine, whereas activity decreased for the bromine and iodine derivatives. A significant correlation between the position of substitution of halogen atom in aromatic ring was found. For instance, switching Br position in phenyl ring can decrease 11-fold, as well as, increase 27-fold (compared to unsubstituted compounds) an activity of the compound. Also very interesting dependencies between the number of halogen substituents in one aromatic ring and biological activity were noted. It is suggested, that the reported effects can be a result of interplay between hydrophobic, halogen bonding and entropic contributions to the ligand binding energy.
Acknowledgments: The study was supported by the National Science Center, Poland, Grant No 2014/15/D/NZ7/01782.
[1] S. Buchini, A. Buschiazzo, S. G. Withers. Angew. Chem. Int. Ed., 2008, 47, 2700. [2] A. C. L. Leite, D. R. M. Moreira, M. V. O. Cardoso, et al. ChemMedChem, 2009, 2, 1339,. [3] G. Gerebtzoff, X. Li-Blatter, H. Fischer, A. Frentzel, A. Seelig. ChemBioChem, 2004, 5, 676. [4] C. L. Gentry, R. D. Egleton, T. Gillespie, et al. Peptides, 1999, 20, 1229. [5] R. Kurczab, Acta Cryst. B, 2017, manuscript accepted. [6] P. Politzer, J.S. Murray, T. Clark, Phys. Chem. Chem. Phys., 2010, 12, 7748. [7] T. Clark, M. Hennemann, J.S. Murray, P. Politzer, J. Mol. Model., 2007, 13, 291.
150 The 10th Joint Meeting on Medicinal Chemistry 2017
P-75
SYNTHESIS AND BIOLOGICAL POTENTIAL OF SERIES A AND B MODIFIED STEROIDAL D-LACTONES
Ivana Kuzminac,[a],* Marina Savić,[a] Dimitar Jakimov,[b] Olivera Klisuric,[c] Andrea Nikolić[a] and Marija Sakač[a]
[a] Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia [b] Oncology Institute of Vojvodina, Put Dr Goldmana 4, 21204 Sremska Kamenica, Serbia [c] Department of Physics, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia * [email protected]
During recent years a number of new steroidal D-lactones with modifications in A and B-rings has been reported by our research group.[1-3] Among those modifications it can be observed that introduction of 5α or 6β hydroxy and/or 6-keto groups has shown significant influence on biological activity, especially on anticancer activity.[1,3] With this in mind, various steroidal derivatives with hydroxy, keto and/or metoxy groups in positions 3, 5 and 6 were synthesized starting from corresponding androstane-17a-lactone,[2] obtained according to a known procedure. Molecular and crystal structures were confirmed by detailed NMR (1H, 13C, HSQC 2D, 2D HMBC, NOE- experiments) and X-ray analysis. For eleven compounds, seven new and four that were already reported, antiproliferative activity was tested against a panel of human cancer cell lines and one healthy human cell line. In order to investigate the effect of different polar groups in synthesized molecules on cytotoxic activity, in analysis of the results has been established correlations between structure and activity of the tested compounds. Bioavailability of these compounds was assessed by comparing calculated molecular properties with the criteria for Lipinski[4] and Veber[5] rules.
[1] M.P. Savić, E.A. Djurendić, E. Petri, A. Ćelić, O.R. Klisurić, M.N. Sakač, D.S. Jakimov, V.V. Kojić, K.M. Penov Gaši, RSC Advances, 2013, 3, 10385. [2] E. Djurendić, M. Savić, O. Klisurić, M. Sakač, G. Bogdanović, D. Jakimov, K. Penov Gaši, Struct. Chem., 2012, 23, 1761. [3] I. Kuzminac, O. Klisurić, D. Škorić, D. Jakimov, M. Sakač, Struct. Chem., 2016, DOI 10.1007/s11224-016- 0815-9 [4] C.A. Lipinski, F. Lombardo, B.W. Dominy, P.J. Feeney, Adv. Drug Deliv. Rev., 2001, 46, 3. [5] D.F. Veber, S.R. Johnson, H.Y. Cheng, B.R. Smith, K.W. Ward, K.D. Kopple, J. Med. Chem., 2002, 45, 2615.
151 The 10th Joint Meeting on Medicinal Chemistry 2017
P-76
IN SILICO & IN VITRO EVALUATION OF NOVEL INHIBITORS OF MITOCHONDRIAL F1F0-ATPASE
Dimitrios Karagiannis, Panagiotis Efentakis, George Lambrinidis, Ioanna Andreadou and Emmanuel Mikros
Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Greece
ATP synthase is a significant multiprotein complex, proven to be a small rotor machine, either producing or hydrolyzing adenosine triphosphate. So far there is no crystal structure of mitochondrial ATP synthase of mus musculus, which is a very common model for in-vitro and in-vivo tests. Selective inhibition of ATP hydrolase, is of major significance during myocardial ischemia where ATP synthase switch to hydrolyzed activity, wasting ATP, causing dysfunctional mitochondria.[1] In this work, we present the discovery of ATP synthase inhibitors based on virtual and experimental screening methods. In a first step, we constructed for the first time a holistic model of ATP synthase of mus musculus based on homology modeling using all known subunits from PDB. Structure-based screening has been performed targeting the three major inhibition sites already known from literature: a) the ATP-ADP catalytic site b) the oligomycin binding site and c) inside the surface of an annulus made from loops in the 3α and 3β subunits (quercetin & resveratrol binding site). In parallel ligand- based virtual screening, has been carried out based on similarity research to known binders like BMS-199264.[1] The workflow has been implemented on our in-house library of 2000 Natural Products & and synthetic compounds. 48 molecules were selected and further screened in-vitro on isolated murine heart mitochondrial fractions, assessing ATP synthase hydrolytic activity. Mitochondrial fractions and ATP synthase hydrolytic activity was attained after a freeze-thaw cycle of the organelles. Subsequently the hydrolytic activity was measured photometrically. 35 out of 48 (73%) tested compounds exhibited various inhibitory activities at 0.2 mM. 7 molecules appeared to have common scaffold displaying enhanced activity (48–82.5% inhibition) among the other molecular scaffolds. The IC50 of these compounds has been further determined, provided confirmatory evidence that this scaffold achieve an inhibitory action which is premised on the assumption that it can lead us to a novel drug against myocardial ischemia.
[1] G.J Grover, J. Malm, Cardiovasc Ther., 2008, 26, 287.
152 The 10th Joint Meeting on Medicinal Chemistry 2017
P-77
3-AROYL-1,4-DIARYLPYRROLES INHIBIT CHRONIC MYELOID LEUKEMIA CELL GROWTH THROUGH AN INTERACTION WITH TUBULIN
Giuseppe La Regina,[a],* Valentina Naccarato,[a] Antonio Coluccia,[a] Addolorata Maria Luce Coluccia,[b] Ernest Hamel[c] and Romano Silvestri[a]
[a] Institut Pasteur Italy - Cenci Bolognetti Foundation, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Rome, Italy [b] Clinical Proteomics, Polo Oncologico Giovanni Paolo II, ASL - University of Salento, Piazza Muratore 1, I-73100 Lecce, Italy [c] Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, USA * [email protected]
Microtubules are an attractive target for the development of effective anti-leukemia agents.[1] Evidence has accumulated correlating inhibition of tubulin polymerization and leukemic cell proliferation.[2] The activity of colchicine site agents in chronic myeloid leukemia (CML) has not been adequately explored. Recently, starting from previously reported aroylindoles (ARI, 1)[3] we developed a class of 3-aroyl- 1-arylpyrroles (ARAPs, 2) via benzocracking approach by shifting the indole benzene moiety to position 1 of the pyrrole ring.[4] ARAPs proved to be potent inhibitors of both tubulin assembly and cancer cells growth, by binding the colchicine binding site. Pursuing our study on tubulin targeting agents, we designed 3-aroyl-1,4-diarylpyrroles (ARDAPs, 3-16) as potential anticancer agents bearing different substituents at the 1- or 4-phenyl ring (Figure). ARDAPs exhibited potent inhibition of tubulin polymerization, binding of colchicine to tubulin and cancer cell growth. (4-(4-Aminophenyl)-1-phenyl-1H-pyrrol-3-yl)(3,4,5-trimethoxyphenyl)methanone inhibited the proliferation of BCR/ABL-expressing KU812 and LAMA84 cells from CML patients in blast crisis and of hematopoietic cells ectopically expressing the imatinib mesylate (IM)-sensitive KBM5-WT or its IM-resistant KBM5-T315I mutation. The same compound minimally affected the proliferation of normal blood cells, indicating that it may be a promising agent to overcome broad tyrosine kinase inhibitor resistance in relapsed/refractory CML patients. New ARDAP significantly decreased CML proliferation by inducing G2/M phase arrest and apoptosis via a mitochondria- dependent pathway and increased the cytotoxic effects of IM in human CML cells.
Figure: Chemical structures of ARI (1), ARAP (2) and ARDAP (3-16) derivatives.
[1] E.C. de Bruin, J.P. Medema, Cancer Treat. Rev., 2008, 34, 737. [2] D. Bates, E.J. Feris, A.V. Danilov, et al., Cancer Biol. Ther., 2016, 17, 291. [3] G. La Regina, T. Sarkar, R. Bai, et al., J. Med. Chem., 2009, 52, 7512. [4] G. La Regina, R. Bai, A. Coluccia, et al., J. Med. Chem., 2014, 57, 6351.
153 The 10th Joint Meeting on Medicinal Chemistry 2017
P-78
INHIBITION OF DENGUE VIRUS BY NOVEL INHIBITORS OF RNA-DEPENDENT RNA POLYMERASE AND PROTEASE ACTIVITIES
Giuseppe La Regina,[a],* Valeria Famiglini,[a] Domiziana Masci,[a] Antonio Coluccia,[a] Jin- Ching Lee,[b] John Hiscott[a] and Romano Silvestri[a]
[a] Institut Pasteur Italy - Cenci Bolognetti Foundation, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Rome, Italy [b] Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan * [email protected]
Dengue virus (DENV) is the leading mosquito-transmitted viral infection in the world. With more than 390 million new infections annually, and up to 1 million clinical cases with severe disease manifestations, there is an urgent need to develop new antiviral agents that inhibit DENV infectivity.[1] Currently, no licensed antiviral drugs are available to block DENV infection and vector control efforts remain the only means to stop the spread of the infection. In the present study, we focused our attention on the identification of potential anti-DENV inhibitors by targeting the enzymatic activities of the NS5 RdRp polymerase and NS3 protease, in vitro and in vivo. As part of a continuation of our studies,[2,3] we developed new pyrazole derivatives 1-3 as inhibitors of NS5 RdRp polymerase (Figure). Furthermore, virtual screening studies on the NS2B/NS3 protease led us to identify indole derivatives 4-5 as inhibitors of NS3 protease (Figure). New compounds exhibited anti-DENV replication activity without cytotoxicity; two compounds exhibited anti-DENV activity in ICR suckling mouse model of DENV infection. Interestingly, combination treatment with several compounds demonstrated a synergistic inhibitory effect on DENV replication.
Figure: Chemical structures of new anti-DENV agents.
[1] A. Wilder-Smith, E.E. Ooi, S.G. Vasudevan, et al., Curr. Infect. Dis. Rep., 2010, 12, 157. [2] R. Silvestri, M.G. Cascio, G. La Regina, et al., J. Med. Chem., 2008, 51, 1560. [3] V. La Pietra, G. La Regina, A. Coluccia, et al., J. Med. Chem., 2013, 56, 10066.
154 The 10th Joint Meeting on Medicinal Chemistry 2017
P-79
PHENOXYMETHYL DERIVATIVES OF 1,3,5-TRIAZINE AS NOVEL CLASS OF 5-HT6 RECEPTOR LIGANDS
Dorota Łażewska,[a],* Małgorzata Więcek,[a] Michał Stelmasiński,[a] Grzegorz Satała,[b] Rafał Kurczab,[b] Andrzej J. Bojarski,[b] Katarzyna Kieć-Kononowicz[a] and Jadwiga Handzlik[a]
[a] Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland [b] Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków, Poland * [email protected]
The serotonin 5-HT6 receptor (5-HT6R) is the most recently identified member of the 5-HT receptor superfamily. The 5-HT6R, distributed in the central nervous system, is especially involved in the regulation of cognitive and mood processes as well as eating behaviors. Intensive medicinal chemistry efforts led to obtain many potent 5-HT6R ligands and some of them have reached to clinical studies, even to phase III as e.g. LUAE58054 (idalopirdine; Alzheimer’s disease).[1] For proper understanding of the complicity of 5-HT6R pharmacology more potent and selective ligands are necessary. Recently, we have developed a new class of 5-HT6 receptor ligands – benzyl [2] derivatives of 1,3,5-triazine. The most active compounds displayed 5-HT6R affinities in the nanomolar range (Ki = 20-30 nM). As a continuation of that work, a series of phenoxymethyl derivatives of 1,3,5-triazine was synthesized and tested for 5-HT6 receptor affinity. Among obtained structures a potent compound - 4-((2-isopropyl-5-methylphenoxy)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (MST4) - was identified. MST4, while having high nanomolar binding affinity (Ki = 11 nM) for 5-HT6R demonstrated also good selectivity towards other 5-HT receptors (5-HT1A, 5-HT2A, 5-HT7) and starts a new class of potent 5-HT6R ligands.
Acknowledgments: Supported by the Polish National Science Centre (NCN) grants: UMO- 2015/17/B/NZ7/02973 and DEC-2011/02/A/NZ4/00031.
[1] D. Karila, T. Freret, V. Bouet, M. Boulouard, P. Dallemagne, C. Rochais, J. Med. Chem., 2015, 58, 7901. [2] D. Łażewska, R. Kurczab, M. Więcek, K. Kamińska, G. Satała, A.J. Bojarski, K. Kieć-Kononowicz, J. Handzlik, Eur. J. Med. Chem. – manuscript submitted.
155 The 10th Joint Meeting on Medicinal Chemistry 2017
P-80
BLOCKADE OF RAS ACTIVITY BY INHIBITORS OF THE ENZYME ISOPRENYLCYSTEINE CARBOXYL METHYLTRANSFERASE (ICMT)
S. Ortega-Gutiérrez,[a] M. Martín-Fontecha,[a] N. Marín-Ramos,[a] F.J. Ortega,[a] A. Gil,[a] M. Balabasquer,[a] I. Cushman,[b] I.R. Torrecillas,[c] L. Pardo,[c] P.J. Casey,[b] M.R. Philips[d] and M.L. López-Rodríguez[a]
[a] Dpto. de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, Madrid, Spain [b] Dept. of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA [c] Laboratori de Medicina Computacional, Unitat de Bioestadística, Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain [d] NYU Cancer Institute, Smilow Research 1205, NYU School of Medicine, 550 First Avenue, New York, NY 10016, USA * [email protected]
Activating mutations in Ras proteins have been found in almost 30% of all cancers. In absence of its post-translational modifications, Ras losses its ability to induce tumour transformation. Therefore, the blockade of the enzymes involved in these modifications represents an attractive strategy to inhibit Ras activity. Among them, isoprenylcysteine carboxyl methyltransferase (ICMT), which catalyses the last step of the post-translational modifications of Ras, has surged as a new therapeutic target in oncology.[1] However, the lack of inhibitors with in vivo efficacy has impaired its clinical validation. In the search of new ICMT inhibitors, we built a structure-based pharmacophore model using the Methanosarcina acetivorans ICMT (Ma-ICMT) structure[2] as template. After the identification of an initial hit, we carried out an extensive medicinal chemistry program, which led to compound UCM- 1336, which inhibits more than the 90% of ICMT activity at 50 mM with an IC50 value of 2 mM and shows adequate pharmacokinetic properties. In addition, UCM-1336 (i) enhances programmed cell death, affecting specially those cell lines expressing oncogenic mutant K-Ras; (ii) induces mislocalization of all Ras isoforms; (iii) reduces Ras activity and blocks the activation of the downstream MEK/ERK and PI3K/AKT signalling pathways; and (iv) impairs the migratory capacity of tumour cells. All these promising results suggest that UCM-1336 could be a new ICMT inhibitor that would help to definitively validate this enzyme as a therapeutic target of interest for the treatment of cancers characterized by high Ras overactivation, a current unmet clinical need.[3]
Acknowledgments: This work has been supported by grants from the Spanish Ministerio de Economía y Competitividad (MINECO, SAF2016-78792-R).
[1] J.T. Teh, W.L. Zhu, et al., Oncogene, 2015, 34, 3296. [2] J. Yang, K. Kulkarni, et al., Mol. Cell, 2011, 44, 997. [3] M.L. López-Rodríguez, S. Ortega-Gutiérrez, M. Martín-Fontecha, M. Balabasquer, F.J. Ortega, N.I. Marín- Ramos, PCT Int. Appl. WO2014118418 A1 (2014)
156 The 10th Joint Meeting on Medicinal Chemistry 2017
P-81
STUDY FOR THE DEVELOPMENT OF NEW PURINE ANALOGUES AS HIGHLY SPECIFIC LIGANDS AGAINST FUNGAL NUCLEOBASE TRANSPORTERS
Efthymios-Spyridon Gavriil,[a] Spyridon Dimitrakis,[a] Nikolaos Lougiakis,[a] George Lambrinidis,[a] Emmanuel Mikros,[a] Panagiotis Marakos,[a] Nicole Pouli[a] and George Diallinas[b]
[a] Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Athens 15771, Greece [b] Department of Biology, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15784, Greece
Fungal pathogens, and especially Aspergillus fumigatus, constitute an emerging threat due to the increasing number of immunosuppressed patients. The use of specific purine transporters by fungi provides a potential target for the development of new antifungal agents recognized by specific fungal, but not by host, transporters. However, it is surprising that emerging knowledge on fungal transporters has not been rationally exploited until now. In previous works, we have studied structure-function relationships in nucleobase/nucleoside transporters in A. nidulans, a genetically tractable fungus, where we have identified, cloned and fully characterized all 7 major transporters, catalyzing the uptake of purines, pyrimidines, nucleosides and purine analogues, namely UapA, UapC, AzgA, FurD, FurA, FcyB and CntA. In line with our research efforts, based on previously theoretical models describing purine-transporter interactions, we aim to rationally design and synthesize analogues, which will be recognized by specific nucleobase transporters of A. nidulans. We have already developed a number of synthetic derivatives possessing the 3-deazapurine scaffold, that have been found to specifically inhibit FcyB-mediated [3H]-adenine uptake. As a continuation of our research efforts we have designed a number of new 2,4-disubstituted-3- deazapurines, which have been efficiently synthesized, starting from 2-chloro-4-aminopyridine and evaluated for substrate competition assays related to FcyB and AzgA transporters, both of which recognize and transport purines with high affinities at the low μΜ range.
Acknowledgments: This work has been funded by the Special Research Account (ELKE) of the National and Kapodistrian University of Athens.
157 The 10th Joint Meeting on Medicinal Chemistry 2017
P-82
SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL SMALL- MOLECULE PSMA-TARGETED PACLITAXEL CONJUGATES
A. E. Machulkin,[a],* A. P. Ber,[a] I. V. Saltykova,[a] E. K. Beloglazkina,[a] N. V. Zyk,[a] V. E. Koteliansky,[a] and A. G. Majouga[a,b]
[a] Lomonosov Moscow State University, Chemistry Dept., Leninskie gory, Building 1/3, GSP-1, Moscow, 119991, Russian Federation [b] National University of Science and Technology MISiS, 9 Leninskiy pr, Moscow, 119049, Russian Federation * [email protected]
The last year, statistical output was greatly unfavorable and sad since prostate carcinoma (PCa) was the most spread malignant tumor commonly diagnosed around the world and as a leading cause of cancer-related lethal outcomes registered among men in the US with an estimated 233K diagnoses and 30K deaths.[1] Glutamate carboxypeptidase II (GCPII), also known as prostate specific membrane antigen (PSMA) has recently emerged as a prominent biomarker of this pathological state and as an attractive protein trap for drug targeting. [2, 3] In present work we synthesized the series of paclitaxel conjugates, modified with residues of 5- hexynoic acid (7-OH substituted or with modified phenylisoserine residue) with different PSMA ligands was synthesized. Cytotoxic effect of these conjugates was estimated on LNCaP and PC-3 cell lines, structure-activity relationships were studied. Cytotoxicity of the conjugates with amide 1 and 2 bond type between linker and PSMA ligand was (IC50 = 25 nM) significantly higher than corresponding value for the urea residue 4 (IC50 = 1670 нМ), on LNCaP cells. We demonstrated that amide bond type between linker and PSMA ligand is preferable than urea bond type. All ligands and conjugates in this work were isolated individually and described with 1H and 13C NMR methods, mass-spectrometry and LC/MS. For the conjugate 2 primary in vivo studies were performed. This conjugate demonstrated the same tumor growth inhibition as for paclitaxel, in this experiment. Synthetic approaches and biological evaluation of synthesized structures would be minutely discussed in the report.
O O O OH
O NH O O O H OH O O O O O N N O NH X N O n O OH Paclitaxel 1, n=4, X=CH2 O 2, n=9, X=CH2 O O N N 3, n=4, X=NH H H 4, n=9, X=NH OH OH PSMA-vector
Figure: Structure of targeted conjugates of paclitaxel with PSMA ligands.
Acknowledgments: This work was kindly supported by Russian scientific fund № 14-34–00017
[1] R. Siegel, J. Ma, Z. Zou, A. Jemal, CA Cancer J. Clin. 2014, 64, 9−29. [2] C. A. Foss et al., Curr. Med. Chem. 2012, 19, 1346−1359. [3] A. E. Machulkin, et al. J. Drug Target. 2016, 24, 679-93.
This work was kindly supported by Ministry of Education and Science of the Russian Federation № IP- MSU/10-14 (NKR 185/17)
158 The 10th Joint Meeting on Medicinal Chemistry 2017
P-83
DESIGN, SYNTHESIS AND IN VITRO EVALUATION OF MODULATORS OF PFKFB3 AUTOREGULATORY DOMAIN
H. Macut,[a],* X. Hu,[a] D. Tarantino,[b] S. Pellegrino[a] and M. L. Gelmi[a]
[a] DISFARM - Section of General and Organic Chemistry "A. Marchesini", University of Milan, Via Venezian 21, 20133 Milan, Italy [b] Department of Biosciences, University of Milan, Via Celoria 26, 20133, Milan, Italy * [email protected]
Artery and cerebrovascular diseases are the two most common causes of illness and death in developed countries and their primary cause is atherosclerosis, which is characterized by the thickening of the arterial wall. Although beneficial, recent therapeutic strategies have limited efficacy.[1] Current research has shown that targeting dysregulated endothelial cell (EC) metabolism could be a new therapeutic strategy.[2] 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3) enzyme plays a crucial role in the regulation of the EC glycolytic flux and it is up-regulated during angiogenesis,[3] representing thus an innovative target for atherosclerosis therapy. PFKFB3 is a dimeric bifunctional enzyme and possesses a very high kinase to phosphatase activity ratio. Its activity is controlled by the N-terminus autoregulatory domain (AD) in the kinase region. In the crystal structure this domain adopts a β- hairpin shape.[4] We performed virtual screening on the targeted autoregulatory binding site and here we present the synthesis and biological evaluation of the selected library of compounds. In vitro activity and binding assays were carried out on the isolated PFKFB3 enzyme.
[1] J. Goveia, P. Stapor, P. Carmeliet, EMBO Mol. Med., 2016, 6, 1105. [2] D. J. Rader, A. Daugherty, Nature, 2008, 541, 904. [3] J. Chesney, R. Mitchell, F. Benigni, M. Bacher, L. Spiegel, Y. Al-Abed, J.H. Han, C. Metz, R. Bucala, Proc. Natl. Acad. Sci. U S A, 1999, 96, 3047. [4] S.G. Kim, N.P. Manes, M.R. El-Maghrabi, Y.H. Lee, J. Biol. Chem., 2006, 281, 2939.
159 The 10th Joint Meeting on Medicinal Chemistry 2017
P-84
ISOXAZOLE DERIVATIVES AS IMMUNOMODULATORS
Marcin Mączyński,[a],* Angelika Drynda,[b] Stanisław Ryng[a] and Bożena Obmińska-Mrukowicz[b]
[a] Department of Organic Chemistry, Faculty of Pharmacy, Wrocław Medical University, Borowska 211A str., 50-556 Wrocław, Poland [b] Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Wrocław University of Environmental and Life Sciences, Norwida 31 str., 50-375 Wrocław, Poland * [email protected]
The homeostasis of the organism is determined by the cooperation of the immune, nervous and endocrine system. The proper functioning of those systems provides the maintenance of the balance of good health. Immune system principally destroys and eliminates identified foreign structures or abnormal structures of the body. Furthermore, it ensures the integrity and protection of its own normal tissues and supports the tissue regeneration process. Immune-mediated diseases pose a serious challenge for today’s medicine. Substances that would be able to modify the functions of the immune system have been sought for years. Among the substances obtained by chemical synthesis, special attention deserve derivatives of five-membered isoxazole ring. They are the object of interest to many scientists, both chemists seeking to obtain newer compounds, as well as pharmacologists studying their properties. To this fact contribute both that the isoxazole ring is relatively easy to obtain by chemical synthesis, and that the obtained derivatives are non-toxic and have many biological activities, which means that they could have potential application in medicine. The most characteristic for this group of compounds is ability to modify the function of the immune system. In this work we present the immunomodulatory properties of the best described isoxazole derivatives synthesized in recent years.
Compound Chemical structure
Leflunomide
RM-33
RM-11
5-amino-3-methyl-4- isoxazolecarboxylic acid hydrazide
160 The 10th Joint Meeting on Medicinal Chemistry 2017
P-85
PYRROLYL NON-DKA DERIVATIVES AS NOVEL INHIBITORS OF HIV-1 REVERSE TRANSCRIPTASE-ASSOCIATED RIBONUCLEASE H FUNCTION
V. N. Madia,[a],* F. Saccoliti,[a] G. Pupo,[a] V. Tudino,[a] F. Esposito,[b] A. Corona,[b] N. Grandi,[b] E. Tramontano,[b] R. Costi[a] and R. Di Santo[a]
[a] Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, “Sapienza” University of Rome, p.le Aldo Moro 5, I-00185 Roma, Italy [b] Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria SS554, 09142 Monserrato Cagliari, Italy * [email protected]
The AIDS is a complex of pathological manifestations characterized by progressive degeneration of the immune system caused by the HIV virus. An essential enzyme for the retroviral life cycle is reverse transcriptase (RT), an heterodimeric enzyme with two associated activities: the DNA polymerase activity and the ribonuclease H (RNase H) activity that selectively degrades the RNA strand of the hybrid RNA/DNA formed during the synthesis of the minus (-) strand DNA that uses (+) RNA as a template.[1] Despite such a large armamentarium, both acute and chronic toxicities limit the prolonged use of several antiretroviral agents, and this is even more a concern because of the life-long character of the therapy. In addition, the selection of drug-resistant strains and the spreading of such strains in newly infected patients is also an increasing concern, underscoring the pressing demand of novel anti-HIV agents, with a better therapeutic index and a very broad spectrum of activity against the mutants, possibly targeting viral functions not yet explored.[2] In such a scenario, an attractive target turns out to be the RNase H function of HIV-1 reverse transcriptase (RT), which has been little explored although it could be potentially vulnerable to a specific inhibition.[3-6] Although RT is a multifunctional enzyme, all RT inhibitors currently approved for the treatment of HIV infection target only the RT-associated polymerase function, while none of them block the RT RNase H activity. Nevertheless, several studies have demonstrated that the abolition of the HIV-1 RNase H function stops the virus replication, proving to be, therefore, a validated and attractive target for the development of new anti-retroviral agents, in order to enhance the anti-HIV-1 drug armamentarium effectiveness. Despite this, it has been little explored and it needs to be further developed through the support of new HIV/AIDS drug discovery programs, in order to identify more efficient anti-HIV drugs that could be used for therapy.[7,8] To date, only few compounds have been described to inhibit the HIV-1 RNase H function. Among them, aryldiketo acid derivatives proven to inhibit both integrase enzyme and RNase H function of the RT.[9,10] Pursuing our studies on pyrrolyl DKA derivatives as dual inhibitors of IN and RNase H we developed non DKA scaffold and found a new class of compounds that selectively inhibited the RNase H. The data coming from the biological assays will be shown and discussed.
[1] W. S. Hu, S.H. Hughes, Cold Spring Harb Perspect Med., 2012, 2, 1. [2] J. P. Moore, et al., Nature Rev. Mol. Cell Biol., 2000, 1, 40. [3] K. Klumpp, et al., Nucleic Acids Res., 2003, 31, 6852. [4] S.R. Budihas, et al., Nucleic Acids Res., 2005, 33, 1249. [5] E. De Clercq, et al., J. Med. Chem., 2005, 48, 1297. [6] E. Tramontano, Mini Rev. Med. Chem., 2006, 6, 727. [7] E. Tramontano, F. Esposito, R. Badas, R. Di Santo, R. Costi, R., P. La Colla, Antiv. Res., 2005, 65, 117. [8] E. Tramontano, et al., Antiviral Res., 2005, 65, 117. [9] A. Corona, et al., Antimicrob. Agents Chemother., 2014, 58, 6101. [10] L. Pescatori, et al., J. Med. Chem., 2015, 58, 4610.
161 The 10th Joint Meeting on Medicinal Chemistry 2017
P-86
NOVEL ANTIMALARIALS FROM NATURE: EVOLUTIONARY GENERATED VIRTUAL COMPOUND LIBRARIES FROM NATURAL PRODUCTS WITH ANTIPLASMODIAL ACTIVITIES
Samuel Egieyeh,[a,b] James Syce,[a] Alan Christoffels[b] and Sarel F. Malan[a],*
[a] School of Pharmacy, University of the Western Cape, Cape Town, 7535 South Africa [b] South African Medical Research Council Bioinformatics Unit, South African National Bioinformatics Institute, University of the Western Cape, Cape Town, 7535, South Africa * [email protected]
Purpose: There is an urgent need to develop novel antimalarial drugs in view of the mounting disease burden and emergent resistance to the presently used drugs against the malarial parasites. A large number of natural products, especially those used in ethnomedicine for malaria, have shown varying in vitro antiplasmodial activities. Generation of virtual compound libraries based on these natural products presents an opportunity to identify novel potential antimalarial compounds. Methods: Virtual compound libraries were generated with an evolutionary algorithm using unique scaffolds identified from the natural products with in vitro antiplasmodial activities as templates. The virtual compounds generated were characterized by evaluating selected molecular descriptors in comparison to currently registered antimalarial drugs. Other descriptive studies performed included assessment of the toxicity profile, diversity of the compound set, similarity to currently registered antimalarial drugs and prediction of antiplasmodial activity. Results: Two sets of virtual compound libraries were generated: Approved Drug-Like and Natural Product-Like. The results of the characterization showed significant difference (p value < 0.05) in some molecular descriptors (molecular weight, log partition coefficient, hydrogen bond donors and acceptors, polar surface area, shape index, chiral centers, and synthetic feasibility) between the virtual compound libraries and currently registered antimalarial drugs. Tumorigenic and mutagenic substructures were absent in most (> 90%) of the virtual compounds. The virtual compounds showed sufficient structural diversity and the majority were structurally diverse from currently registered antimalarial drugs. Finally, a good fraction of the virtual compound libraries (up to 70%) were predicted as active antiplasmodial agents. Conclusions: A large number of the virtual compounds generated were structurally diverse from currently registered antimalarial drugs and were predicted as active antiplasmodial agents. Filtering and optimization led to a collection of virtual compounds with unique chemotypes that may be synthesized and added to the screening deck against Plasmodium.
162 The 10th Joint Meeting on Medicinal Chemistry 2017
P-87
THE SYNTHESIS OF NEW ARYLPIPERAZINES FOR CNS DISORDERS
Magdalena Malinowska,* Jolanta Jaśkowska, Anna Drabczyk and Damian Kułaga
Organic Chemistry and Technology Insitute, Cracow University of Technology, 24 Warszawska st., Cracow 31-155, Poland * [email protected]
Central nervous system (CNS) diseases are one of the most problematic disorders, which cause various neurological impairments from depression and intellectual disability to epilepsy, autism, and schizophrenia.[1] The current pharmacotherapy takes advantage of the arylpiperazine ligands activity for 5-HT receptors which have a significant role in the occurrence of pathological processes in the neurotransmitter system.[2,3] The ligands can be obtained in various reaction conditions. Conventional syntheses in organic solvent at 150-180°C give the reaction yield from 60-90% and require long process time (14-18h).[4-5] Microwave conditions allow significant reduction of the reaction time to few minutes and, moreover, the synthesis can be solvent-free.[6] In this study we describe the synthesis and evaluation of the reaction conditions of a series of arylpiperazines used for the synthesis of new ligands from the Long Chain Arylpiperazines family for CNS diseases. The syntheses were carried out according to the procedure presented on the Figure.
Cl NH2
N NH . HCl + NH R
R . Cl HCl
Figure: The main synthesis procedure of arylpiperazine derivatives.
The evaluation of the synthesis conditions included the influence of the kind of a solvent, the reaction temperature and time, as well as the presence of microwave radiation on the process progress. The obtained compounds were identified using chromatographic (HPLC) and spectroscopic methods (IR, 1HNMR). The described procedure is efficient and the products are isolated by simple filtration like hydrochloride salts. It is applicable to various substituted anilines to give corresponding N- phenylpiperazine hydrochlorides. All the products are found to be above 95% pure by HPLC.
Acknowledgments: The study was financially supported by the National Centre for Research and Development, Project LIDER VI (No. LIDER/015/L-6/14/NCBR/2015).
[1] G-H. Huang, Z-L. Sun, H-J Li, D-F. Feng, Mol. Cell Neurosci., 2017, 80, 18. [2] D. Hoyer, J.P. Hannon, G.R. Martin, Pharmacol. Biochem. Behav., 2002, 4, 533. [3] J.S. Dileep Kumar, V.J. Majo, J. Prabhakaran, J.J. Mann, Bioorg. Med. Chem. Lett., 2014, 24, 4759. [4] L. Ravilla, V.S. Naidu, K. Nagarajan, Tetrahedron Lett., 2015, 56, 4541. [5] C.A. Boateng, O.M. Bakare, J. Zhan, A.K. Banala, C. Burzyński, E. Pommier, T.M. Keck, P. Donthamsetti, J.A. Javitch, R. Rais, B.S. Slusher, Z-X. Xi, A.H. Newman, J. Med. Chem., 2015, 58, 6195. [6] I. Konstantinov, K. Bukhryakov, Y. Gezentswey, M. Krasavin, Lett. Org. Chem., 2011, 8, 628.
163 The 10th Joint Meeting on Medicinal Chemistry 2017
P-88
BIOLOGICAL EVALUATIONS OF AMIDINE AND AMIDOXIME SUBSTITUTED HETEROCYCLES WITH 1,2,3-TRIAZOLYL SPACER
Silvija Maračić,[a] Petra Grbčić,[b] Mirela Sedić,[b,c] Sandra Kraljević Pavelić[b,c] and Silvana Raić-Malić[a],*
[a] University of Zagreb, Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, Marulićev trg 19, HR-10000 Zagreb, Croatia [b] University of Rijeka, Department of Biotechnology, Radmile Matejčić 2, HR-51000 Rijeka, Croatia [c] University of Rijeka, Centre for high-throughput technologies, Radmile Matejčić 2, HR-51000 Rijeka, Croatia * [email protected]
Molecular hybridization is a new concept in drug design and development based on the combination of pharmacophoric moieties of different bioactive substances to produce a new hybrid compound with improved affinity and efficacy, when compared to the parent drugs.[1] This approach was adopted for design and synthesis of diversified library of benzofused heterocycle–1,2,3-triazole conjugates to evaluate their cytostatic and antibacterial activities. Thus, coumarin–1,2,3-triazole– benzofused heterocycle hybrids emerged as the class of compounds exhibiting the highest antiproliferative activity.[2] While 5,6-disubstituted furo[2,3-d]pyrimidine-2-one derivative exhibited selective activity against hepatocellular carcinoma (HepG2) and cervical carcinoma (HeLa) cells with higher potencies than the reference drug 5-fluoruracil, benzothiazole–1,2,3-triazole–coumarin hybrid showed potent anti-Moraxella catarrhalis activity.[3,4] Novel hybrids of aromatic nitrile and heterocycle linked via 1,2,3-triazole scaffold were syntesized by regioselective Cu(I)-catalyzed azide-alkyne 1,3- dipolar cycloaddition. Nitrile derivatives were used as precursors for synthesis of amidine and amidoxime substituted selected heterocycles. Results of antiproliferative evaluations for newly synthesized compounds on human tumor and normal cell lines will be presented.
[1] S. Raić-Malić, A. Meščić, Curr. Med. Chem., 2015, 22, 1462. [2] T. Gazivoda Kraljević, A. Harej, M. Sedić, S. Kraljević Pavelić, V. Stepanić, D. Drenjančević, J. Talapko, S. Raić-Malić, Eur. J. Med. Chem., 2016, 124, 794. [3] T. Gregorić, M. Sedić, P. Grbčić, A. Tomljenović Paravić, S. Kraljević Pavelić, M. Cetina, R. Vianello, S. Raić-Malić, Eur. J. Med. Chem., 2017, 125, 1247. [4] S. Maračić, T. Gazivoda Kraljević, H. Čipčić Paljetak, M. Perić, M. Matijašić, D. Verbanac, M.Cetina, S. Raić-Malić, Bioorg. Med. Chem., 2015, 23, 7448.
164 The 10th Joint Meeting on Medicinal Chemistry 2017
P-89
DESIGN, SYNTHESIS AND CYTOTOXIC ACTIVITY EVALUATION OF NEW AMINOSUBSTITUTED PYRAZOLOPYRIDINES
Nikolaos Lougiakis,[a] Vasiliki Giannouli,[a] Ioannis K. Kostakis,[a] Panagiotis Marakos,[a] Nicole Pouli,[a] Orestis Argyros[b] and Constantin Tamvakopoulos[b]
[a] National and Kapodistrian University of Athens, School of Health Sciences, Department of Pharmacy, Division of Pharmaceutical Chemistry, Panepistimiopolis-Zografou, Athens 15771, Greece [b] Division of Pharmacology-Pharmacotechnology, Biomedical Research Foundation, Academy of Athens, Soranou Efesiou 4, Athens 11527, Greece
Numerous purine derivatives have been designed and used as selective inhibitors of enzymes and receptors. Depending on their substitution pattern and the wide variety of the substituents, these compounds were found to exhibit a broad range of biological and pharmaceutical properties. Isosteric purine analogues, have also been developed in the attempt to explore the therapeutic potential or improve the physicochemical and pharmacokinetic properties of the parent derivatives. Within a research project aiming in the discovery of new antiproliferative agents, we have synthesized a number of new 7-arylaminosubstituted pyrazolo[3,4-c]pyridines and have determined their cytotoxic activity against a panel of cancer cell lines. Certain compounds among these series exhibited potent antiproliferative activity and blocked specifically the cell cycle. As a continuation of our efforts here we present the design and synthesis of a number of new substituted pyrazolo[3,4-c]pyridines and the evaluation of their cytotoxicity. The synthesis of the derivatives was accomplished using N-(2-chloro-4-methyl-3-pyridin)acetamide as starting material, which has derived from the commercially available 2-amino-4-picoline. The above mentioned acetamide underwent intramolecular cyclization and upon suitable manipulation was converted to 7- chloropyrazolo[3,4-c]pyridine-5-carbonitrile. This intermediate was used for the introduction of 3- alkyl or 3-aryl substituents as well as for the insertion of 7-arylamino- and 5-alkylaminomethyl- groups, in order to obtain the target derivatives. The new compounds underwent a preliminary screening concerning the evaluation of their cytotoxic activity against a panel of human cancer cell lines (MCF-7, T47D, MDA 231, HCC1954, PaCa2 and SCOV3). A number of the derivatives proved to be active, showing IC50 values in the low µΜ range. The preliminary biological evaluation of the derivatives revealed that the presence of a 3-isopropyl or 3-phenylgroup is in favor of the cytotoxic activity of these compounds. Position 5- of the pyrazolopyridine ring system appears more flexible in terms of substituents, since a variety of substituents were used and provided derivatives with interesting antiproliferative activity.
Acknowledgments: This work has been funded by the Special Research Account (ELKE) of the National and Kapodistrian University of Athens.
165 The 10th Joint Meeting on Medicinal Chemistry 2017
P-90
IN VITRO CITOTOXITY AND ANTI-TUMOR INVESTIGATION OF PHENYLBORONIC ACID
Maja Marasović,[a],* Mladen Miloš,[a] Siniša Ivanković[b] and Ranko Stojković[b]
[a] Department of Biochemistry Faculty of Chemistry and Technology, University of Split, Split, Croatia [b] Division of Molecular Medicine, Ruđer Bosković Institute, Zagreb, Croatia * [email protected]
The increased interest in recent years for the boronic acids and their derivatives is related to their new applications as biologically active compounds. Our previous in vitro and in vivo studies have demonstrated that dipotassium-trioxohydroxytetrafluorotriborate K2[B3O3F4OH] affects the growth of [1] cancer cells. Based on promising results of K2[B3O3F4OH] and recent researches of other authors on phenylboronic acid,[2,3] we decided to test cytotoxicity and antitumor effects of phenylboronic acid in vitro on standard tumor cell lines: 4T1 mammary adenocarcinoma, B16F10 melanoma and squamous cell carcinoma SCCVII. Crystal violet method was performed to measure cell growth inhibition rate. Experiments were carried out in microtiter plates with 96 wells and 1×104 tumor cells/250 ml of medium was applied in each well. After 24 h, when the cells reached confluence, the old cultured medium was replaced with a fresh one and phenylboronic acid was added to the cultures to the final concentrations of 0.1, 1.0 and 10 mg/ml. Control cells were incubated in RPMI medium without addition of the tested substance. Absorbance was measured at 540 nm using a microplate reader. The absorbance at 590 nm is proportional to the number of surviving cells. Each experiment was done in quadruplicate. Inhibition of cell growth relative to controls was calculated according to the formula: Inhibition of cell growth (%)=(C-T)/C×100, where T denotes the mean absorbance of treated cells, and C indicates the mean absorbance of untreated (control) cells. The LC50 concentrations were calculated using probit analysis. The detailed in vitro investigation undoubtedly showed that phenylboronic acid affects the growth of cancer cells. The proliferation of cells depends on the concentration so that aqueous solution of phenylboronic acid, in the concentrations less then 1 mg/ml, has weak influence on the cell growth, but at the concentrations of 10 mg/ml, significantly slows cells growth. The 4T1 and SCCVII cells show lower sensitivity to the cytotoxic effects of phenylboronic acid compared to B16F10 cells. Although phenylboronic acid has a slightly weaker effect than K2[B3O3F4OH], the promising results encourage further research.
[1] S. Ivanković, R. Stojković, Z. Galić, B. Galić, J. Ostojić, M. Marasović, M. Miloš, J. Enzyme Inhib. Med. Chem., 2014, 30, 354. [2] T.M. Bradke, C. Hall, S.W. Carper,G.E. Plopper, Cell Adhes. Migr., 2008, 2, 153. [3] X. Wang, H. Tang, C. Wang, J. Zhang, W. Wu, X. Jiang, Theranostics, 2016, 6, 1378.
166 The 10th Joint Meeting on Medicinal Chemistry 2017
P-91
MICROWAVE ASSISTED SYNTHESIS OF SOME NEW THIAZOLIDINE-2,4- DIONE DERIVATIVES AS POTENTIAL ANTIMICROBIAL AGENTS
Gabriel Marc,[a],* Ioana Ionuţ,[a] Dan Vodnar,[b] Adrian Pîrnău,[c] Brîndușa Tiperciuc[a] and Ovidiu Oniga[a]
[a] Department of Pharmaceutical Chemistry, “Iuliu Hațieganu” University of Medicine and Pharmacy, 12 Ion Creangă Street, RO-400012 Cluj-Napoca, Romania [b] Department of Food Science, University of Agricultural Sciences and Veterinary Medicine, 3-5 Mănăștur Street, RO-400372 Cluj-Napoca, Romania [c] National Institute for Research and Development of Isotopic and Molecular Technologies, RO 400293 Cluj-Napoca, Romania * [email protected]
Infections with resistant fungal or bacterial strains are nowadays a big challenge of treatment in all health care systems worldwide. Especially in the immune-compromised hosts, it represents one of the most life-threatening complications, giving a poor prognosis to the infected patients. For example, the commensal Candida sp. or Staphylococcus sp. are common in humans, but frequent became dangerous pathogens.[1] It is imperative that new substances with putative antimicrobial properties are found. This approach came in order to avoid their resistance achieved during time. Inhibitors with different mechanism than classic antibacterials and antifungals could be developed based on in silico techniques. Molecular modelling and ADMET can be used in order to develop more potent compounds at lower doses, with less toxicity or interactions and with better pharmacokinetics.[2] Thiazolidine-2,4-dione derivatives were synthesized under microwave irradiation. First, Knoevenagel condensation in position 5 of the thiazolidine-2,4-dione ring was performed using various carbonyl compounds. Nitrogen atom was substituted using various α-halo-ketones. The purity of the new synthesized thiazolidine-2,4-dione derivatives was confirmed by thin layer chromatography and liquid chromatography. The structure of the new compounds was confirmed by spectral analysis: IR, MS and 1H-NMR and by quantitative elemental analysis. Compounds were screened in vitro for their ability to inhibit the growth of some standardized bacterial and fungal strains. In silico evaluations were performed in order to find potential interactions of novel molecules to some bacterial or fungal strains key proteins using AutoDock 4.2[3] and an ADMET study using Swiss ADME. [4] Our screening showed that the new compounds have promising antimicrobial activity.
[1] S. Berne, L. Kovačič, M. Sova, N. Kraševec, S. Gobec, I. Križaj, et al., Bioorg. Med. Chem., 2015, 23, 4264. [2] C.A. Lipinski, F. Lombardo, B.W. Dominy, P.J. Feeney, Adv. Drug Deliv. Rev., 2001, 46, 3. [3] G.M. Morris, R. Huey, W. Lindstrom, M.F. Sanner, R.K. Belew, D.S. Goodsell, et al., J. Comput. Chem., 2009, 30, 2785. [4] A. Daina, V. Zoete, ChemMedChem, 2016, 11, 1117.
167 The 10th Joint Meeting on Medicinal Chemistry 2017
P-92
WEB-4D-QSAR OF 17β-HYDROXYSTEROID DEHYDROGENASE TYPE 3 INHIBITORS
Eduardo B. de Melo,[a] Tuanny P. Schmidt[a] and João Paulo A. Martins[b],*
[a] Department of Pharmacy, Western Paraná State University (UNIOESTE), Cascavel, PR, Brazil [b] Department of Chemistry, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil * [email protected]
Prostate cancer is the most common cancer type found in men and, unfortunately, the treatment has numerous side effects. It is believed that the enzyme 17β-hydroxysteroid dehydrogenase type 3 is an interesting target of study in the development of new drugs against the disease. The objective of this work was to perform a 4D-QSAR study with a set of 49 compounds (benzylidene oxazolidinedione and thiazolidinediones derivatives), with inhibitory effect on this enzyme, synthesized and published initially by Harada et al.[1] This study is accomplished with a new web based software running LQTA-QSAR[2] methodology called Web-4D-QSAR (https://github.com/rougeth/Web-4D-QSAR). After descriptors generation with this new web browser interface, variable selection was carried out using Ordered Predictors Selection (OPS)[3] algorithm implemented at QSAR Modeling[4] program. Model building was performed using Partial Least Squares (PLS) regression. Based on this approach it was possible to obtain a model with the 2 2 following attributes: n= 42; R = 0.779; RMSEC= 0.338; F= 68.735; Q LOO= 0.655 RMSECV= 0.423; 2 2 2 nprediction= 7; R pred= 0.784; RMSEP= 0.282; average rm (pred)-scaled= 0.674; rm -scaled= 0.147; k= 2 2 1.018; k’= 0.981; |R 0-R ’0|= 0.039. These obtained results may be useful as a tool to allow a better comprehension about the inhibitory mechanism of these compounds over 17β-hydroxysteroid dehydrogenase, helping thus in the development of new inhibitors agents with potential to be employed in the prostate cancer treatment. The authors would like to thank Brazilian Agencies Fundação de Amparo à Pesquisa de Minas Gerais (FAPEMIG), Conselho Nacional de Desenvolvimento Científico (CNPq) and Fundação Araucária for the support.
[1] K. Harada, et al., Bioorg. Med. Chem., 2012, 55, 5951. [2] J.P.A Martins, J. Chem. Inf. Model., 2009, 49, 1428. [3] R.F. Teófilo, J.P.A. Martins, M.M.C. Ferreira, J. Chemom., 2009, 23, 32. [4] J.P.A. Martins, M.M.C. Ferreira, Quim. Nova, 2013, 36, 554.
168 The 10th Joint Meeting on Medicinal Chemistry 2017
P-93
WEB-4D-QSAR OF URACIL DERIVATIVES DESCRIBED AS THYMIDINE PHOSPHORYLASE INHIBITORS
João Paulo A. Martins[a] and Eduardo B. de Melo[b],*
[a] Department of Chemistry, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil [b] Department of Pharmacy, Western Paraná State University (UNIOESTE), Cascavel, PR, Brazil * [email protected]
Thymidine phosphorylase (TP) is a multifunctional protein frequently overexpressed in many types of cancer, as bladder, colorectal, esophageal, pancreatic, and others, and is associated with the promotion of tumorigenesis, angiogenesis, metastasis, and the inhibition of apoptosis. As various types of anticancer treatments stimulate TP expression, probably owing to their pro-angiogenic and antiapoptotic properties, the suppression of this protein could hypothetically slow down or suppress the recovery of cancer cells, thus providing beneficial supplementary effects. The objective of this work was to perform a 4D-QSAR study with a set of 37 compounds (uracil derivatives), with inhibitory effect on this enzyme, synthesized and published initially by Yano et al.[1,2] This study is accomplished with a new web based software running LQTA-QSAR[3] methodology called Web-4D- QSAR (https://github.com/rougeth/Web-4D-QSAR). After descriptors generation with this new web browser interface, variable selection was carried out using Ordered Predictors Selection (OPS)[4] algorithm implemented at QSAR Modeling[5] program. Model building was performed using Partial Least Squares (PLS) regression. Based on this approach it was possible to obtain a model with the following attributes: Descriptors: 23; latent variables: 1; n= 29; R2= 0.899; RMSEC= 0.375; F= 2 2 240.327; Q LOO= 0.853 RMSECV= 0.453; nprediction= 8; R pred= 0.901; RMSEP= 0.383; average 2 2 2 2 rm (pred)-scaled= 0.829; rm -scaled= 0.074; k= 1.031; k’= 0.968; |R 0-R ’0|= 0.007. These obtained results may be useful as a tool to allow a better comprehension about the inhibitory mechanism of this class of compounds over thymidine phosphorylase, helping thus in the development of new inhibitors agents with potential to be employed in the cancer therapy. The authors would like to thank Brazilian Agencies Fundação de Amparo à Pesquisa de Minas Gerais (FAPEMIG), Conselho Nacional de Desenvolvimento Científico (CNPq) and Fundação Araucária for the support.
[1] S. Yano, et al., Bioorg. Med. Chem., 2004,
12, 3443. [2] S. Yano, et al., Bioorg. Med. Chem., 2004, 12, 3431 [3] J.P.A. Martins, J. Chem. Inf. Model., 2009, 49, 1428. [4] R.F. Teófilo, J.P.A. Martins, M.M.C. Ferreira, J. Chemom., 2009, 23, 32. [5] J.P.A. Martins, M.M.C. Ferreira, Quim. Nova, 2013, 36, 554.
169 The 10th Joint Meeting on Medicinal Chemistry 2017
P-94
SYNTHESIS AND DETERMINATION OF PHYSICOCHEMICAL PROPERTIES OF NEW POTENTIAL ANTIMYCOBACTERIAL DRUGS
Pavlína Marvanová,[a],* Tereza Padrtová,[a] Klára Odehnalová,[a] Otakar Humpa[b] and Petr Mokrý[a]
[a] Department of Chemical Drugs, University of Veterinary and Pharmaceutical Sciences Brno, Palackého třída 1, 612 42 Brno, Czech Republic [b] CEITEC—Central European Institute of Technology, Masaryk University, Kamenice 753/5, 62500 Brno, Czech Republic * [email protected]
Due to worldwide microbial resistance to commonly used therapeutic agents, antibiotics and antifungals, there is a search for new active compounds even in different therapeutical groups of drugs. The pharmacophore of N-arylpiperazine moiety can be found in chemical structure of many compounds that showed promising antimycobacterial activity.I In this study, new arylcarbonyloxyaminopropanole derivatives bearing substituted N-phenylpiperazine moiety were prepared and their physicochemical properties were determined. The compounds, 3-(4-arylpiperazin-1-yl)-2- R + hydroxypropyl 4-alkoxybenzoates (Figure) were OH N - H Cl prepared as hydrochloride salts via multi-step + H OO N synthesis starting from 4-alkoxybenzoic acids and - their Cl structure and purity were verified by available methods of instrumental analysis (1H FT-NMR, 13C FT- NMR, FT-IR, TLC, HPLC). The lipophilicity index Fig.1 (log k) was determined by means of RP-HPLC and ionizability (pKa) was determined by means of CZE. The in vitro activity of final compounds against O 1 Mycobacterium tuberculosis, Mycobacterium R smegmatis, Mycobacterium kansasii and Mycobacterium marinum will be evaluated and given into correlation with their physicochemical properties.
Acknowledgments: Part of the work was carried out with the support of core facilities of CEITEC— Central European Institute of Technology under CEITEC, open access project, ID number LM2011020, funded by the Ministry of Education, Youth and Sports of the Czech Republic under the activity “Projects of major infrastructures for research, development and innovations”.
[1] I. Malík, et al. Molecules, 2016, 21, 1274.
170 The 10th Joint Meeting on Medicinal Chemistry 2017
P-95
EXPLORATION OF NEW ANTICANCER CHEMOTHERAPEUTIC AGENTS BASED ON ANTITUMOR NATURAL PRODUCT ANDRASTINS
Shuqiang Yin, Quan Li, Aki Kohyama, Kenji Sugimoto and Yuji Matsuya*
Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan * [email protected]
Andrastins, isolated from the cultures of Penicillium sp. FO-3929 in 1996, are reported to exert ras protein farnesyltranferase inhibitory activity.[1] Thus, they are anticipated to be promising anti-cancer agents because farnesylation of the ras oncogene protein is essential for its function. Andrastins possess a unique sterically hindered cis-hydrindane ring system with vicinal quaternary carbons. Although their unusual structure and promising biological activity has attracted broad synthetic interest, no total syntheses and medicinal chemistry of andrastins have been reported so far. Herein, we report an efficient method for the construction of key skeleton of Andrastins utilizing o-xylylene cycloaddition strategy.
Me O C Me R3 Me D Me
A H OH R1 CO2Me R2 H Me Me B
Andrastin A: R1 = OAc, R2 = H, R3 = CHO 1 2 3 Andrastin B: R = OAc, R = H, R = CH2OH Andrastin C: R1 = OAc, R2 = H, R3 = Me 1 2 3 Andrastin D: R = R = O, R = CHO
Inspired by the power of intramolecuar cycloaddition of o-xylylenes thermolytically generated from benzocyclobutenes for the synthesis of polycyclic system, we decided to construct the steroidal skeletion of Andratins through a successive electrocyclic reactions. Coupling reaction of benzocyclobutene unit with corresponding aldehyde furnished the AD fragment 1. After decyanation, the product was subjected to intramolecular Diels-Alder reaction to give the key skeleton 2 via an o- xylylene intermediate. This compound is versatile precursor of various Andrastins and analogous derivatives, and medicinal chemistry based on these Andrastin compounds are now in progress in our laboratory.
O HO O HO O NC O 1) decyanation Andratins 2) Diels-Alder reaction MeO H CO2Me CO2Me 1 MeO 2
[1] S. Omura, et al. J. Antibiot., 1996, 49, 418; J. Antibiot., 1996, 49, 1278.
171 The 10th Joint Meeting on Medicinal Chemistry 2017
P-96
DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL PYRROLE-BASED AS EZH2 INHIBITORS
R. Mazzone,[a],* C. Zwergel,[a] M. Tafani,[c] A. Nebbioso,[d] L. Altucci,[d] A. Mai[a] and S. Alente[a]
[a] Department of Drug Chemistry and Technologies, University “La Sapienza”, P. le A. Moro 5, 00185 Rome, Italy [b] Department of Biology and Biotechnology, University of Pavia, via Ferrata 9, 27100 Pavia, Italy [c] Department of Experimental Medicine, University “La Sapienza”, Viale Regina Elena 324, 00161 Rome, Italy [d] Naples 2nd University Department of Biochemistry Biophysics and General Pathology Via De Crecchio 7, 800127 Naples, Italy * [email protected]
Polycomb repressive complex 2 (PRC2) mediates gene silencing of target genes involved in cell cycle regulation, cell fate and differentiation, senescence and cancer.[1] Enhancer of Zeste Homologue 2 (EZH2) is the catalytic subunit of PRC2 and, together with two other proteins (EED and SUZ12), specifically catalyzes lysine methylation. Indeed, EZH2 induces methylation of histone H3 on lysine 27 up to trimethylation by using S-adenosyl-L-methionine (SAM) as the co-substrate. Actually, GSK126 and two other clinical candidates, Tazemetostat and CPI-1205, are in phase I or I/II clinical trials for treatment of malignancies.[2] Prompted by this great clinical promise for cancer treatment, we planned to perform a structural simplification and modification on the indazole scaffold leading to novel pyrazole-based small molecules able to inhibit EZH2 as well as to decrease H3K27m3 levels in cancer. Among newly obtained pyrazole derivatives of the first series, 1a (Figure) displayed growth arrest and autophagy induction in leukemia and solid cancer cells.[3] Pursuing with a wider SAR investigation, pyrazole was replaced in the second series by a pyrrole nucleus, and various substituents (alkyl, aryl or different aromatic rings and arylalkyl group) have been inserted at the N1 position (1b, Figure Further optimization by introduction of various substituents in ortho, meta or para position of
IC50 15.4 M IC50 5.8-38.5 M IC50 0.33 M the N1-phenyl ring have been carried out. All new synthesized pyrrole-based compounds have been screened against the EZH2/PRC2 MT to determine their inhibition activities. Selected compounds have been tested in different cancer cell lines (leukemia U937 and NB4, human breast cancer cells MDA-MB231, neuroblastoma Kelly and SH-SY5Y) to determine their effect on cell proliferation. Our biological results indicate that 1c (Figure) is the most potent compound in our hands so far, according to its biochemical potency. We will go on with design and synthesis of more potent derivatives, inspired by the meta-phenyl substitution carried by 1c, and with further studies in other cancer cells including cancer stem cells.
[1] I. Comet, E. M. Riising, B. Leblanc, K. Helin, Nat. Rev. Cancer, 2016, 16, 12. [2] G. Stazi, C. Zwergel, A. Mai, S. Valente, Exp. Opin. Ther. Pat., 2017, 27, 797. [3] P. Mellini, B. Marrocco, D. Borovika, L. Polletta, S. Saladini, G. Stazi, C. Zwergel, P. Trapencieris, E. Ferretti, M. Tafani, S. Valente, A. Mai, submitted to J. Med. Chem., 2017.
172 The 10th Joint Meeting on Medicinal Chemistry 2017
P-97
SYNTHESIS OF NOVEL 13α-ESTRONE DERIVATIVES AS POTENTIAL 17β-HSD1 INHIBITORS
Ildikó Bacsa,[a] Rebeka Jójárt,[a] János Wölfling,[a] Gyula Schneider,[a] Bianka Edina Herman,[b] Mihály Szécsi[b] and Erzsébet Mernyák[a],*
[a] Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720, Szeged, Hungary [b] 1st Department of Medicine, University of Szeged, Korányi fasor 8–10, H-6720 Szeged, Hungary * [email protected]
Novel 13α-estrone derivatives were synthesized by Sonogashira coupling. Transformations of 2- or 4-iodo regioisomers of 13α-estrone and its 3-methyl ether were carried out under different conditions in a microwave reactor. 2-Iodo isomers were reacted with p-substituted phenylacetylenes using Pd(PPh3)4 catalyst and CuI as a cocatalyst. Coupling reactions of 4-iodo derivatives could be achieved by changing the catalyst to Pd(PPh3)2Cl2. The newly synthesized phenethynyl derivatives were partially or fully saturated. Compounds bearing a phenolic OH group furnished benzofurans under the conditions used for the partial saturation. The inhibitory effects of the compounds on human placental 17β-hydroxysteroid dehydrogenase type 1 isozyme (17β-HSD1) were investigated by an in vitro radiosubstrate incubation method. Certain 3-hydroxy-2-phenethynyl or -phenethyl derivatives proved to be potent 17β-HSD1 inhibitors, displaying submicromolar IC50 values. These compounds may serve as suitable tools for ligand-based enzyme studies. Further derivatizations may lead to nanomolar inhibitors and may provide promising candidates for drug development.
I
R1O 1
Pd(PPh3)4 R2 2 CuI, NEt3 R2 R O Pd/C O 20 bar H2 6 C H C Pd(PPh3)2Cl2 or Pd(OAc)2 H H 1 KOH/DMF R1O R O 3 9 H H C C R1 = H or Me 2 2 R MeO R = H or Me or OMe or F or CF3 5
O Pd/C O 20 bar H2 H Pd(PPh3)2Cl2 or 7 Pd(OAc) H H 2 1 KOH/DMF R1O R O R2 C 4 C MeO C H H C R2 2 R 10
Pd(PPh3)2Cl2 R2 CuI, NEt3 8
R1O I 2 Acknowledgments: The authors are grateful for financial support from the Hungarian Scientific Research Fund OTKA K113150. The work of Erzsébet Mernyák in this project was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences.
173 The 10th Joint Meeting on Medicinal Chemistry 2017
P-98
ANTITUMORAL AND ANTIVIRAL ACTIVITIES OF NOVEL 1,2,3-TRIAZOLYL APPENDED L-ASCORBIC ACID DERIVATIVES
Andrijana Meščić,[a] Anja Harej,[b,c] Višnja Stepanić,[d] Sandra Kraljević Pavelić,[b,c] Dominique Schols[e] and Silvana Raić-Malić[a],*
[a] Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, HR-10000 Zagreb, Croatia [b] Department of Biotechnology, University of Rijeka, Radmile Matejčić 2, HR-51000 Rijeka, Croatia [c] Centre for High-throughput Technologies, University of Rijeka, Radmile Matejčić 2, HR-51000 Rijeka, Croatia [d] Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, 10 000 Zagreb [e] Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium * [email protected]
L-Ascorbic acid is known as a ubiquitous carbohydrate of vital importance in living beings. Some pyrimidine and purine derivatives of 4,5-didehydro-5,6-dideoxy- and 6-deoxy-L-ascorbic acid exhibited selective and efficient cytostatic activities and displayed antiviral activities.[1] The 1,2,3- triazole moiety is extensively used in medicinal chemistry as a pharmacophore to modify known bioactive molecules and to potentiate their biological activities.[2,3] Although click reactions are traditionally conducted in batch process, the progress toward increased sustainability that requires novel approaches with reduced environmental impact opened up in recent years continuous-flow as a novel alternative to conventional batch-based synthesis.[4] Realizing the benefits of flow chemistry as green and sustainable process and in continuation of our study towards the synthesis of 1,2,3- triazole-containing heterocycle pharmacophores, our aim was to improve the practical applicability of Cu(I)-catalyzed azide–alkyne 1,3-dipolar cycloaddition (CuAAC) to provide diverse C-6- substituted 1,2,3-triazolyl 4,5-unsaturated L-ascorbic acid derivatives using innovative enabling ultrasound and continuous flow hybrid system.
The results of in vitro screening and in silico analysis will be presented.
[1] T. Gazivoda, M. Šokčević, M. Kralj, L. Šuman, K. Pavelić, E. De Clercq, G. Andrei, R. Snoeck, J. Balzarini, M. Mintas, S. Raić-Malić, J. Med. Chem., 2007, 50, 4105. [2] S. Raić-Malić, A. Meščić, Curr. Med. Chem., 2015, 22, 1462. [3] S.B. Ötvös, I.M. Mándity, L. Kiss, F. Fülöp, Chem. Asian J., 2013, 8, 800. [4] A. Meščić, A. Šalić, T. Gregorić, B. Zelić, S. Raić-Malić, RSC Adv., 2017, 7, 791.
174 The 10th Joint Meeting on Medicinal Chemistry 2017
P-99
IDENTIFICATION OF NEW INHIBITORS OF PRMTs BY A MULTI- SUBSTRATE-ADDUCT APPROACH
C. Milite,[a],* D. Rescigno,[a] A. Feoli,[a] S. Castellano[a,b] and G. Sbardella[a]
[a] Dipartimento di Farmacia, Università degli Studi di Salerno, Via Giovanni Paolo II, 132, 84084, Fisciano (SA), Italy [b] Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, Via S. Allende, 1, 84081 Baronissi (SA) Italy * [email protected]
The methylation of arginine residues is a prevalent posttranslational modification found in both nuclear and cytoplasmic proteins, which is involved in a number of different cellular processes, including transcriptional regulation, RNA metabolism, and DNA damage repair. Enzymes of the protein arginine N-methyltransferase (PRMT) family catalyze the transfer of a methyl group from the donor S-adenosyl-l-methionine (SAM or AdoMet) to the guanidinium side chain of arginine residues in the target protein. Despite extensive research aimed at better understand the role of PRMTs in physiological and pathological pathways, there have been only a few publications to date describing small-molecule chemical modulators of the PRMTs. A few years ago, starting from AMI-1 (the first selective inhibitor of PRMTs)[1] we identified EML108, which was characterized by an improved selectivity profile among methyltransferases and a good cellular activity.[2] Moreover, docking studies clearly showed that EML108 bind SAM and arginine pocket without fully occupying them. Starting from this evidence, we herein report the design and the synthesis of new PRMTs inhibitors based on the naphthalene scaffold of EML108. Firstly, we prepared some derivatives bearing a guanidine moiety connected to the naphthalene scaffold via a variable linker. After optimization, we further functionalized this scaffold with an adenosine moiety (Figure). This multi-substrate-adduct approach lead to the identification of new sub-micromolar inhibitors of the arginine methyltransferase PRMTs.
Figure: Multi-substrate-adduct approach to the discovery of new inhibitor of PRMT1.
[1] D. Cheng, et al., J. Biol. Chem., 2004, 279, 23892. [2] S. Castellano, et al., ChemMedChem, 2010, 5, 398.
175 The 10th Joint Meeting on Medicinal Chemistry 2017
P-100
SYNTHESIS AND EVALUATION OF NEW N-ACYLETHANOLAMINES PPAR-α LIGANDS PLANNED FROM CARDANOL
Camila de Oliveira Miranda,[a],* Carolyn Cummins[b] and Luiz A. Soares Romeiro[a]
[a] Post Graduate Program in Pharmaceutical Sciences, University of Brasilia, Faculty of Health Sciences, Darcy Ribeiro Campus, Brasil [b] Nuclear Hormone Receptors in Human Health and Disease Laboratory, University of Toronto, Canada * [email protected]
N-acylethanolamines are fatty acid amides that act on receptors and enzymes – notably PPAR and FAAH enzyme – modulating pathophysiological conditions.[1,2] Novel perspectives for neuroprotection involve the improvement of cognitive ability through mechanisms that include the synergistic activation of PPAR and CB1 receptors; activation of CB1 receptor and inhibition of FAAH; or by direct activation of PPAR-α by selective agonists.[1-3] Considering that the phenolic lipids of Cashew Nut Shell Liquid have structural similarity to fatty acids and that previous results have shown that anacardic and isoanacardic acids showed a weak agonist profile for PPARs,[4,5] we synthesized, and evaluated preliminary in vitro activity of novel N- acylethanolamines designed from cardanol. The synthetic strategy present here proved to be effective for obtaining 13 intermediates and 9 target compounds in yields ranging from 47 % to 91 %.
Figure: Synthetic route of the N-acylethanolamines, LDT 351 – 358.
Preliminary in vitro evaluation of the target compounds at 10 μM, 25 μM and 50 μM against luciferase for PPAR-α by reporter gene assay in HEK293 human embryonic kidney cells allowed the identification 4 derivatives (LDT352 – LDT355) as capable of activating PPAR transcription in relation to solvent activity. LDT352 and LDT353 derivatives present EC50 equal to 12 μM and 14 μM, respectively, while the other compounds are under EC50 determination and evaluation against to the FAAH enzyme.
[1] L.V. Panililio, Z. Justinova., S.R. Goldberg, Pharmacol. Ther., 2013, 138, 84. [2] C. Mazzola, J. Medalie, M. Scherma, Learn. Memory, 2009, 16, 332. [3] E. Di Tomaso, M. Beltramo, D. Piomelli, Nature, 1996, 382, 677. [4] P.S. Alves, Master’s Dissertation, Universidade de Brasília, Brasil, 2015. [5] F.J.G. Queiroz, Master’s Dissertation, Universidade de Brasília, Brasil, 2015.
176 The 10th Joint Meeting on Medicinal Chemistry 2017
P-101
DEVELOPMENT OF NOVEL REAGENTS FOR GENERATING ISLETS Β- CELLS AND ENHANCING THEIR FUNCTION BASED ON CLUSTERED NANOFORMULATION OF NEUROLIGIN-2 MIMETICS
Munder Anna,[a] Shtriker Efrat,[a] Viskind Olga,[a] Korshin Edward,[a] Chessler Steven[b] and Gruzman Arie[a],*
[a] Department of Chemistry, Faculty of Exact Sciences, Bar-Ilan University, Ramat-Gan, Israel [b] Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, University of California, Irvine, California, United States * [email protected]
Β-cell membrane and presynaptic zones of neurons have sites of similar protein complexes mediating secretion of bioactive molecules. Synaptic proteins that mediate interactions between neurons and guide the formation and functional maturation of synapses have been recently identified. These synapse-inducing proteins include neuroligins and their binding partners: neurexins. It was found that insulin secretion and the proliferation rate of β-cells increased when β- cells were co-cultured with cells overexpressing neuroligins. We propose that neuroligin-derived molecules arranged in clusters can enhance β-cell functions by increasing insulin secretion, functional maturity and protecting in stress conditions. Several peptides were derived from crystal structures of different neuroligins and neurexins using molecular modeling method. Based on these results, we designed and fabricated poly(amidoamine) dendrimer decorated by the peptide. The compound increased insulin secretion, induced the formation of islets-like cellular structures, proliferation rate and protected β-cell line against oxidative and ER stresses. Identical effect on the insulin secretion was also obtained in isolated mice islets. Moreover, diabetic mice treated by our compound significantly reduced blood glucose level in comparison to untreated mice. In summary, we report about the development of a new class of potential antidiabetic compounds. Such systems might support β-cell differentiation and viability in vitro, which will increase survival of further β-cell transplants in vivo. Such approach of using the neuron secretion machinery presented in β-cells as a target for antidiabetic drug design was never reported before.
177 The 10th Joint Meeting on Medicinal Chemistry 2017
P-102
TARGETING PLASMODIUM FALCIPARUM GLUCOSE-6-PHOSPHATE DEHYDROGENASE IN THE PURSUIT OF NOVEL ANTIMALARIAL AGENTS
Diego Muñoz-Torrero,[a],* Nelson Alencar,[b] Irene Sola,[a] María Linares,[c] Caterina Pont,[a] Luca Di Palma,[a] Carla Barbaraci,[a] Cristina Sampedro,[a] Jordi Juárez-Jiménez,[b] Paloma Abad,[c] Susana Pérez-Benavente,[c] Jerónimo Lameira,[d] José M. Bautista[c] and F. Javier Luque[b],*
[a] Laboratory of Pharmaceutical Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences and Institute of Biomedicine (IBUB), University of Barcelona (UB), Av. Joan XXIII 27-31, E-08028, Barcelona, Spain [b] Department of Nutrition, Food Science and Gastronomy, Faculty of Pharmacy and Food Sciences, and IBUB, UB, Av. Prat de la Riba 171, E-08921 Santa Coloma de Gramenet, Spain [c] Departamento de Bioquímica y Biología Molecular IV and Instituto de Investigación Hospital 12 de Octubre, Universidad Complutense de Madrid, Avda. Puerta de Hierro s/n, Ciudad Universitaria, E- 28040, Madrid, Spain [d] Laboratório de Planejamento e Desenvolvimento de Fármacos-LPDF, Instituto de Ciências Exatas e Naturais- ICEN, Universidade Federal do Pará – UFPA, Av. Augusto Correa, Nº 1- Bairro: Guamá, Cep: 66.075-900, Belém-Pará, Brazil * [email protected]; [email protected]
There currently exists a dire need for safe and inexpensive new antimalarial drugs, which are effective against multiple life cycle stages of Plasmodium falciparum, and act through mechanisms that differ from those of the available drugs to prevent drug resistance. The enzyme glucose-6-phosphate dehydrogenase (G6PD) of P. falciparum has emerged as a promising target for antimalarial drug discovery, in the light of its key role in parasite development and survival and of the protective effect against malaria infection observed under human G6PD deficiency conditions. Here we describe the construction of a homology model of PfG6PD, which has enabled the identification of key structural differences at the enzyme active site as compared with the human enzyme. We have exploited these changes for rationally designing a novel family of selective substrate analog-based inhibitors of PfG6PD, some of which display micromolar affinity, good PfG6PD over hG6PD selectivity, and low cytotoxicity, but weak antiplasmodial activity in phenotypic assays, likely as a consequence of a poor internalization of the compounds in the parasite cell. Work is in progress for improving the physicochemical / pharmacokinetic properties of this class of compounds.
178 The 10th Joint Meeting on Medicinal Chemistry 2017
P-103
A SYNTHESIS OF “DUAL WARHEAD” β-ARYL ETHENESULFONYL FLUORIDES AND ONE-POT REACTION TO β-SULTAMS
Praveen K. Chinthakindi,[a] Kimberleigh B. Govender,[a] A. Sanjeeva Kumar,[a] Hendrik G. Kruger,[a] Thavendran Govender,[a] Tricia Naicker[a],* and Per I. Arvidsson[a,b]
[a] Catalysis and Peptide Research Unit, University of KwaZulu-Natal, Durban, South Africa [b] Science for Life Laboratory, Drug Discovery & Development Platform & Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden * [email protected]
Herein, we report an operationally simple, ligand- and additive-free oxidative boron-Heck coupling that is compatible with the ethenesulfonyl fluoride functional group. The protocol proceeds at room temperature with chemoselectivity and E-isomer selectivity and offers facile access to a wide range of β-aryl/heteroaryl ethenesulfonyl fluorides from commercial boronic acids. Furthermore, we demonstrate a “one-pot click” reaction to directly transform the products to aryl-substituted β- sultams.
[1] P.K. Chinthakindi, H.G. Kruger, T. Govender, T. Naicker,P.I. Arvidsson, J. Org. Chem., 2016, 81, 2618. [2] J. Dong, L. Krasnova, M.G. Finn, K.B. Sharpless, Angew. Chem., 2014, 53, 9430. [3] A. Narayanan, L.H. Jones, Chem. Sci., 2015, 6, 2650.
179 The 10th Joint Meeting on Medicinal Chemistry 2017
P-104
SYNTHESIS AND CYTOTOXIC PROPERTIES OF NEW DERIVATIVES OF BENZOFURANS
M. Napiórkowska,[a] M. Cieślak,[b] K. Królewska,[b] J. Kaźmierczak-Barańska[b] and B. Nawrot[b]
[a] Chair and Department of Biochemistry, Medical University of Warsaw, 1 Banacha Str., 02-097 Warsaw, Poland [b] Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, 112 Sienkiewicza Str., 90-363 Łódź, Poland
Benzofuran skeleton occupies an important position in organic chemistry and is considered as one of the most important heterocyclic ring because of its diverse biological profile. This structural unit is a central part of a variety of biological active compounds. Benzofuran derivatives have been reported to possess several biological properties such as antiviral, immunosuppressive, antioxidant, antifungal, anti-inflammatory, antimicrobial, antifungal, analgesic, antihyperglycemic, and antitumor activities. Active compounds are both, synthetic as well natural derivatives. Well known natural compounds are Cicerfuran, Conocarpan and Ailanthoidol. In our previously studied[1,2] group of derivatives we have identified several benzofurans that , presented highest cytotoxicity to leukemia cells, lines K562, HL-60, respectively (IC50 * in the range of 0.1-10 µM). On the contrary, these compounds were non-toxic to non-tumor endothelial cells (HUVEC) and tumor adherent cells (HeLa). Because high activity of evaluated compounds we decided to continue our work on the field of these derivatives. The main stage of synthetic works was the modification of the structure of benzofuran derivatives in order to obtain products with improved solubility and bioavailability, while retaining their biological activity. In order to improve the solubility of the compounds hydrophilic groups such as - OH, NH2, COOH were introduced to their structure. Thus we have synthesized 12 new derivatives (Figure). The structures of all new compounds were established by 1HNMR, 13CNMR and HR MS spectra.
-COOH, -CONH -CHCH2Br, -CH Br -COOH, -CONH2 2 3 2 -Br,Br -H H3CO -COOCH3 -COOCH 3 H CO OH 3 -COOH, -CONH , COCH3 2 O H CO -CH , -CH Br -CH , -CH Br 3 -COOCH3 3 2 3 2 Br2HC Br 2HC COCH3 -CHOHCHBr O O 2 -CHOHCHBr2
-COCHBr2 -COCHBr2 O O Figure: Examples of modifications in the structures of the compounds.
The obtained compounds were tested for their cytotoxic properties in cervix carcinoma (HeLa), chronic myelogenous leukemia (K562), acute lymphoblastic leukemia (MOLT-4) and normal endothelial (HUVEC) cells using MTT assay. In these screening studies we have identified four compounds that showed toxicity towards both HeLa, K562 and MOLT-4 cell lines. SAR analysis showed that the presence of a halogen atom in the structure of benzofuran derivatives seems to be a crucial factor inducing their toxicity.
[1] M. Krawiecka, B. Kuran, J. Kossakowski, M. Cieslak, J. Kazmierczak-Barańska, K. Królewska, B. Nawrot, EP 2631232 A1, 2013. [2] M. Krawiecka, B. Kuran, J. Kossakowski, M. Cieslak, J. Kazmierczak-Barańska, K. Królewska, B. Nawrot, Anticancer Agents Med. Chem., 2014, 15, 115.
180 The 10th Joint Meeting on Medicinal Chemistry 2017
P-105
INVESTIGATION OF THE ANTIPROLIFERATIVE AND ANTIHYPERGLYCEMIC ACTIVITIES OF NEW THIAZOLIDINEDIONE DERIVATIVES
Cristina Nastasă,[a] Daniel Scherman,[b] Alina Pârvu,[c] Ovidiu Oniga[a] and Brîndușa Tiperciuc[a]
[a] Department of Pharmaceutical chemistry, ”Iuliu Hațieganu” University of Medicine and Pharmacy, Faculty of Pharmacy, Cluj-Napoca, Romania [b] Unité de Pharmacologie Chimique et Génétique et d'Imagerie, INSERM U1022 - CNRS UMR8151, Paris, France [c] Department of Physiopathology, ”Iuliu Hațieganu” University of Medicine and Pharmacy, Faculty of Medicine, Cluj-Napoca, Romania * [email protected]
Cancer represents a global threat, each year millions of persons losing their lives because of this disease.[1] For its limitation, an early diagnose, a careful monitoring and the finding of new efficient drugs, with limited secondary effects, are urgently needed. Diabetes is an important issue for the health system, due to its severe and life-threatening complications.[2] Thiazole and its derivatives (thiazolidine, thiazolidinedione) are frequently cited in literature for their antiproliferative,[3] antidiabetic[4] and antioxidant activities. Thiazolidinediones (glitazones) are drugs already used in the treatment of type 2 diabetes.[5] This research project had as goals the investigation of the antiproliferative and antihyperglycemic effects of a series of newly synthesized thiazolidinediones. The antiproliferative activity of 16 thiazolidinedione derivatives, previously [6] synthesized, was evaluated by the MTT test, calculating IC50 on 2 tumor cell lines (B16 and CT26). For the antihyperglycemic potential, an experimental model of diabetes was induced by the intraperitoneal injection of streptozotocin, in rats. After hyperglycemia was produced, animals received, by gavage, suspensions of 6 thiazolidinedione derivatives, previously synthesized.[7-9] Their effects were compared with the reference antidiabetic pioglitazone. The compounds demonstrated promising inhibitory effects against the studied tumor cell lines. Thiazolidinediones 3, 7 and 9 exhibited best antiproliferative activity against B16 cells and compounds 1, 2 and 6, against CT26, respectively. Reduction of hyperglycemia, manifested in the animals treated with the tested molecules, was superior to pioglitazone, the antidiabetic drug used as reference. This project was realized with the support of ”Iuliu Hațieganu” University of Medicine and Pharmacy internal grant no. 4944/7/08.03.2016.
[1] WHO Media Centre http://www.who.int/mediacentre/factsheets/fs297/en/. [2] F. Paneni, J.A. Beckman, M.A. Creager, F. Cosentino, Eur. Heart J., 2013, 34, 2436. [3] M.S. Abdel-Maksoud, M.-R. Kim, M.I. El-Gamal, M.M. Gamal El-Din, J. Tae, H. Choi, K.-T. Lee, K. Yoo, C.-H. Oh, Eur. J. Med. Chem., 2015, 95, 453. [4] S.-J. Yang, W. Lee, E.-A. Kim, K. Nam, H.-G. Hahn, S. Choi, S.-W. Cho, Eur. J. Pharmacol., 2014, 736, 26. [5] L.A. Faine, M. Rudnicki, F.A. César, B.L. Heras, L. Boscá, E.S. Souza, M.Z. Hernandes, S.L. Galdino, M.C.A. Lima, I.R. Pitta, D.S.P. Abdalla, Curr. Med. Chem., 2011, 18, 3351. [6] C. Nastasă, B. Tiperciuc, A. Pârvu, M. Duma, I. Ionuţ, O. Oniga, Arch. Pharm., 2013, 346, 481. [7] C. Nastasă, B. Tiperciuc, L. Vlase, A. Pîrnău, O. Oniga, Studia UBB Chemia, 2015, LX(4), 239. [8] C. Nastasă, M. Duma, C. Marie, D. Scherman, B. Tiperciuc, O. Oniga, Dig J Nanomater. Biostruct., 2013, 8, 1079. [9] C.M. Nastasă, M. Duma, A. Pîrnău, L. Vlase, B. Tiperciuc, O. Oniga, Clujul medical, 2016, 89, 122.
181 The 10th Joint Meeting on Medicinal Chemistry 2017
P-106
ANTICARCINOGENIC POTENTIAL OF PLUM (Prunus domestica L.) KERNEL EXTRACTS OBTAINED BY SUBCRITICAL WATER
Nataša Nastić,[a],* Slavica Ražić,[b] Ana Damjanović,[c] Aleksandra Cvetanović,[a] Višnja Gaurina Srček,[d] Igor Slivac,[d] Kristina Radošević[d] and Jaroslava Švarc-Gajić[a]
[a] Faculty of Technology, University of Novi Sad, Bulevar cara Lazara 1, 21000 Novi Sad, Serbia [b] Faculty of Pharmacy, Department of Analytical Chemistry, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia [c] Laboratory for Biological Response Modifiers, Department for Experimental Oncology, Institute of Oncology and Radiology of Serbia, Belgrade, Serbia [d] Faculty of Food Technology and Biotechnology, University of Zagreb, Pierottijeva 6, 10000 Zagreb, Croatia * [email protected]
Colorectal cancer is the third most common cancer and one of the leading causes of morbidity and mortality.[1] Last years of the twentieth century were marked with increased worldwide interest in herbal medicine and natural health-promoting preparations. Published research confirms that plants and plant by-products are rich in valuable phytochemicals with health benefits against cancer and other diseases. Consumption of plums (Prunus domestica L.) is believed to be beneficial for treat blood circulation, digestive disorders, diabetes, and obesity.[2] High fibre content in plums promote digestion and peristalsis thus it is beleived that regular consumption of this fruit may play a role in the prevention of colorectal cancer. Kernels recovered from plum pit are still unexploited plant resources and agricultural by-product. In recent years, valorisation of organic by-products by different approaches has gained great interest. In this respect, the efforts have been directed to development and application of environmentally-benign extraction techniques, such as subcritical water extraction. The main goal of the present study was, therefore, to examine anticarcinogenic potential of subcritical water extracts of plum kernels. Biological activity was tested by in vitro assay using human colorectal adenocarcinoma cell line (LS-174T). Bioactive compounds from plum kernels were extracted by subcritical water in house-made extractor at different temperatures (25- 100 °C), while other parameters were constant. Obtained extracts were assessed for their anticarcinogenic potential using methyl thiazole tetrazolium (MTT assay). Table 1: The influence of the extraction temperature on anticarcinogenic activity of plum kernel extracts obtained by subcritical water
o , Temperature [ C] IC50 [µg/ml] * 25 12.28±1.46 40 13.41±1.72 60 8.81±0.52 80 14.90±0.93 100 / *Mean value ± 2SD of three replications
Obtained results confirmed anticarcinogenic activity of the plum kernel extracts against colorectal cancer (Table 1). The highest anticarcinogenic potential on LS-174T with the IC50 values of 8.81 ± 0.52 μg/ml was provided by the extraction at temperature of 60°C. In conclusion, this research represents a pioneering work to further investigations directed towards identification of pharmacologically-active compounds in plum kernels for the purpose of new anti-cancer drug design and development.
[1] F.A. Haggar, R.P. Boushey, Clin. Colon Rectal Surg., 2009, 22(04), 191. [2] T.S. Li, Vegetables and fruits: nutritional and therapeutic values. CRC Press, 2008.
182 The 10th Joint Meeting on Medicinal Chemistry 2017
P-107
IN VITRO SCREENING OF ANTICARCINOGENIC PROPERTIES OF CHERRY STEM EXTRACTS OBTAINED BY SUBCRITICAL WATER
Nataša Nastić,[a],* Višnja Gaurina Srček,[b] Kristina Radošević,[b] Igor Slivac,[b] Aleksandra Cvetanović,[a] Vesna Novakov[a] and Jaroslava Švarc-Gajić[a]
[a] Faculty of Technology, University of Novi Sad, Bulevar cara Lazara 1, 21000 Novi Sad, Serbia [b] Faculty of Food Technology and Biotechnology, University of Zagreb, Pierottijeva 6, 10000 Zagreb, Croatia * [email protected]
The development of new anticancer drugs based on naturally occurring biologically active compounds continues to be a major focus in cancer research. The use of natural by-products from agriculture and food production processes to extract valuable compounds has become more and more common in recent years. Sweet and sour cherry (Prunus avium L. and Prunus cerasus L.) stems attract the interest of scientific community due to their long use in alternative medicine as sedative and diuretic in form of infusions and decoctions.[1,2] Due to high content of flavonoids and potassium, it has been reported that cherry stems contribute to suppression of inflammation and have positive effects on cardiovascular system and smooth muscles. In the present study, cherry stem extracts were prepared by subcritical water and valorised by testing their biological activity in vitro using hepatocellular carcinoma (HepG2) and breast adenocarcinoma (MCF-7) cell lines. Bioactive compounds from sweet and sour cherry stems were extracted by subcritical water at extraction temperature of 150 °C, extraction pressure of 30 bar, extraction time of 30 min and convective mass transfer defined by vibration frequency of the reaction vessel of 3 Hz. The cancer cells were exposed to the different volume ratios of extracts (1 v/v to 20 v/v) for 72 h and the effects on cell growth were evaluated using the CellTiter 96® Aqueous One Solution Cell Proliferation Assay (Promega, USA).
Table 1: IC50 values of sweet and sour cherry stem extracts obtained by subcritical water IC50 [v/v] HepG2 MCF-7 P. avium stems 18.29 17.99 P. cerasus stems >20 >20
Comparing the survival of HepG2 and MCF-7 cells treated with obtained extracts, and the calculated IC50 values it can be concluded that subcritical water extracts of P. avium stems had higher anticarcinogenic potential than P. cerasus stems.
[1] N. Hooman, F. Mojab, B. Nickavar, P. Pouryousefi-Kermani, Pakistan J. Pharm. Sci., 2009, 22, 381. [2] S. Shamsi, Int. J. Green Pharm. (IJGP), 2017, 11(01).
183 The 10th Joint Meeting on Medicinal Chemistry 2017
P-108
DESIGN, SYNTHESIS AND ANTICONVULSANT ACTIVITY OF NEW PIPERAZINAMIDES DERIVED FROM 3-ISOBUTYL-2,5- DIOXOPYRROLIDIN-1-YL-ACETIC ACID
Jolanta Obniska,[a],* Małgorzata Góra,[a] Sabina Rybka,[a] Krzysztof Kamiński[a] and Anna Rapacz[b]
[a] Department of Medicinal Chemistry, Jagiellonian University, Medical College, 9 MedycznaStreet, 30-688 Kraków, Poland [b] Department of Pharmacodynamics, Jagiellonian University, Medical College, 9 Medyczna Street, 30-688 Kraków, Poland * [email protected]
Recent studies from our laboratory have demonstrated the various anticonvulsant activity among the amides derived from 2,5-dioxopyrrolidin-1-yl-acetic acid with different substituents at position-3 of pyrrolidine-2,5-ring.[1,2] In these series of derivatives the most active were compounds with methyl and ethyl group at position-3 of imide ring. Taking into consideration these results, in search of new anticonvulsant agents, in the present study new piperazinamides with the 3-isobutyl-2,5-dioxo- pyrrolidin-1-yl-acetic acid as a core fragment have been synthesized (Figure). O O F N R N CH CH N N 3 N N 3 CH O O 3 O O
3CH ED = 82.74 mg/kg (MES ip in mice) 50 R = H, 2-F, 4-F, 2-Cl, 2,3-Cl, 2-CF , 2-CH , ED = 40.34 mg/kg (sc.PTZ ip in mice) 3 3 50 3-CH 2-OCH , 3-OCH 3, 3 3
The target compounds were synthesized in two-step procedure. The starting 2-isobutyl-succinic acid was prepared according to the method described previously.[1,2] In the next step the cyclocondensation of obtained acid with 2-amineacetic acid yielded in 3-isobutyl-2,5-dioxo- pyrrolidin-1-yl-acetic acid. The final compounds were obtained in the coupling reaction of 3-isobutyl- 2,5-dioxo-pyrrolidin-1-yl-acetic acid with equimolar amounts of appropriate 4-phenylpiperazines in the presence of carbonyldiimidazole reagent. All obtained compounds have been evaluated for their anticonvulsant activity in the MES and scPTZ seizure tests.
Acknowledgments: This study was supported by the grant of National Scientific Centre, Poland (Grant No DEC-No-2013/11/B/NZ7/02081).
[1] J. Obniska, A. Rapacz, S. Rybka, B. Powroźnik, E. Pękala, P. Żmudzki, K. Kamiński, Eur. J. Med. Chem., 2015, 102, 14. [2] J. Obniska, A. Rapacz, S. Rybka, M.Góra, K. Kamiński, K. Sałat, P. Żmudzki, Bioorg.Med. Chem., 2016, 24, 1598.
184 The 10th Joint Meeting on Medicinal Chemistry 2017
P-109
IDENTIFICATION OF 3-[3, 4-BIS-(TERT-BUTYL-DIMETHYL- SILANYLOXY)-PHENYL]-PROPIONIC ACID AS AN ADIPONECTIN EXPRESSION ENHANCER
Tsutomu Oikawa,[a],* Motomu Inoue,[a] Yurie Ueno,[a] Atsuko Motojima,[a] Nobuyasu Matsuura,[b] Tomio Saito[c] and Hiroyuki Osada[c]
[a] School of Nutrition and Dietetics, Kanagawa University of Human Services, Yokosuka, Kanagawa 238- 8522, Japan [b] Faculty of Science, Okayama University of Science, Okayama, Okayama 700-0005, Japan [c] Chemical Biology Department, RIKEN Advanced Science Institute, Saitama 351-0198, Japan * [email protected]
Patients with diabetes have been increasing worldwide, and the patient number has been estimated to rise from 171 million in 2000 to 366 million in 2030. [1] Type 2 diabetes mellitus accounts for over 90% of all diabetes. Type 2 diabetes is characterized by decreased insulin secretion and insulin resistance. Thus overcoming insulin resistance is an important issue in the prevention and/or treatment of type 2 diabetes. Recent studies have shown that adiponectin, an adipocyte-derived hormone-like protein, exerts insulin-sensitizing and anti-diabetic effects, indicating the protein represents a potential target for treating and/or preventing type 2 diabetes. Also, expression of adiponectin has been shown occur during adipogenesis. Based on our hypothesis that molecues that induce adipocyte differentiation could also act as stimulators of adiponectin expression, we screened a novel small-molecule stimulator of adiponectin expresssion, using the system involving differentiation of ST-13 preadipocytes as an indicator, and found that some small molecules, including nobiletin, norlichexanthone, testufuran A and nocapyrones, induced adipogenesis in ST- 13 cells and upregulated adiponectin expression.[2-5] Furthermore, using the cell-based screen system, we carried out screening of 1,056 compounds from RIKEN NPDepo library, for finding out compounds that caused adipocyte differentiation. Of them, several compounds remarkably caused adipogenesis in ST-13 cells treated, as judged from a microscopic observation of celluar accumulation of lipid droplets. They include 3-[3, 4-bis-(tert-butyl-dimethyl-silanyloxy)- phenyl]- propionic acid (1), astemisole, corticosterone and glibenclamide. Herein, we report the identification of 1 as an adiponectin expression enhancer. Oil red O staining showed that 1 promoted adipogenesis in ST-13 cells. Real-time RT-PCR assay confirmed that 1 increased the mRNA expression of aP2 and PPARγ2, markers of adipocyte differentiation. Western blot analysis demonstrated that 1 enhanced the extracellular secretion of adiponectin protein. An increase in adiponectin mRNA level was also observed in the ST-13 cells treated with 1. The increased adiponectin mRNA was blocked by actinomycin D treatment, implying that the increase is the result of upregulated transcription. These results identified 1 as an enhancer of adiponectin expression. Additionally 1 significantly increased the mRNA expression of glucose transporter 4 that plays a key role in glucose uptake in adipocytes and muscle cells, compared with the vehicle. These findings suggest the possibility that 1 has the potential to treat and/or prevent type 2 diabetes and other lifestyle-related diseases like metabolic syndrome.
[1] S. Wild, et al. Diabetes Care. 2004, 27, 1047. [2] K. Kunimasa, et al., Bioorg. Med. Chem. Lett., 2009, 19, 2062. [3] M. Ikeda, et al., Med. Chem., 2011, 7, 250. [4] T. Akiyama, et al., Tetrahedron, 2013, 69, 6560. [5] Y. Kim, et al., Mar. Drugs, 2014, 12, 4110.
185 The 10th Joint Meeting on Medicinal Chemistry 2017
P-110
SYNTHESIS AND BIOLOGICAL ACTIVITY OF 3-AMINOTHYMOQUINONE
Una Glamočlija,[a],* Subhash Padhye,[b] Selma Špirtović-Halilović,[a] Amar Osmanović,[a] Elma Veljović,[a] Sunčica Roca,[c] Irena Novaković,[d] Sandra Kraljević Pavelić,[e] Anja Harej[e] and Davorka Završnik[a]
[a] Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Sarajevo, Zmaja od Bosne 8, 71000 Sarajevo, Bosnia and Herzegovina [b] Interdisciplinary Science and Technology Research Academy, University of Pune, 2390-B, Hidayatullah Road, 411001 Pune, India [c] NMR Centre, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia [d] IHTM, Center for Chemistry, University of Belgrade, Njegoševa 12, 11000 Belgrade, Serbia [e] Department of Biotechnology, University of Rijeka, Radmile Matejčić 2, 51000 Rijeka, Croatia * [email protected]
Thymoquinone (TQ) is a natural benzoquinone with various biological and medicinal activities. The main disadvantage of TQ is its low aqueous solubility. In the present work we report the synthesis and biological activities of TQ derivative, 3-aminothymoquinone (ATQ). ATQ was prepared according to published literature reports,[1] with slight modifications (Figure). The structure was identified by elemental analysis and characterized in solution by mass spectrometry and NMR spectroscopy.
O O
CH3COOH + NaN 3 Reflux 3 hours NH2 O O Thymoquinone 3-aminothymoquinone Figure: Synthesis of 3-aminothymoquinone from starting compound thymoquinone.
Antimicrobial activity was determined against four Gram-positive and four Gram-negative bacteria strains and three fungi using diffusion and micro-dilution methods. It was observed that antibacterial activity is diminished in case of ATQ when compared to TQ. On the other hand, ATQ showed strong antifungal activity in all tested fungi (Candida albicans ATCC 10231, Saccharomyces cerevisiae ATCC 9763 and Aspergillus brasiliensis ATCC 16404) with minimal inhibitory concentration (MIC) values significantly lower when compared to TQ and Nystatin which was used as the reference drug. Antiproliferative activity of TQ and ATQ was evaluated in five different cell lines: SW620 (metastatic human colon adenocarcinoma), CFPAC (ductal pancreatic adenocarcinoma), HepG2 (hepatocellular carcinoma), HeLa (cervical adenocarcinoma) and WI38 (human lung fibroblasts). ATQ had stronger effects in all tested cell lines when compared to TQ. In conclusion, ATQ, which is the C-3 amino derivative of TQ, exerts significantly higher antifungal and antitumor activity, when compared to parent compound.
[1] M. Yusufi, S. Banerjee, M. Mohammad, S. Khatal, K. Venkateswara Swamy, E. M. Khan, A. Aboukameel, F. H. Sarkar, S. Padhye, Bioorg. Med. Chem. Lett., 2013, 23, 3101.
186 The 10th Joint Meeting on Medicinal Chemistry 2017
P-111
SYNTHESIS AND ANTICONVULSANT ACTIVITY OF NEW PHENOXYACETHAMIDE DERIVATIVES OF AMINES, AMINOALKANOLS OR AMINO ACIDS
Katarzyna Pańczyk,[a],* Anna Waszkielewicz,[a] Dorota Żelaszczyk,[a] Ewa Żesławska,[b] Karolina Słoczyńska,[c] Paulina Koczurkiewicz,[c] Elżbieta Pękala[c] and Henryk Marona[a]
[a] Department of Bioorganic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna Str. 9, 30-688 Kraków, Poland [b] Department of Chemistry, Institute of Biology, Pedagogical University, Podchorążych Str. 2, 30-084 Kraków, Poland [c] Department of Pharmaceutical Biochemistry, Jagiellonian University Medical College, Medyczna Str. 9, 30-688 Kraków, Poland * [email protected]
Within the present study nineteen new 2,3-dimethyl-, 2,6-dimethyl- or 2,4,6-trimethylphenoxy- acetamide derivatives of amines, aminoalkanols or amino acids were designed for potential anticonvulsant activity (Figure). O O R: 2,3-(CH ) , 2,6-(CH ) or 2,4,6-(CH ) Z 3 2 3 2 3 3 R Z: amine, aminoalkanol or amino acid
Figure: General formula of title compounds.
All title compounds were obtained via multistep chemical synthesis. Firstly, appropriate phenols were transformed into substituted phenoxyacetyl chlorides. The obtained acid chlorides were the subject of aminolysis in order to obtain the final products. In case of several compounds, the reaction was carried out with the use of amino acid ester hydrochlorides and was followed by reaction with either [1] NaHCO3, ammonia or methylamine. The identity and purity of synthesized compounds was confirmed by means of analytical HPLC analysis, LCMS and spectral methods (1H and 13C NMR). Three active compounds were the subject of crystallography studies, which confirmed their configuration. Antiepileptic activity and neurological toxicity assays were carried out by the Epilepsy Therapy Screening Program, ETSP, Epilepsy Branch, National Institute of Neurological and Communicative Disorders and Stroke, National Institutes of Health in Rockville, USA. All compounds were the subject of preliminary screening for anticonvulsant activity and neurotoxicity (rotarod) in mice after i.p. administration, including 6 Hz[2] and MES or MES and scMET as models of convulsions. Several most active compounds were the subject of additional studies, including MES in rats after p.o. administration. For compound 7 (R-(-)-2-(2,6-dimethylphenoxy)-N-(1-hydroxypropan-2- yl)acetamide) ED50 (12 mg/kg b.w., rats, p.o.) and TD50 (>500 mg/kg b.w., rats, p.o.) values have been established. The most active compounds were the subject of preliminary safety testing. Four active compounds were evaluated for their potential mutagenic activity with the use of Ames test.[3] No mutagenicity was observed, however all tested compounds showed moderate to strong antimutagenic effect. Compound 7 was additionally tested in vitro for cytotoxicity against astrocytes and showed no toxic effect in the used concentrations.
Acknowledgments: This work was supported by the National Science Centre, Poland, decision on grant no. DEC-2015/17/N/NZ7/00966.
[1] H. Marona, A. M. Waszkielewicz, E. Szneler Acta Pol. Pharm. - Drug Des., 2005, 62, 345. [2] M. E. Barton, B. D. Klein, H. H. Wolf, H. S. White Epilepsy Res., 2001, 47, 217. [3] K. Mortelmans, E. Zeiger Mutat. Res., 2000, 455, 29.
187 The 10th Joint Meeting on Medicinal Chemistry 2017
P-112
THEORETICAL PREDICTION OF LIPOPHILICITY OF THIOSEMICARBAZIDE DERIVATIVES
Agata Paneth,* Tomasz Plech, Dominika Janowska, Szymon Kosiek, Nazar Trotsko and Monika Wujec
Department of Organic Chemistry, Medical University of Lublin, Poland * [email protected]
Since it is important to carefully monitor logP values at the lead selection level and during lead optimization to ensure that the clinical candidates are within an acceptable lipophilicity range, we have focused our attention on finding a computational tool that would be applicable to rapid and accurate predictions of lipophilicity of thiosemicarbazide-based compounds. From the thermodynamical point of view the equilibrium constant K (at a given temperature and standard concentration) is given by the equation:
∆ = − where G is Gibbs free energy, R is universal gas constant and T – absolute temperature. It thus should be possible to evaluate logKo-w values by computing Gibbs free energies of a given molecule in aqueous/octanol solutions. Expanding recent reports[1] we have tested three continuum solvent models (IEFPCM, CPCM, SMD) with the DFT B3LYP functional expressed in several basis sets (6-31+G(p,d), 6-311++G(d,p), aug-cc-pVDZ, def2-DZVP, def2-TZVP). Initially RM-1 optimized structures were reoptimized in the gas phase at the given theory level and then three types of calculations were performed. Firstly, energies for the gas phase structures with inclusion of the solvent model were calculated. Secondly, reoptimization with solvent model included has been performed for both liquid phases. Finally, frequency calculations for the structures optimized with solvent models have been carried out in order to calculate ZPEs and thermal corrections to Gibbs free energies. Among tested methods SMD/B3LYP/def-TZVP turned out to be most promising in terms of speed of calculations and agreement of the results with the experimental data. We have found that results from the first two methods correlate linearly with the experimental values (see Figure) with logP = 1.38logKo-w+0.92, where Ko-w is calculated equilibrium constant. SP opt 4 2
2 1
0 0 0 2 4 6 0 2 4 6
Figure: Correlation of experimental logP with energy calculated (left panel) and reoptimized (right panel) values obtained theoretically.
The results obtained with inclusion of thermal correction and ZPEs does not correlate with the experimental results. This is probably the result of double-counting liquid solvent contribution since continuum solvent models are parametrized to directly provide Gibbs free energies at the standard state. Comparison of the above results shows that SMD/B3LYP/def2-TZVP// B3LYP/def2-TZVP calculations are promising for theoretical prediction of lipophilicity for the class of compounds considered herein.
Acknowledgements: The project was funded by the National Science Centre (decision number: 2012/05/D/NZ7/02278).
188 The 10th Joint Meeting on Medicinal Chemistry 2017
P-113
NOVEL SPIRO CARBOCYCLIC HYDANTOIN-DERIVATIVES WITH POTENT ANTITRYPANOSOMAL ACTIVITY
Vasiliki Pardali,[a] Martin C. Taylor,[b] John M. Kelly[b] and Grigoris Zoidis[a],*
[a] School of Health Sciences, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, 15771, Athens, Greece [b] Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, U.K. * [email protected]
Human African Trypanosomiasis (HAT) or sleeping sickness is a vector borne-parasitic disease, resulting from infections with flagellated unicellular parasites of the species T. brucei. Approximately, 65 million people in 36 countries in sub-Saharan Africa are at risk of HAT infection, which has been recognized by World Health Organization as a Neglected Tropical Disease. Nowadays, only a few clinically useful drugs are available which suffer from severe side effects. Thus, the research has been focused on the discovery of new trypanocidal agents and the identification of new drug-targets in T. brucei.[1] Based on previous analogues of 2,6-diketopiperazine core which showed high potency against T. brucei, we rationally designed and synthesized new derivatives of 2,4-diketoimidazolidine scaffold, also known as hydantoin, endowed with the acetohydroxamic acid unit at the imidic nitrogen, as potential metal-chelating moiety.[2] A variety of lipophilic carbocyclic rings have been used as spiro substituents at position 5, in order to increase the affinity for the target. A further structural modification was accomplished by attaching an additional methyl group at the amidic nitrogen, so as to increase their binding capacity, which interestingly led to an increased activity for almost all derivatives. The novel compounds exhibited considerably potent activity against T. brucei with IC50 values in low nanomolar range. The cytotoxicity of the newly synthesized analogues was extremely small for mammalian cells and the selectivity indices were significantly high. The aforementioned findings indicate that the novel 2,4-spiro carbocyclic diketoimidazolidine scaffold emerge as valuable platform for developing antitrypanosomal agents and for further biological investigation.
[1] R. Brun, J. Blum, F. Chappuis, C. Burri, Lancet, 2010, 375, 148. [2] C. Fytas, G. Zoidis, N. Tzoutzas, M.C. Taylor, G. Fytas, J.M. Kelly, J. Med. Chem., 2011, 54, 5250.
189 The 10th Joint Meeting on Medicinal Chemistry 2017
P-114
SYNTHESIS AND BIOLOGICAL EVALUATION OF HYDROXAMATE COMPOUNDS AS HDAC6 INHIBITORS
Hui Yeon Mok, Han Pyo Son, Seung Yeop Baek, Hyun-Ju Park and Young Hoon Jung*
School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Korea * [email protected]
Epigenetic pathways are related to the cellular enzymes, including Histone deacetylase inhibitors(HDACs), which have key role in regulation of gene expression. Abnormal epigenetic pathways of cellular enzymes cause a human cancer, and this pathway was focused on target for developing anticancer drugs. HDACs catalyze the removal of acetyl group form the α-amino groups of lysine residues leads to gene transcription. It is reported that HDAC is associated with decreased expression tumor suppressor genes. Consequently, the identification of potential HDAC inhibitor is an important therapeutic strategy for treatment of cancers. HDAC inhibition has emerged as an attractive target for the development of new anti-tumor agents. In previous study, the lead compound has been found from novel non-hydroxamate compounds as prospective hits with significant HDAC inhibitor activities. In the present study, hydroxamate HDACs inhibitor’s derivatives have been designed, synthesized and their activity will be evaluated by enzymatic HDAC assay.
[1] So-Jin Kim, Ki Seon Baek, Hyun-Ju Park, Young Hoon Jung and Sun-Mee Lee, Br. J. Pharmacol., 2016, 173, 1045.
190 The 10th Joint Meeting on Medicinal Chemistry 2017
P-115
DRUG DESIGN AND SYNTHESIS OF NEW INDOLYLARYLSULFONES AS HIV-1 NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
S. Passacantilli,[a],* V. Famiglini,[a] G. La Regina,[a] A. Coluccia,[a] D. Masci,[a] J. A. Estè,[b] G. Maga[c] and R. Silvestri[a]
[a] Istituto Pasteur Italia – Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy [b] AIDS Research Institute – IrsiCaixa, Hospitals Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain [c] Institute of Molecular Genetics IGM-CNR, National Research Council, via Abbiategrasso 207, I- 27100 Pavia, Italy * [email protected]
HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) are key drugs of highly active antiretroviral therapy (HAART) in the clinical management of AIDS/HIV-1 infection. Our recent studies showed that indolylarylsulfones (IASs) bearing a cyclic moiety at the 2-carboxamide nitrogen linked through a short spacer group were endowed with potent antiretroviral activity.[1,2] Based on the results previously obtained, we aimed to expand the SAR studies by the introduction of new aryl or heteroaryl portions to the indole nucleus. Interestingly, for the first time IASs endowed with asymmetric centre have shown significant differences in term of antiretroviral potency. In particular, the (R)-enantiomer proved to be exceptionally potent and uniformly superior to the (S)-enantiomer against the whole viral panel. Docking studies showed that the methyl group of the (R)-enantiomer (Figure) pointed toward the cleft created by the K103N mutation, differently from the corresponding group of (S)-counterpart. By calculating the solvent accessible surface, we observed that the exposed area of the RT in complex with (S)-enantiomer was larger than the area of the (R)-complex.[3]
[1] G. La Regina, A. Coluccia, et al. J. Med. Chem,. 2012, 55, 6634. [2] V. Famiglini, G. La Regina, et al. Eur. J. Med. Chem., 2014, 80, 101. [3] V. Famiglini, G. La Regina, et al. J. Med. Chem., 2014, 57, 9945.
191 The 10th Joint Meeting on Medicinal Chemistry 2017
P-116
NEW (AMINOMETHYLENE)BISPHOSPHONATES OBTAINED FROM HETEROCYCLIC AMINES AND THEIR BIOLOGICAL ACTIVITY
Patrycja Miszczyk,[a],* Ewa Chmielewska[a], Błażej Dziuk[b], Joanna Wietrzyk[c] and Paweł Kafarski[a],*
[a] Department of Bioorganic Chemistry, Faculty of Chemistry, University of Science and Technology, Wybrzeze Wyspianskiego 27, 50-370 Wroclaw, Poland [b] Faculty of Chemistry, University of Opole, Oleska 48, 45-052 Opole, Poland [c] Ludwik Hirszfeld Institute of Immunology and Experimental Therapy Polish Academy of Sciences, Rudolfa Weigla 12, 3-114 Wroclaw, Poland * [email protected]
The three-component condensation between amines, triethyl orthoformate and diethyl phosphate (Figure 1) is perhaps the simplest and most commonly used preparation of N-substituted (aminomethylene)bisphosphonic acids [1].
P(O)(OEt) 2 P(O)(OH)2 HCl/H O R R 2 + HP(O)(OEt)2 + HC(OEt)3 R NH2 N P(O)(OEt) 2 N P(O)(OH)2 H H Figure 1: The three-component condensation between amines, triethyl orthoformate and diethyl phosphate.
The studies have shown that application of heterocyclic amines, such as triazole derivatives or purine base, in three-component condensation can give unexpected products having very interesting chemical structure. The biological studies have been shown that these compounds (Figure 2) can play a role as potential antiosteoporotic agent in the treatment of diseases [2] associated with calcium metabolism.
Figure 2: New bisphosphonate as antiosteoporotic agent.
[1] E. Dąbrowska, A. Burzyńska, A. Mucha, E. Matczak-Jon, W. Sawka-Dobrowolska, Ł. Berlicki, P. Kafarski, J. Organomet. Chem., 2009, 694, 3806. [2] E..Chmielewska, P. Kafarski, Open Pharm. Sci. J., 2016, 3, 56.
192 The 10th Joint Meeting on Medicinal Chemistry 2017
P-117
Abstract retracted for technical reasons
193 The 10th Joint Meeting on Medicinal Chemistry 2017
P-118
Abstract retracted for technical reasons
194 The 10th Joint Meeting on Medicinal Chemistry 2017
P-119
SYNTHESIS, ANTIBACTERIAL ACTIVITY AND SAR STUDY OF NOVEL AMIDINO 2-SUBSTITUTED BENZIMIDAZOLE DERIVATIVES
Nataša Perin,[a] Marijana Hranjec,[a] Mihaela Perić,[b] Hana Čipčić Paljetak,[b] Mario Matijašić,[b] Višnja Stepanić,[c] Donatella Verbanac,[b] Grace Karminski-Zamola[a] and Kristina Starčević[d],*
[a] Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, HR-10000 Zagreb, Croatia [b] Department for Intercellular Communication, University of Zagreb School of Medicine, Šalata 2, HR- 10000 Zagreb, Croatia [c] Division of Molecular Medicine, Laboratory for Epigenomics, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000 Zagreb, Croatia [d] Department of Animal Husbandry, Faculty of Veterinary Medicine, University of Zagreb, Heinzelova 55, HR-10000 Zagreb, Croatia * [email protected]
Bacterial organisms causing infectious diseases represent an increasing public health problem regardless of the current availability of numerous antimicrobial agents. Staphylococcus aureus represents a major Gram-positive human pathogen while Moraxella catarrhalis is establishing its role as an emerging respiratory Gram-negative pathogenic microorganism.[1] A series of novel 2-substituted benzimidazole derivatives were synthesized and their antibacterial activity was assessed against Gram-positive and Gram-negative bacteria.[2] The specific moiety at the 2-position of the benzimidazole was extensively modified with several fused heterocyclic functional groups containing nitrogen and sulphur heteroatoms.[3] In addition, the influence of different amidino groups at the position 5 of benzimidazole scaffold was evaluated. The values of clogP (a partition coefficient) and clogD7.5 (calculated distribution coefficient, pH 7.5) were determined and the lipophilic character of compounds has been found to be important parameter for the observed activity of the tested benzimidazole derivatives against M. catarrhalis. The indolo 2- substituted benzimidazole 13a demonstrated solid activity against S. aureus (MICs 16 µg/mL) and M. catarralis (MICs 2 µg/mL). Furthermore, the SAR results obtained in this study will be applied for the further optimization of this heteroaromatic core and for the design of novel derivatives in order to improve initially observed antibacterial activity.
[1] R. Karalusa, A. Campagnari, Microbes Infect., 2000, 2, 547. [2] K. Starčević, M. Kralj, K. Ester, I. Sabol, M. Grce, K. Pavelić, G. Karminski-Zamola, Bioorg. Med. Chem., 2007, 15, 4419. [3] M. Hranjec, M. Kralj, I. Piantanida, M. Sedić, L. Šuman, K. Pavelić, G. Karminski-Zamola, J. Med. Chem., 2007, 50, 5696.
195 The 10th Joint Meeting on Medicinal Chemistry 2017
P-120
CHEMICAL COMPOSITION AND BIOACTIVE EFFECTS OF LAVENDER ESSENTIAL OIL FROM MONTENEGRO
Svetlana Perović,[a],* Snežana Pantović,[b] Valentina Šćepanović,[a] Andrej Perović[a] and Biljana Damjanović-Vratnica[c]
[a] Department of Biology, Faculty of Natural Science and Mathematics, Dz. Vasingtona bb, Podgorica, Montenegro [b] Faculty of Medicine, University of Montenegro, Krusevac bb, Podgorica, Montenegro [c] Faculty of Metallurgy and Technology, University of Montenegro, Dz. Vasingtona bb, Podgorica, Montenegro * [email protected]
Essential oils, used as part of naturopathic therapy, have been found to be beneficial in the fields of dermatology, gastritis, respiratory complaints, wound healing, and genital infections. The general properties of lavender oil are antibacterial, antifungal, carminative (smooth muscle relaxant), sedative, antidepressant, promoting wound healing, and increasing the detoxification of enzymes associated with insecticide resistance. This study investigates chemical composition and antimicrobial activity of hydrodistillated essential oil of Lavandula officinalis from Montenegro and effects on autonomic nervous system (ANS). The oil was analyzed by GC-MS technique in order to determine the majority compounds while dilution method was used to determine minimal inhibitory concentration (MIC). Twenty healthy volunteers participated in the experiments. The present study assessed autonomic parameters such as blood pressure, heart rate, and skin temperature to determine the arousal level of the autonomic nervous system. In addition, subjects were asked to estimate their mood responses such as feeling pleasant or unpleasant, uncomfortable, sensuality, relaxation, or refreshing in order to assess subjective behavioral arousal. Chemical analysis by GC-MS identified 31 compounds in lavender essential oil representing 96.88 % of the total oil. Linalool (24.84%), was a major component, together with linalyl acetate (22.39%), 1,8 cineole (18.13 %) and camphor (12.88%). The investigated lavender oil from Montenegro consisted mostly of oxygenated monoterpenes (87.95%) and monotepene hydrocarbons (7%). The essential oil exhibited antimicrobial activity against Escherichia coli (ATCC 25922), Staphylococcus aureus (ATCC 25923), Listeria monocytogenes (ATCC 19111), Proteus mirabilis (ATCC 25933) and Candida albicans (ATCC 10231) with an MIC of 1.4ml/ml. The results revealed that lavender oil caused significant decreases of blood pressure, heart rate, and skin temperature, which indicated a decrease of autonomic arousal. In terms of mood responses, the subjects in the lavender oil group categorized themselves as more active, fresher and relaxed.
Acknowledgements: Financial support of this work to Montenegrian Ministry of Science (Project E!9906) is gratefully acknowledged.
196 The 10th Joint Meeting on Medicinal Chemistry 2017
P-121
NOVEL СONJUGATES OF DOXORUBICIN WITH ASGP-RECEPTOR LIGANDS FOR TARGETED DELIVERY
R. A. Petrov,[a] S. A. Petrov,[a] E. E. Ondar,[a] S. Yu. Maklakova,[a] I. V. Saltykova,[a] E. K. Beloglazkina,[a] A. G. Majouga[a,b] and V. E. Koteliansky[a,c]
[a] Chemistry Dept., Moscow State University, Moscow, Leninskie gory, building 1/3, 119991 [b] National University of Science and Technology “MISIS”, Moscow, Leninsky pr., building 4, 119049. [с] Skolkovo Institute of Science and Technology, Moscow, Skolkovo Innovation Center, Building 3,143026 * [email protected]
Hepatocellular carcinoma is the most common liver tumor, as a result of malignant transformation of hepatocytes. Every year more than 700 000 cases of this disease are diagnosed in the world[1]. One of the most promising ways to increase the efficiency of chemotherapy is the targeted delivery of drugs into the hepatocytes using the ASGP-receptor which recognize galactose derivatives. This receptor is located predominantly on liver cells surface and binds selectively to the hydroxyl groups in the 3rd and the 4th position of galactose. The outer part of the receptor consists of three subunits, each of them binds to galactose. In this work we investigate the synthetic approaches to the conjugates containing N-acetyl-2-deoxy-2-aminogalactopyranose moiety demonstrating high affinity to the ASGP-receptor for the delivery of doxorubicin into hepatocytes[2,3]. Obtained conjugates have been studied in vitro by MTT assay on HepG2 cell line.
HOOC
N N N N3 O O O O COOH CH2 CH2 OH NHAc OH NHAc CH OH 3 OH Doxorubicin 1 Or Or EDC, NHS, OH CuI, Et3N, OH DMF, rt rt O O O O N N3 N N OH NHAc OH NHAc COOH OH 2 OH 4
N OH N 5 N O O OH OH O O CH2
OH NHAc OH O O OH O NH 6 3CH R OH O O O O OH N
CH3 N N OH NHAc OH
[1] Y.Kumar, P.Sharma, N.Bhatt, K.Hooda. Asian Pac J Cancer Prev, 2016 17 (2), 473-478. [2] S. Yu. Maklakova, F. A. Kucherov, R.A. Petrov, V. V. Gopko, G. A. Shipulin, T. S. Zatsepin,E. K. Beloglazkina, N. V. Zyk, A. G. Majouga, and V. E. Kotelianskya, 2015 Russ. Chem. Bull., International Edition, 64(7), 1655. [3] Mamidyala S. K et al. J. Am. Chem.Soc., 2012, 134, 1978−1981 The work was supported by the RSF grant №17-14-01316.
197 The 10th Joint Meeting on Medicinal Chemistry 2017
P-122
SYNTHESIS, CHARACTERIZATION AND CYTOTOXICITY OF PHENOLIC COPPER(II) COMPLEXES
Vladimir P. Petrović,[a],* Dušica Simijonović,[a] Zorica D. Petrović,[a] Marko N. Živanović[b] and Snežana D. Marković[b]
[a] University of Kragujevac, Faculty of Science, Department of Chemistry, Radoja Domanovića 12, 34000 Kragujevac, Serbia [b] University of Kragujevac, Faculty of Science, Department of Biology and Ecology, Radoja Domanovića 12, 34000 Kragujevac, Serbia * [email protected]
In continuation of examination of the anticancer activity of metal-Schiff bases complexes,[1] we synthesized three chelate complexes of phenolic Schiff bases and the life important Cu2+ ion.[2] The obtained complexes were structurally characterized using experimental (IR and elemental analysis) and theoretical tools (Density Functional Theory). Comparison of experimental and calculated spectra of all complexes did not provide enough data to conclude which isomer prevails. On the basis of relative free energies, it is revealed that biologically the most active complex, with free phenolic OH group in ortho position, possess trans-square planar geometry (Figure).
Figure: The optimised structure of the biologically the most active complex 1.
Biological in vitro testings on two cancer cell lines and one line of healthy cells (HCT-116, MDA-MB- 231, and MRC-5, respectively) indicated that all examined complexes induced enormous oxidative/nitrosative stress followed with enhanced cytotoxicity of healthy and cancer cells.
[1] V.P. Petrović, M.N. Živanović, D. Simijonović, J. Đorović, Z.D. Petrović, S.D. Marković, RSC. Adv., 2015, 5, 86274. [2] R.A. Festa, D.J. Thiele, Curr. Biol., 2011, 21, R877.
198 The 10th Joint Meeting on Medicinal Chemistry 2017
P-123
THIOSEMICARBAZIDE DERIVATIVES WITH 4-NITROPHENYL GROUP AS MULTI-TARGET DRUGS
Monika Pitucha,[a],* Małgorzata Miazga-Karska,[b] Agnieszka A. Kaczor,[c,d] Katarzyna Klimek,[b] Zbigniew Karczmarzyk,[e] Maciej Woś,[a] Waldemar Wysocki,[e] Grazyna Ginalska,[b] Zofia Urbanczyk-Lipkowska[f] and Maja Morawiak[f]
[a] Department of Organic Chemistry, Faculty of Pharmacy with Division of Medical Analytics, Medical University, 4A Chodzki St., PL-20093 Lublin, Poland [b] Department of Biochemistry and Biotechnology, Faculty of Pharmacy with Division of Medical Analytics, Medical University, 1 Chodzki St., PL-20093 Lublin, Poland [c] Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Faculty of Pharmacy with Division for Medical Analytics, 4A Chodźki St., PL-20059 Lublin, Poland [d] University of Eastern Finland, School of Pharmacy, Department of Pharmaceutical Chemistry, Yliopistonranta 1, P.O. Box 1627, FI-70211 Kuopio, Finland [e] Department of Chemistry, Siedlce University of Natural Sciences and Humanities, 3 Maja 54 St. , PL- 08110 Siedlce, Poland [f] Institute of Organic Chemistry, Polish Academy of Sciences, 44/52 Kasprzaka St., PL-01224 Warsaw, Poland * [email protected]
The thiosemicarbazide derivatives (Figure) with 4-nitrophenyl group were obtained and tested for their antibacterial and antiproliferative activity. Our results showed that some compounds possessed antibacterial activity against S. aureus, S. epidermidis, S. mutans and S. sanguinis. The cytotoxicity of these compounds is moderate, thus the compounds display good therapeutic safety in vitro. Additionally, two substances inhibited A549, HepG2 and MCF-7 cell division. Moreover, PASS software was used to detect another biological activity. It turned out that novel compounds can cause α-glucosidase inhibition. This was confirmed in vitro. To investigate the mode of interaction with the molecular target, compounds exhibiting α-glucosidase inhibition were docked to glucose binding site and exhibited a similar binding mode as glucose. In conclusion we obtained a series of new thiosemicarbazide derivatives with 4-nitrophenyl group with high multi- target biological activity in vitro. Structure-Activity analysis revealed that - depending of the substituent - thiosemicarbazides can be used as a potential antibacterial, antiproliferative and anti- diabetic substances.
O 2 R NH 1 S R NH NH S NH NH NH
O NO NO2 2
199 The 10th Joint Meeting on Medicinal Chemistry 2017
P-124
DESIGN AND SYNTHESIS OF NEW SUBSTITUTED NUCLEOSIDES AS POTENTIAL ANTI-HCMV AGENTS
Maria Gerasi, Georgios Papadakis, Nikolaos Lougiakis, Panagiotis Marakos and Nicole Pouli
Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Athens 15771, Greece
Human cytomegalovirus (HCMV) is a widespread opportunistic pathogen that belongs to the family of DNA herpesviruses (HHV-5). Cytomegalovirus infections are associated with severe morbidity and mortality in high risk patients because of immune system disabilities. There are currently available only three systemic drugs for treatment or prophylaxis of HCMV diseases, all targeted at the viral DNA polymerase, namely Ganciclovir and its prodrug Valganciclovir, Foscarnet and Cidofovir. However, their clinical effectiveness is limited due to severe side effects and the development of resistance. Accordingly, there is a need for the discovery of new anti-HCMV agents that are less toxic, more effective, orally bioavailable and endowed with novel mechanism of action. Within this context, research efforts have led to the development of a number of polyhalogenated benzimidazole nucleosides, exemplified by 2,5,6-trichloro-1-(β-d-ribofuranosyl)benzimidazole (TCRB), that strongly inhibit viral replication targeting a DNA maturation and processing step, which does not occur in normal eukaryotic cells. The structurally related Maribavir proved even more potent against HCMV and has entered clinical trials. In an effort to contribute in the structure-activity relationship studies of these series and explore the spatial limitation of the target enzymes we have designed a number new derivatives which can be considered as Maribavir isosters. Thus, we report in this presentation the preparation of the target nucleosides, which are 2-aminosubstituted analogues of the 1- and 3-position isomers of imidazo[4,5-b]pyridine.
Acknowledgments. This work has been funded by the Special Research Account (ELKE) of the National and Kapodistrian University of Athens.
200 The 10th Joint Meeting on Medicinal Chemistry 2017
P-125
SCREENING PHYSIOLOGICALLY RELEVANT SUBSTRATES OF ALDOSE REDUCTASE: ENZYME ACTIVITIES AND DIFFERENTIAL INHIBITION
Marta Soltesova Prnova,[a],* Jana Ballekova,[a] Yoel Rodriguez,[b,c] Magdaléna Májeková[a] and Milan Stefek[a]
[a] Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Dubravska cesta 9, 841 04 Bratislava, Slovakia [b] Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA [c] Department of Natural Sciences, Hostos Community College of CUNY, Bronx, NY 10451, USA * [email protected]
Aldose reductase (AR) is an NADPH-dependent reductase of rather poor selectivity, which is apparently disposed to accommodate both hydrophilic and hydrophobic aldehyde substrates. However, this enzyme seems to be not fully permissive owing to its capability to discriminate between different substrates of the same group. The ability of a variety of substrates to interact with AR at different efficacy indicates that these molecules may interact with the enzyme in multiple interactive modes. This characteristic of AR enzyme offers the possibility of identifying aldose reductase inhibitors allowing to discriminate among different substrates. Recently, a new generation of aldose reductase differential inhibitors (ARDIs) has been proposed aimed at preferentially inhibiting the reduction of either hydrophilic or hydrophobic substrates.[1,2] Thus, ARDIs may be projected to the selective inhibition of AR with the preference to normalize fluxing of glucose through the polyol pathway in diabetic patients without interfering with the detoxification of toxic products of lipid peroxidation. O O N N N H3CO SH N N N O OH
OH O
1 2
In the present study, the enzyme activities of rat lens aldose reductase saturated with physiologically relevant substrates including glyceraldehyde, glucose, galactose, xylose, erythrose, methylglyoxal, 4-hydroxynonenal (HNE), 4-hydroxynonenal glutathione (GS-HNE) were screened. Idose, glucose close congener, and the reference p-nitrobenzaldehyde were used as substrates for comparison. Two novel aldose reductase inhibitors, 3-mercapto-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid (1) and 2-(2-(ethoxycarbonyl)-8-methoxy-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)acetic acid (2), were subjected to differential inhibition assessment. Computational molecular modeling was used to understand the experimental data. Different interactive modes with the aldose reductase enzyme for the tested molecules were suggested. The results may contribute to the efforts in searching for pharmacological/therapeutical applications of ARDIs.
Acknowledgments: This work was supported by Slovak Research and Development Agency under the contract NO. APVV-15-0455, SAS-Tubitak JRP 2015/7, VEGA 2/0033/14 and VEGA 2/0041/15.
[1] A. Del-Corso, et al., PLoS One, 2013, 8 (9), e74076. [2] M. Cappiello, et al., Biochem. Biophys. Res. Commun., 2014, 445 (3), 556.
201 The 10th Joint Meeting on Medicinal Chemistry 2017
P-126
POST HEROIN DOSE TISSUE DISTRIBUTION OF 6- MONOACETYLMORPHINE (6-MAM) WITH MALDI IMAGING
Belin G. Teklezgi,[a] Annapurna Pamreddy,[a] Sooraj Baijnath,[a] Nirmala D. Gopal,[b] Tricia Naicker,[a] Hendrik G. Kruger[a] and Thavendran Govender[a],*
[a] Catalysis and Peptide Research Unit, University of KwaZulu-Natal, Westville Campus, Durban, South Africa [b] Department of Criminology, University of KwaZulu-Natal, Durban, Republic of South Africa * [email protected]
Heroin is an illicit opioid drug which is commonly abused and leads to dependence and addiction. Heroin is considered a pro-drug and is rapidly converted to its major active metabolite 6- monoacetylmorphine (6-MAM) which mediates euphoria and reward through the stimulation of opioid receptors in the brain.[1] The aim of this study was to investigate the distribution and localization of 6-MAM in the healthy Sprague Dawley rat brain following intraperitoneal (i.p.) administration of heroin (10 mg/kg), using matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI-MSI), in combination with quantification via liquid chromatography mass spectrometry (LC- MS/MS). These findings revealed that 6-MAM is present both in plasma and brain tissue with a Tmax of 5 min (2.8 µg/mL) and 15 min (1.1 µg/mL), respectively. MSI analysis of the brain showed high intensities of 6-MAM in the thalamus-hypothalamus and mesocorticolimbic system including areas of the cortex, caudate putamen, and ventral pallidum regions.[2] This finding correlates with the distribution of opioid receptors in the brain, according to literature.[3] In addition, we report a time- dependent distribution in the levels of 6-MAM, from 1 min with the highest intensity of the drug observed at 15 min, with sparse distribution at 45 min before decreasing at 60 min 1. This is the first study to use MSI as a brain imaging technique to detect a morphine’s distribution over time in the brain.
[1] J.M. Andersen, Å. Ripel, J. Pharm. Exp. Ther., 2009, 331, 153. [2] B. Teklezgi, A. Pamreddy, J. Mol. Histol., 2017,doi:10.1007/s10735-017-9726-3. [3] J. Le Merrer, J.A. Becker, Physiol. Rev., 2009, 89, 1379.
202 The 10th Joint Meeting on Medicinal Chemistry 2017
P-127
RATIONAL DESIGN OF NEW POTENT NON-NUCLEOSIDE INHIBITORS OF TERMINAL DEOXYNUCLEOTIDYL TRANSFERASE ACTIVE IN LEUKEMIC CELLS
G. Pupo,[a],* A. Coluccia,[a] A. Messore,[a] V. N. Madia,[a] F. Saccoliti,[a] L. Pescatori,[a] R. Costi,[a] G. Maga,[b] E. Crespan[b] and R. Di Santo[a]
[a] Dipartimento di Chimica e Tecnologie del Farmaco, “Sapienza” University of Rome, p.le Aldo Moro 5, 00185, Rome, Italy [b] Istituto di Genetica Molecolare, IGM-CNR, National Research Council, Pavia, via Abbiategrasso, 207, 27100, Pavia, Italy * [email protected]
Mammalian terminal deoxyribonucleotidyl transferase (TDT) catalyzes the non-template-directed polymerization of deoxyribonucleoside triphosphates and has a key role in V(D)J recombination during lymphocyte and repertoire development. Elevated TDT activity is showed in leukemic cells of acute lymphocytic leukemia and in the chronic myelogenous leukemia crisis. This finding is connected to a poor prognosis and response to chemotherapy. DNA polymerase lambda (Pol ), homolog to TDT,[1] can synthesize DNA in a template-independent pathway. Pol might be involved in the nonhomologous end joning (NHEJ) recombinational repair pathway of DNA double strand breaks. During a random screening on various polymerases we found some aryl diketo hexenoic acids (DKHAs) (RDS 2119, RDS 2153, RDS 2184) (see Figure), previously synthesized by us as anti-viral agent, as hits showing interesting activity against mammalian terminal deoxyribonucleotidyl transferases.[2,3]
O OH O O OH COOH COOH N N COOH N O OH Figure: Hit RDS 2119 RDS 2153 RDS 2184 compounds obtained from random screening.
Thus, we started SAR studies on DKHAs and found compounds that specifically target TdT behaving as nucleotide-competitive inhibitors.[4] These compounds showed a selective toxicity toward MOLT-4 overespressing TdT, compared to HeLa cells, that well correlate with in vitro selectivity for TdT. The binding site of two of these inhibitors was determined by cocrystallization with TdT, explaining why these compounds are competitive inhibitors of the deoxynucleotide triphosphate (dNTP). These studies opened the possibility to the rational design of TdT inhibitors. Starting form the observed binding pose of inhibitors cocrystallized within the catalytic core, we noted that the phenyl substituent or the benzyl group on pyrrole ring could occupy two different pockets. Thus, we decidesd to design and synthesize compounds bringing two aryl moieties. The design, synthesis and biological assays performed on newly synthesized compounds will be reported and discussed.
[1] U. Hübscher, G. Maga, G. Spadari, Ann. Rev. Biochem., 2002, 71, 133. [2] G. A. Locatelli, R. Di Santo, E. Crespan, R. Costi, Mol. Pharmacol., 2005, 68, 538. [3] R. Di Santo, G. Maga, Curr. Med. Chem., 2006, 13, 2353. [4] R. Costi, G. Cuzzucoli Crucitti, L. Pescatori, A. Messore, L. Scipione, S. Tortorella, A. Amoroso, E. Crespan, P. Campiglia, B. Maresca, A. Porta, I. Granata, E. Novellino, J. Gouge, M. Delarue, G. Maga, R. Di Santo, J. Med. Chem., 2013, 56, 7431.
203 The 10th Joint Meeting on Medicinal Chemistry 2017
P-128
SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL 2- (HETERO)ARYL-6-(2-IMIDAZOLINYL)BENZOTHIAZOLES AS ANTICANCER AGENTS
Livio Racané,[a],* Lucija Ptiček,[a] Mirela Sedić,[b] Petra Grbčić,[b] Sandra Kraljević Pavelić,[b] Irena Sović[c] and Grace Karminski-Zamola[c]
[a] Department of Applied Chemistry, Faculty of Textile Technology, University of Zagreb, Prilaz baruna Filipovića 28a, 10000 Zagreb, Croatia [b] Department of Biotechnology, Centre for high-throughput technologies, University of Rijeka, Radmile Matejčić 2, 51000 Rijeka, Croatia [c] Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićevtrg 20, P. O. Box 177, 10000 Zagreb, Croatia * [email protected]
Benzothiazole as an important pharmacophore, has recently emerged as a privileged scaffold in drug discovery[1] due to a variety of pharmacological properties, and its derivatives offer a high degree of structural diversity that has proven useful for the search of new therapeutic agents.[2] Through the last decade, our scientific focus has been placed on this particular series of heterocyclic compounds, with an emphasis on their synthesis, study of anticancer activities and DNA binding properties. Recently, we efficiently synthesized a series of 2-thienyl- and 2-benzothienyl-substituted 6-(2-imidazolinyl)benzothiazole derivatives, investigated their antitumor effects and explored the possible involvement of key enzymes regulating sphingolipid metabolism.[3] We have found in this group of sulphur-containing heterocycles the 2-benzothienyl derivative to have remarkable and selective cytostatic activity. One of the major mechanisms accounting for observed cytostatic effects was induction of apoptosis, probably due to specific inhibition of acid ceramidase activity. Based on these results a novel series of title compounds are synthesized and evaluated for their potential as anticancer agents.
An efficient synthesis is achieved by the condensation reaction of 2-amino-5-(2- imidazolinium)benzenethiolate with the corresponding aldehydes or carboxylic acid and compounds were isolated as monocationic highly water soluble mesylates. The in vitro antiproliferative activity against several human cancer cell lines is tested.
[1] A.A. Weekes, A.D. Westwell, Curr. Med. Chem., 2009, 16, 2430. [2] R.S. Keri, M.R. Patil, S.A. Patil, S. Budagupi, Eur. J. Med. Chem., 2014, 89, 207. [3] L. Racané, M. Sedić, N. Ilić, M. Aleksić, S. KraljevićPavelić, G. Karminski-Zamola, Anti-Cancer Agents Med. Chem., 2017, 17, 57.
204 The 10th Joint Meeting on Medicinal Chemistry 2017
P-129
NEW PRIMAQUINE AMIDES WITH HYDROXYPHENYL AND HALOGENPHENYL SUBSTITUENTS
Zrinka Rajić Džolić, Maja Beus and Branka Zorc*
Department of Medicinal Chemistry, University of Zagreb, Faculty of Pharmacy and Biochemistry, A. Kovačića 1, 10000 Zagreb, Croatia * [email protected]
Cancer is one of the leading causes of death worldwide.[1] Moreover, cancer is a very heterogenous disease, and cancer cells are prone to mutagenesis which leads to drug resistance. Therefore, novel and more efficient therapies are needed. Antimalarial drugs are known to exhibit antiproliferative activity, with several antimalarials in the clinical trials.[2] Almost a decade our group is focused on the synthesis and evaluation of primaquine derivatives as anticancer agents.[3] Recently, we have reported synthesis and biological activity of urea and bis-urea primaquine derivatives with hydroxyphenyl or halogenphenyl substituents, which exerted strong antiproliferative activity against a panel of tumour cell lines, with significant selectivity towards breast cancer cell line, MCF-7.[4] This work aims at simplifying the spacer between PQ and hydroxyphenyl or halogenphenyl substituents, which would provide simpler structures and more straightforward synthesis. Synthetic pathway to PQ derivatives 3 is outlined in the Scheme and it involves three steps: coupling of PQ with monomethyl succinate, hydrolysis of the obtained methyl ester 1, and coupling of the carboxylic acid 2 with the desired aniline derivative. In both cases, coupling was achieved by the activation of carboxylic acid with 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), in the presence of N-ethyl-N,N-diisopropylamine (DIEA). All reactions were performed at room temperature, reaction times were short and synthetic yields were high. Purification of the target compounds was straightforward, and their structures were confirmed by 1H and 13C NMR, IR and MS spectroscopy.
O O O
HO CH3 O O NH O LiOH, MeOH, H2O NH HATU, DIEA, DCM H N NH2 N N CH3 O PQ 1 O
O O
X, OH, CF3 X, OH, CF3 H2N NH O NH O H H N N HATU, DIEA, DCM N N OH N 2 3 H O O Cytostatic evaluation on a panel of cancer cell lines is in progress.
Acknowledgments: This work has been fully supported by the Croatian Science Foundation under the project number IP-09-2014-1501.
[1] http://www.who.int/mediacentre/factsheets/fs297/en/ [2] R. Duffy, et al, Drug Discov. Today, 2012, 17, 942. [3] G. Džimbeg, et al, Eur. J. Med. Chem., 2008, 43, 1180; M. Šimunović, et al, Bioorg. Med. Chem., 2009, 17, 5605; Z. Rajić, et al, Acta Pharm., 2010, 60, 325; I. Perković, et al, Eur. J. Med. Chem., 2012, 52, 227; I. Perković, et al, J. Enz. Inhib. Med. Chem., 2013, 28, 601; K. Pavić, et al, Eur. J. Med. Chem., 2014, 86, 502; K. Pavić, et al, Molecules, 2016, 21, 1629. [4] I. Perković, et al, Eur. J. Med. Chem., 2016, 124, 622.
205 The 10th Joint Meeting on Medicinal Chemistry 2017
P-130
SYNTHESIS AND EVALUATION OF MULTI-TARGET LIGANDS PLANNED FROM CARDANOL FOR THE TREATMENT OF ALZHEIMER'S DISEASE
Giselle de Andrade Ramos,[a],* Luiz A. Soares Romeiro,[a] Manuela Bartolini,[b] Paul E. Fraser[c] and Ling Wu[c]
[a] Graduate Program in Pharmaceutical Sciences, University of Brasilia, Faculty of Health Sciences, Darcy Ribeiro Campus, Brasilia. [b] Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, Bologna. [c] Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Avenue, M5T 2S8. * [email protected]
Alzheimer's disease is a progressive neurodegenerative disorder that presents dementia as a classic clinical manifestation among other symptoms.[1,2] In the context of a research line aimed to the development of new multi-target ligands, is described the synthetic route of new compounds planned from cardanol, as well the preliminary evaluation of their inhibitory profiles against hAChE/hBChE and the anti aggregation A activity. Thus, the cardanol mixture was converted to the acetylated compound by alkylation, the obtained mixture was subjected to oxidative cleavage via ozonolysis, followed by reductive treatment obtaining the alcohol LDT71. The primary alcohol was converted to the corresponding acid LDT108 by treatment with Jones reagent. This acid derivative was also converted to the corresponding amide intermediates via mixed anhydride reaction. Therefore, these derivatives were reduced to the correspondent amines by reduction reaction. Finally, these amide/amine intermediates was subjected to the Mannich reaction. The acetylcholinesterase assay showed the ligands ability to inhibit the enzymes. For Series 3, LDT638 (AChE IC50 30,0 μM, BChE IC50 6,12 μM) showed the best dual profile; meanwhile LDT636 and LDT544 showed selectivity for hBChE. For Series 1/2, LDT577 (AChE IC50 7,2 μM; BChE IC50 1,28 µM) and LDT579 (AChE IC50 6,68 μM; BChE IC50 0,47 µM) were the best. Tests against A aggregation for Series 3 showed that LDT544, LDT636 and LDT640 were able to destabilizing the secondary structures of the protein. However, LDT638 induced a -sheet transition. The conclusion of the biological evaluation regarding the anticholinesteric and anti-aggregant profile are underway, which will allow us to rationalize the results and establish the structure-activity relationship. The antioxidant potential is one of the prospects in this work.
[1] A. Darvesh S.B. Hopkins, A.C. David, C. Geula, Nature Rev. Neurosci., 2003, 4, 2. [2] L.F. Nunes Lemes, et al, Eur. J. Med. Chem., 2015, 108, 687.
206 The 10th Joint Meeting on Medicinal Chemistry 2017
P-131
DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL G9A INHIBITORS FROM A SCAFFOLD HOPPING APPROACH
D. Rescigno,[a],* C. Milite,[a] M. Viviano,[a] S. Castellano[a,b] and G. Sbardella[a]
[a] Dipartimento di Farmacia, Università degli Studi di Salerno, Via Giovanni Paolo II, 132, I-84084 Fisciano, Italy [b] Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, Via Salvador Allende, I- 84081 Baronissi, Salerno, Italy * [email protected]
The lysine methyltransferase G9a (also known as EHMT2) catalyses the addition two methyl groups to lysine 9 of histone H3. Due to its central role in epigenetic control, the aberrant activity of this enzyme is associated to several diseases including cancer. In particular, recent evidences revealed G9a involvement in the progression of REST-expressing (repressor element (RE)-1 silencing transcription factor) medulloblastomas.[1] Only a few among the selective inhibitors of G9a reported to date are useful chemical probes for cell-based and animal studies.[2] Starting from the inhibitor UNC0638,[3] we applied a scaffold hopping approach to develop novel chemical entities endowed with high affinity towards G9a. In particular, we replaced the quinazoline core, common to most of the reported inhibitors, with 1,4-benzodiazepine nucleus, known to be a privileged structure. We chose the 3,4-dihydro-5H-benzo[e][1,4]diazepin-5-one scaffold, that can be obtained through an efficient and gram-scale continuous-flow protocol, previously optimized by our group.[4] Moreover, this scaffold could be easily decorated to provide a number of highly functionalized potential ligands (Figure). To validate our approach, we designed and synthesized a small library of UNC0638 analogues. The UNC0638 benzodiazepine analogue (EML741) showed a good activity in a peptide-based AlphaLISA, together with a promising membrane permeability profile (PAMPA-BBB).
Figure: General scheme of our scaffold hopping approach.
[1] P. Taylor, J. Fangusaro, V. Rajaram, S. Goldman, I. B. Helenowski, T. MacDonald, M. Hasselblatt, L. Riedemann, A. Laureano, L. Cooper, V. Gopalakrishnan, Mol. Cancer Ther., 2012, 11, 1713. [2] H. Ü. Kaniskan, J. Jin, ACS Chem. Bio. 2015, 10, 40. [3] M. Vedadi, D. Barsyte-Lovejoy, F. Liu, S. Rival-Gervier, A. Allali-Hassani, V. Labrie, T. J. Wigle, P. A. DiMaggio, G. A. Wasney, A. Siarheyeva, A. Dong, W. Tempel, S.-C. Wang, X. Chen, I. Chau, T. J. Mangano, X.-P. Huang, C. D. Simpson, S. G. Pattenden, J. L. Norris, D. B. Kireev, A. Tripathy, A. Edwards, B. L. Roth, W. P. Janzen, B. A. Garcia, A. Petronis, J. Ellis, P. J. Brown, S. V. Frye, C. H. Arrowsmith, J. Jin, Nat. Chem. Biol., 2011, 7, 566. [4] M. Viviano, C. Milite, D. Rescigno, S. Castellano, G. Sbardella, RSC Adv., 2015, 5, 1268.
207 The 10th Joint Meeting on Medicinal Chemistry 2017
P-132
SYNTHESIS OF MULTIANTENNARY MANNOSE DERIVED DESMURAMYL PEPTIDES
Rosana Ribić,[a] Marija Paurević,[b] Nora Tir[a] and Srđanka Tomić[a],*
[a] University of Zagreb, Faculty of Science, Department of Chemistry, Horvatovac 102a, HR-10000 Zagreb, Croatia [b] University of Josip Juraj Strossmayer, Department of Chemistry, Ulica cara Hadrijana 8/A, HR - 31000 Osijek, Croatia * [email protected]
Muropeptides are fragments of unique polymers that build up the cell wall of bacteria called peptidoglycans. Muramyl dipeptide (MDP), N-acetylmuramyl-L-alanyl-D-isoglutamine, is the smallest structural unit of peptidoglycans showing the immunostimulating activity and desmuramyl peptides are MDP analogues lacking the hydrophilic carbohydrate moiety. Numerous derivatives with different groups at C- and N-terminus of the L-Ala-D-isoGln moiety are known.[1] We have designed, prepared and evaluated desmuramyl peptides with incorporated lipophilic adamantyl group as well as their mannosylated derivatives.[2] Mannose derived desmuramyl peptides showed great immunostimulating potential. Attached mannose allows the targeting of cell surface mannose specific lectins, while adamantane group enables the anchoring of the peptidoglycan ‘cargo’ to the membrane lipid bilayer. In the prepared liposomal vehicles adamantane group penetrated into the lipid bilayer while mannose was exposed at the liposome surface and served in targeting mannose receptors.[3] In order to improve lectin-carbohydrate binding we have developed methodology for the stereoselective synthesis of di- and tri-antennary mannose derivatives of desmuramyl peptides. Strength of overall mannose – lectin interaction will be enhanced by increasing the number of mannose subunits. Method efficiency will be presented on the synthesis of di- and tri-antennary mannose derivatives of desmuramyl peptides, including novel adamantyl triazole derivative.
[1] C. Ogawa, Y.-J. Liu, K. S. Kobayashi, Curr. Bioact. Compd., 2011, 7, 180. [2] R. Ribić, L. Habjanec, B. Vranešić, R. Frkanec, S. Tomić, Chem. Biodivers., 2012, 9, 777. [3] A. Štimac, S. Šegota, M. Dutour Sikirić, R. Ribić, L. Frkanec, V. Svetličić, S. Tomić, B. Vranešić, R. Frkanec, Biochim. Biophys. Acta - Biomembr., 2012, 1818, 2252.
208 The 10th Joint Meeting on Medicinal Chemistry 2017
P-133
MOLECULAR MODELING AND SYNTHESIS OF PYRUVATE DEHYDROGENASE KINASE INHIBITORS AS A POTENTIAL ANTICANCER TARGETS
Agata Rosińska,* Urszula Kijkowska-Murak and Dariusz Matosiuk
Chair and Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Medical University of Lublin, Raclawickie 1 Street, 20-059 Lublin, Poland * [email protected]
PDH (pyruvate dehydrogenase) is a key enzyme controlling the rate of glucose oxidation, and the availability of gluconeogenetic precursors. Activation of PDH in skeletal muscle and liver may increase glucose uptake and reduce glucose production. Recent studies shown that metabolic switch (Warburg effect) in cancer cells is regulated by pyruvate dehydrogenase kinase (PDK)[1-3].PDK is one part of the pyruvate dehydrogenase complex, which contains various catalytic and regulatory enzymes, which are responsible for the conversion of pyruvate into acetyl-CoA. The activity of pyruvate dehydrogenase is regulated by its phosphorylation status. The phosphorylation of PDH by PDK inhibits its activity and trigger metabolic shift from mitochondrial respiration to cytoplasmic glycolysis [4-6]. PDK2 or Pyruvate Dehydrogenase Kinase 2 is a member of the PDHK family that phosphorylates and inactivates the Pyruvate Dehydrogenase (PDH) and it has been suggested that PDK2 also involves in the proliferation of cancer cells. In these study we design pyruvate dehydrogenase kinase inhibitors in silico and using BioSolveIT GmbH software. The PDK2 structure were discovered using ReCore module and two fragments databases: ZINC a free database of commercially-available compounds for virtual screening and The Cambridge Structural Database (CSD). The results were validated through docking in FlexX and Surflex programs.
[1] C.W. Lu, S.C. Lin, K.F. Chen, Y.Y. Lai, S.J. Tsai, J. Biol. Chem., 2008, 283, 2106. [2] J.W. Kim, I. Tchernyshyov, G.L. Semenza, C.V. Dang, Cell Metab., 2006, 3, 177. [3] I. Papandreou, R.A. Cairns, L. Fontana, A.L. Lim, N.C. Denko, Cell Metab., 2006, 3, 187. [4] M. Kato, R.M. Wynn, J.L. Chuang, S.C. Tso, M. Machius, J. Li, D.T. Chuang, Structure, 2008, 16, 1849. [5] M.S. Patel, L.G. Korotchkina, Exp. Mol. Med., 2001, 33, 191. [6] T.E. Roche, Y. Hiromasa, Cell. Mol. Life Sci. 2007, 64, 830.
209 The 10th Joint Meeting on Medicinal Chemistry 2017
P-134
DISCOVERY OF NOVEL DIARYL SULFIDE DERIVATIVES AS INHIBITORS OF TRYPANOTHIONE REDUCTASE ENZYME
F. Saccoliti,[a],* V. N. Madia,[a] G. Pupo,[a] V. Tudino,[a] G. Colotti,[b] G. Angiulli,[b] A. Fiorillo,[b] P. Baiocco,[b] T. Di Muccio,[c] M. Gramiccia,[c] L. Scipione,[a] R. Costi,[a] A. Ilari[b] and R. Di Santo [a]
[a] Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, “Sapienza” Università di Roma, p.le Aldo Moro 5, I-00185 Roma, Italy [b] Istituto di Biologia e Patologia Molecolari – CNR, and Dipartimento di Scienze Biochimiche, “Sapienza” Università di Roma p.le Aldo Moro 5, I-00185 Roma, Italy [c] Dipartimento di Malattie Infettive, Parassitarie e Immunomediate, Istituto Superiore di Sanità, viale Regina Elena 299, I-00161 Roma, Italy * [email protected]
Trypanosomatidae protozoa are the causative agents of several tropical diseases, such as African sleeping sickness, Chagas’s disease and various forms of leshmaniasis, causing millions of deaths every year mainly in the developing world.[1] Nowadays, no safe and efficacious drugs are available for the treatment of most of these neglected tropical diseases, and, furthermore, high costs and increasing number of drug-resistant pathogens render the treatment even difficult.[2,3] Therefore, there is a strong need to develop more efficient and affordable antiprotozoal compounds and identify new promising targets. In this context an innovative approach is targeting protein essential for the parasite survival but absent in the human host. Instead of the mammalian redox defense machinery based on glutathione, the trypanosomatid parasites possess trypanothione as the main defending [4–6] system against oxidative damage. Trypanothione (TSH2) is kept in its reduced state by trypanothione reductase (TR), a NADPH dependent flavoprotein which acts as key enzyme of the trypanothione pathway, being critical for the protozoan survival, thus representing an attractive and promising target for the development of new potential drugs.[6,7] Furthermore, due to structural differences between the protozoan enzyme and the human homolog glutathione reductase (GR), a selective therapeutic approach might be possible. Following the discovery of some related compounds described in literature as TR inhibitors,[7] we evaluate the antiprotozoal activities of our in-house diaryl sulfide derivatives and some of the them proved to be active in whole cell assays, showing inhibitory activities within the micromolar range on different protozoa. Moreover, we found that our derivative RDS 777 was able to inhibit TR of L. infantum (LiTR) with good efficiency, showing a Ki of 0.25 mM that is six times lower than that of Sb(III), the active form of antimonials being the most used drug against leishmaniasis.[8] Thus, we solved the X-ray structure of LiTR in its oxidized state in complex with RDS 777 at 3.5 Å resolution, disclosing its mechanism of action. Indeed, this structure shows that the compound localizes at the catalytic site, engaging interactions with the residues more involved in the catalysis namely: Glu466', Cys57, Cys52 and Tyr110 thereby inhibiting the trypanothione binding. These data provide important insight that could be very helpful for future development of this class of inhibitors endowed with focused structural modifications in order to increase affinity and potency against protozoan target.
[1] M. H. Gelb, W. G. Hol, Science, 2002, 297, 343. [2] R. L. Krauth-Siegel, et al., Angew. Chem., 2005, 44, 690. [3] R. L. Krauth-Siegel, et al., Parasitol. Res. 2003, 90, 77. [4] M. Comini, et al., Free Radic. Biol. Med. 2014, 73, 229. [5] G. Colotti, et al., Future Med. Chem. 2013, 15, 1861. [6] A. Fiorillo, et al., PLoS Negl. Trop. Dis. 2012, 6, e1781. [7] B. Stump, et al., Org. Biomol. Chem., 2008, 6, 3935. [8] F. Saccoliti, et al., J. Enzyme Inhib. Med. Chem. 2017, 32, 304.
210 The 10th Joint Meeting on Medicinal Chemistry 2017
P-135
PSORALENE DERIVATIVES INHIBITORS OF THE β5i SUBUNIT OF THE IMMUNOPROTEASOME
Eva Shannon Schiffrer, Izidor Sosič, Martina Gobec, Irena Mlinarič-Raščan and Stanislav Gobec*
Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia * [email protected]
The eukaryotic 26S proteasome is the heart of the ubiquitin-proteasome system. The system is responsible for maintaining protein homeostasis and regulation of many cellular processes, such as antigen processing, signal transduction, cell differentiation and apoptosis. Its 20S core particle has three enzymatically active subunits which have distinct substrate specificities. Two types of proteasome exist, the constitutive proteasome which is expressed in all eukaryotic cells and the immunoproteasome which is predominantly expressed in cells of hematopoietic origin. The β5i (chymotrypsin-like) subunit of the immunoproteasome prefers neutral, hydrophobic residues at the cleavage site and β5i-selective compounds are currently being investigated for possible application in autoimmune and inflammatory diseases, where the immunoproteasome activity is upregulated.[1,2] The majority of currently available inhibitors have a peptidic backbone which makes them prone to poor metabolic stability and low bioavailability. In a previous study it was established that psoralene derivatives with an oxathiazolone “warhead” act as nonpeptidic covalent and irreversible inhibitors of the β5i subunit.[1] With the intent of establishing a structure-activity relationship, a series of oxathiazolone-substituted psoralene-based derivatives with variations at R1 of the parent compound was synthesised. The compounds will be characterised in in vitro and cell-based assays to assess their potency and selectivity in comparison with other subunits.
Figure: Simplified general scheme for the synthesis of oxathiazolone-substituted psoralene-based derivatives with variations at R1 and the parent compound with its characteristics.
[1] I. Sosič, M. Gobec, B. Brus, D. Knez, M. Živec, J. Konc, S. Lešnik, M. Ogrizek, A. Obreza, D. Žigon, D. Janežič, I. Mlinarič-Raščan, S. Gobec, Angew. Chem., 2016, 55, 5745. [2] T. Muchamuel, M. Basler, M. Aujay, E. Suzuki, K. Kalim, C. Lauer, C. Sylvain, E. Ring, J. Shields, J. Jiang, P. Shwonek, F. Parlati, S. Demo, M. Bennett, C. Kirk, M. Groettrup, Nat. Med. 2009, 15, 781.
211 The 10th Joint Meeting on Medicinal Chemistry 2017
P-136
THE APPLICATION OF FMO-EDA CALCULATION TO STUDY THE SELECTIVITY OF 2-CHLOROPHENYL-PIPERAZIN DERIVATIVE TO SEROTONIN AND DOPAMINE RECEPTORS
Paweł Śliwa,[a],* Jolanta Jaśkowska[a] and Rafał Kurczab[b]
[a] Faculty of Chemical Engineering and Technology, Cracow University of Technology, Warszawska 24, 31- 155 Cracow, Poland [b] Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Cracow, Poland * [email protected]
Long-chain arylpiperazines (LCAP) are one of the commonly studied class of bioactive compounds due to their potential therapeutic effects caused by interactions with different subtypes of serotonin receptors. A number of studies have been aimed at examining the impact of LCAP structure modifications on the affinity, selectivity and function at a given receptor protein.[1] In this study the structure of 2-{6-[4-(2-chlorophenyl)piperazin-1-yl]hexyl}-2,3-dihydro-1H-isoindole- 1,3-dione complexed with five receptors (5-HT1AR, 5-HT2AR, 5-HT6R, 5-HT7R, D2R) has been investigated by means of quantum mechanical methods. At the beginning, the test compound was docked to receptors (homology models based on …) and next optimized with ONIOM method. For thus obtained structures FMO-EDA calculations were performed. Results shed some lights on the interpretation of the experimental results concerning the affinity to receptors, as well as they provided the reasonable binding energies and binding patterns of ligand- protein interactions.
Acknowledgments:The study was financially supported by the National Centre for Research and Development, Project LIDER VI (No. LIDER/015/L-6/14/NCBR/2015).
[1] P. Kowalski. et al., Arch. Pharm. Chem. Life Sci., 2013, 346, 339.
212 The 10th Joint Meeting on Medicinal Chemistry 2017
P-137
AN ASPARTATE-AMINE SALT BRIDGE – THE ETS-NOCV STUDY
Paweł Śliwa,[a],* Rafał Kurczab[b] and Andrzej J. Bojarski[b]
[a] Faculty of Chemical Engineering and Technology, Cracow University of Technology, Warszawska 24, 31- 155 Cracow, Poland [b] Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Cracow, Poland * [email protected]
The human G-protein-coupled receptors (GPCRs) represent the most important set of potential therapeutic targets.[1] It is well known that the ligand binding site of aminergic GPCRs is located within the transmembrane (TM) region of the receptor and D3.32 is common as an anchoring point throughout the entire biogenic amine family.[1-3] Aspartic acid acting as the counterion for the charged amine, forming the interaction responsible for a correct ligand orientation.[4] Theoretical study indicated that D3.32 is directly involved in agonist and antagonist binding for the aminergic GPCRs.[5] Considering the above, it was reasonable to undertake advanced theoretical study on the nature of salt bridge, which are exactly the double charge-assisted hydrogen bond (+/-CAHB). For this purpose, the ETS-NOCV (the natural orbitals for chemical valence (NOCV) combined with extended- transition-state method (ETS), [6]) calculations were performed for the model systems representing the all possible scenarios in biological interactions.
E1 =-27.3 kcal/mol E2 =-3.6 kcal/mol E3 =-2.8 kcal/mol
Figure: N-methyl-piperidinum – aspartate.
The results indicated that the main force of +/-CAHB is the charge transfer from an oxygen atom of aspartic acid. The binding is enhanced by the flow of electron density between the oxygen atoms of D, as illustrated by the third -type orbital NOCV.
[1] R.P. Bywater, J. Mol. Recognit. 2005, 18, 60. [2] A.J. Kooistra, S.Kuhne, I.J.P. de Esch, R. Leurs, C. de Graaf, British J. Pharmacol., 2013, 170, 101. [3] K. Kristiansen, W.K. Kroeze, D.L. Willins, E.I. Gelber, J.E. Savage, R.A. Glennon, B.L. Roth, J. Pharmacol. Exp. Ther., 2000, 293, 735. [4] M. Sencanski, V. Sukalovic, K. Shakib, V. Soskic, L. Dosen-Micovic, S. Kostic-Rajacic, Chem. Biol. Drug. Des., 2014, 83, 462. [5] A. Ranganathan, R.O. Dror, J. Carlsson, Biochemistry, 2014, 53, 7283. [6] M. Mitoraj, A. Michalak, J. Mol. Model., 2007, 13, 347.
213 The 10th Joint Meeting on Medicinal Chemistry 2017
P-138
STEROID RECEPTOR BINDING AFFINITIES OF SELECTED MODIFIED STEROIDS- A SCREENING TOOL FOR IDENTIFICATION OF POTENTIAL THERAPEUTICS
Sofija S. Bekić,[a] Marija N. Sakač,[a] Suzana S. Jovanović-Šanta,[a] Edward T. Petri[b] and Andjelka S. Ćelić[b],*
[a] Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia [b] Department of Biology and Ecology, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 2, 21000 Novi Sad, Serbia * [email protected]
Identification of compounds for treatment of prostate and breast cancer remains a major goal of biomedical research, since these diseases are leading causes of death among men and women worldwide. Currently the most effective treatment strategies include blocking the proliferative effects of steroid hormones by binding structurally similar synthetic analogues to steroid receptors. Intensive research has been focused on the synthesis of structurally modified steroid hormones with high affinity for these receptors, in order to obtain potential drug candidates. Modified androstane and estrane derivatives are an especially interesting class of compounds in the treatment of receptor- mediated diseases. There are numerous steroid receptor binding assays described in the literature. Muddana and Peterson developed fluorescent cellular biosensor by expressing the ligand binding domain (LBD) of some steroid receptors marked with yellow fluorescent protein (YFP) in Sacharomyces cerevisiae for identification of steroid receptor ligands and quantification of their binding affinity.[1] Our goal was to improve the sensitivity and selectivity of this assay and to test binding affinities of some selected modified steroids. This simple, economical and sensitive assay can be applied as a preliminary screen for libraries of steroid receptor ligands. Further examination of steroid derivative binding affinities was performed using docking or in vitro studies.
[1] S.S. Muddana, B.R.Peterson, ChemBioChem, 2003,4, 848.
214 The 10th Joint Meeting on Medicinal Chemistry 2017
P-139
DEVELOPMENT OF BIOORTHOGONAL 2-NITROIMIDAZOLE BASED HYPOXIA SENSITIVE PROBES
Barbara Sohr,[a],# Christoph Denk,[a] Thomas Wanek[b] and Hannes Mikula[a],*
[a] Institute of Applied Synthetic Chemistry, Vienna University of Technology (TU Wien), Vienna, Austria [b] Health and Environment Department, Biomedical Systems, Austrian Institute of Technology, Seibersdorf, Austria # Recipient of a DOC Fellowship of the Austrian Academy of Sciences * [email protected]
Hypoxia is a low oxygen condition often observed in a variety of solid tumors and associated with high therapy resistance, invasiveness and metastasis. To properly plan and adjust cancer treatment, it is of vital importance to identify, measure and localize hypoxic regions. Current methods, e.g. PET imaging using 18F-labeled hypoxia sensitive probes such as 18F-FAZA, lack satisfactory tumor-to- background ratios attributed to slow tumoral retention, unspecific accumulation in normal (normoxic) tissue and washout of the probe.[1] In this work, we focused on the development of novel hypoxia sensitive probes that enable two-step pretargeting strategies based on bioorthogonal chemistry. The inverse electron demand Diels-Alder (IEDDA)-initiated conjugation between 1,2,4,5-tetrazines and strained dienophiles (e.g. trans- cyclooctenes, TCOs) has been proven to be a highly efficient and fast bioorthogonal ligation[2] and was therefore used within this study. The above-mentioned two-step process will consist of (1) administration of a TCO-tagged hypoxia sensitive probe that is specifically trapped in hypoxic cells and (2) administration of a tetrazine-modified compound, e.g. as pull down reagent (PDR) that selectively binds to the probe through bioorthogonal ligation. Depending on the nature of the tetrazine-modified agent the pretargeted hypoxia probe can be used for a wide range of applications (Figure 1) making it a remarkably versatile chemical tool for biomedical research. Figure 1: Possible applications for hypoxia To achieve hypoxia probes. sensitivity a 2- nitroimidazole (NIM) moiety was incorporated in our target compounds (as shown exemplarily in Figure 2). NIM is known to specfically Figure 2: TCO-tagged accumulate in hypoxic cells after intracellular reduction of the NO2 hypoxia probe. moiety.[3] IEDDA ligation of the prepared probes was investigated using already available PDRs to acquire kinetic data and facilitate characterization of conjugation products. Furthermore, in vitro stability, cell permeability and accumulation in hypoxic cells were studied. Results on the synthesis and in vitro evaluation of TCO-tagged NIM derivatives as bioorthogonal hypoxia probes will be presented.
[1] S. Carlin, J.L. Humm, J. Nucl. Med., 2012, 53, 1171. [2] M.L. Blackman, M. Royzen, J.M. Fox, J. Am. Chem. Soc., 2008, 130,13518. [3] J.D. Chapman, A.J. Franko, J. Sharplin, Br. J. Cancer, 1981, 43, 546.
215 The 10th Joint Meeting on Medicinal Chemistry 2017
P-140
NEUROPROTECTIVE POTENTIAL OF LINEZOLID: A QUANTITATIVE AND DISTRIBUTION STUDY VIA MASS SPECTROMETRY
Sooraj Baijnath,[a],* Chivonne Moodley,[b] Bongani Ngcobo,[b] Sanil D. Singh,[c] Gert Kruger,[1] Per I. Arvidsson,[a,d] Tricia Naicker,[a] Alexander Pym[b] and Thavendran Govender[a]
[a] Catalysis and Peptide Research Unit, School of Pharmacy and Pharmacology, University of KwaZulu- Natal, Westville Campus, Durban, South Africa [b] Africa Health Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa [c] Biomedical Resource Unit, University of KwaZulu-Natal, Westville Campus, Durban, South Africa [d] Science for Life Laboratory, Drug Discovery & Development Platform & Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden * [email protected]
Tuberculosis (TB) has been the scourge of the human race for many years, claiming countless numbers of lives along the way. This is further complicated by the ability of Mycobacterium tuberculosis (M.tb) infect extra-pulmonary sites, more specifically the brain. These forms of TB are difficult to treat due to the problems associated with drug delivery across the blood brain barrier (BBB). Linezolid (LIN) and clofazimine (CFZ) are two of the more promising anti-TB antibiotics in recent times, with proven ability to penetrate the BBB. In this study Balb/c mice were aerosol infected with M.tb H37Rv and treated for four weeks with both LIN (100 mg/kg.b.w) and CFZ (100 mg/kg.b.w). Concurrently, we investigated if an aerosol TB infection would lead to the dissemination of TB bacilli into the brain. Post-treatment brain and lung CFU’s were determined together with serum, lung and brain drug concentrations. CFZ displayed a strong bactericidal effect in the lung, while LIN had a bacteriostatic effect. M.tb appeared after one week post-infection in the untreated group (2.38 ± 0.43 log10CFU) and more surprisingly after two weeks post-infection in the LIN (1.14 ± 0.99 log10CFU). TB bacilli could not be detected in the brains of the CFZ group. To the best of our knowledge, this is the first study to show the appearance of M.tb in the brain after an aerosol TB infection in a mouse. This study also demonstrates the potential of CFZ to protect against the development of extra- pulmonary TB of the CNS.
[1] S. Baijnath, S. Naiker, A. Shobo, C. Moodley, J. Adamson, B. Ngcobo, L.A. Bester, S.D. Singh, H.G. Kruger, T. Naicker, T. Govender, J. Mol. Hist., 2015, 46, 439. [2] S. Baijnath, A. Shobo, L.A. Bester, S.D. Singh, H.G. Kruger, T. Naicker, P.I. Arvidsson, T. Govender, J. Mol. Hist., 2016, 47, 429.
216 The 10th Joint Meeting on Medicinal Chemistry 2017
P-141
SYNTHESIS, ANTITUMOR AND ANTIOXIDATIVE ACTIVITY OF NITRO AND AMINO SUBSTITUTED BENZIMIDAZOLE AND BENZOTHIAZOLE 2- CARBOXAMIDES
Irena Sović,[a] Ida Boček,[a] Petra Roškarić,[a] Marijeta Kralj,[b] Irena Martin Kleiner,[b] Kristina Starčević[c] and Marijana Hranjec[a],*
[a] Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, Marulićev trg 20, Zagreb, Croatia [b] Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, Zagreb, Croatia [c] Faculty of Veterinary Medicine, Heinzelova 55, Zagreb, Croatia * [email protected]
Heterocyclic compounds containing benzimidazole and benzothiazole have been found very interesting to medicinal and organic chemists and are extensively studied due to their well known and wide biological activities. Over the past several years we have become interested in antitumor activity of different derivatives of benzimidazole and benzothiazole carboxamides, and recently in their antioxidative activity.[1,2] Oxidative stress, as a result of excessive production and accumulation of free radicals, is one of the leading causes of many degenerative diseases such as Alzheimer's and Parkinson's disease, inflammatory processes and DNA damage leading to carcinogenesis. In this report we present synthesis, antitumor and antioxidative activity of novel nitro and amino substituted benzimidazole and benzothiazole carboxamides. For the synthesis of novel compounds we have used methods of classical linear organic synthesis starting from aromatic acyl halogenides which gave in the reaction with substituted 2-aminobenzimidazoles or 2-aminobenzothiazoles corresponding carboxamides. Antiproliferative activity in vitro of selected compounds was tested on several human tumor cell lines and the antioxidant properties were determined by DPPH and FRAP methods.[3]
[1] M. Hranjec, I. Sović, I. Ratkaj, G. Pavlović, N. Ilić, L. Valjalo, K. Pavelić, S. Kraljević Pavelić, G. Karminski- Zamola, Eur. J. Med. Chem., 2013, 59, 111. [2] L. Racane, R. Stojković, V. Tralić- Kulenović, H. Cerić, M. Đaković, K. Ester, A. Mišir Krpan, M. Radić Stojković, Eur. J. Med. Chem., 2014, 86, 406. [3] M. Tireli, K. Starčević, T. Martinović, S. Kraljević Pavelić, G. Karminski- Zamola, M. Hranjec, Mol. Divers., 2017, 21, 201.
217 The 10th Joint Meeting on Medicinal Chemistry 2017
P-142
ESTIMATION OF BINDING AFFINITY FOR SOME SYNTHESIZED COUMARIN DERIVATIVES WITH RECEPTORS IMPORTANT FOR BACTERIAL GROWTH AND DEVELOPMENT
Selma Špirtović-Halilović,[a],* Elma Veljović,[a] Mirsada Salihović,[b] Aida Šapčanin,[b] Amar Osmanović,[a] Nihada Škrijelj[a] and Davorka Završnik[a]
[a] Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Sarajevo, Bosnia and Herzegovina [b] Department of Natural Sciences in Pharmacy, Faculty of Pharmacy, University of Sarajevo, Bosnia and Herzegovina * [email protected]
In silico methods have been used to estimate possible ways of binding for selected coumarin derivatives with two receptors, amylase and gyrase (PDB: 1BAG and 1KZN), which are known to be important in life process of some bacteria.[1,2] Docking analyses provided comparison of binding energies, inhibitory constants, number of hydrogen bonds, as well as amino acids involved in the interaction of analyzed compounds. Binding energies of tested compounds and amylase were between -4.78 and -3.9 kcal mol-1, while binding energies of tested compounds with gyrase were between -6.99 and -4.63 kcal mol-1. Obtained results revealed possible hydrophobic interactions between ligands and receptors. Moreover, correlation between in silico calculated parameters and in vitro biological testing of antimicrobial activity has been examined.
[1] L.W. Tari, M. Trzoss, D.C. Bensen, X. Li, Z. Chen, T. Lam, J. Zhang, C.J. Creighton, M.L. Cunningham, B. Kwan, M. Stidham, K.J. Shaw, F.C. Lightstone, S.E. Wong, T.B. Nguyen, J. Nix, J. Finn, Bioorg. Med. Chem. Lett., 2013, 23, 1529. [2] C. Anderle, M. Stieger, M. Burrell, S. Reinelt, A. Maxwell, M. Page, L. Heide, Antimicrob. Agents Chemother., 2008, 52, 1982.
218 The 10th Joint Meeting on Medicinal Chemistry 2017
P-143
ANTIBACTERIAL THIAZOLIN-4-ONES AS POTENTIAL DNA GYRASE AND TOPOISOMERASE IV INHIBITORS
Anca Stana,[a],* Radu Tamaian,[b,c] Dan C. Vodnar,[d] Ovidiu Oniga[a] and Brîndușa Tiperciuc[a]
[a] Department of Pharmaceutical Chemistry, “Iuliu Hațieganu” University of Medicine and Pharmacy, 41 Victor Babeș Street, RO-400012 Cluj-Napoca, Romania [b] National Institute for Research and Development for Cryogenic and Isotopic Technologies, 4th Uzinei Street, RO-240050 Râmnicu Vâlcea, Romania [c] SC Biotech Corp SRL, 4th Uzinei Street, RO-240050 Râmnicu Vâlcea, Romania [d] Department of Food Science and Technology, University of Agricultural Sciences and Veterinary Medicine, 3-5 Manăştur Street, RO-400372 Cluj-Napoca, Romania * [email protected]
Despite the numerous antimicrobial agents approved for the treatment of infections, the emergence of infectious diseases and the dramatically increasing number of pathogens resistant to different classes of currently available anti-infective agents resulted in the acute need to implement new strategies for developing new antimicrobial chemotherapeutics towards which there is little antimicrobial resistance or no cross-resistance. [1] The type IIA topoisomerases, DNA topoisomerase IV subunit A and DNA gyrase subunit A, are both involved in supercoiled DNA relaxation and play a crucial role in the bacterial transcription and replication process. Therefore, dual targeting of these enzymes is a good strategy in the research of new antibacterial compounds.[2] 23 previously synthesized thiazolin-4-ones [3] were prospected for their antibacterial activity. Minimum inhibitory concentrations and minimum bactericidal concentrations were determined, employing the broth microdilution method. All the synthesized compounds were tested against Staphylococcus aureus ATCC 49444 and Escherichia coli ATCC 25922. Moxifloxacin (Mox) was used as positive control. All the synthesized thiazolin-4-ones presented good antibacterial properties. Overall, the compounds were more active against S. aureus ATCC 49444 than against E. coli ATCC 25922. The most active compounds were the thiazolin-4-one derivatives 10 and 9b, displaying better antibacterial activities than moxifloxacin. All the investigated molecules (the thiazolin-4-one derivatives and reference compound) were virtually subjected to docking, against the generated homology models of bacterial DNA topoisomerase IV subunit A and DNA gyrase subunit A in order to investigate their potential binding mode and binding affinity. The docking results against DNA topoisomerase IV subunit A indicated that six thiazolin-4-ones derivatives (6e and 9a-e) are more potent inhibitors than Mox against DNA topoisomerase IV subunit A. Eight thiazolin-4-one derivatives (6d-e, 8 and 9a-e) are more potent inhibitors than the reference compound against DNA gyrase subunit A. The results of compounds’ docking towards the bacterial type IIA topoisomerases indicated that derivative 6c had a medium inhibitory activity and could be used for dual targeting of these topoisomerases, while compound 8 had a promising behavior (medium inhibitor of topoisomerase and strong inhibitor of gyrase).
[1] I. Chopra, C. Schofield, M. Everett, A. O’Neill, K. Miller, M. Wilcox, et al., Lancet Infect. Dis., 2008, 8, 133. [2] M.A. Azam, J. Thathan, S. Jubie, Bioorg. Chem., 2015, 62, 41. [3] A. Stana, D.C. Vodnar, R. Tamaian, A. Pîrnău, L. Vlase, I. Ionuț, O. Oniga, B. Tiperciuc, Int. J. Mol. Sci., 2017, 18(1), 177.
219 The 10th Joint Meeting on Medicinal Chemistry 2017
P-144
DESIGN, SYNTHESIS, X-RAY STUDIES AND BIOLOGICAL EVALUATION OF NOVEL CHALCONE DERIVATIVES – POTENTIAL MICROTUBULE TARGETING AGENTS
Tomasz Stefanski,[a] Rafał Kurczab,[b] Artur Korzanski,[a] Katarzyna Skonieczka,[c] Barbara Grolik,[c] Emilia Kania,[d] Barbara Bojko,[d] Zbigniew Dutkiewicz,[e] Agnieszka Gielara-Korzańska,[e] Renata Mikstacka[f], Adam Hogendorf[b] and Maciej Kubicki[a]
[a] Department of Crystallography, Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89B, 61- 614 Poznan, Poland [b] Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Krakow, Poland [c] Department of Clinical Genetics, Faculty of Medicine, Ludwig Rydgier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, A. Jurasza 2, 85-089 Bydgoszcz, Poland [d] Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Ludwig Rydgier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, A. Jurasza 2, 85-089 Bydgoszcz, Poland [e] Department of Chemical Technology of Drugs, Faculty of Pharmacy, Poznan University of Medical Sciences, Grunwaldzka 6, 60-780 Poznan, Poland [f] Department of Inorganic and Analytical Chemistry, Faculty of Pharmacy, Ludwig Rydgier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, A. Jurasza 2, 85-089 Bydgoszcz, Poland * [email protected]
The microtubular system with its dynamic nature characterized by the polymerization and depolymerization of α,β-tubulin heterodimers, is essential in a variety of cellular processes, including maintenance of cell shape, regulation of motility and cell division.[1] Because of the latter function microtubules are one of the significant and more successful molecular target for designing of new active molecules possessing anticancer activity. Among this group of compounds chalcones (1,3- diphenylprop-2-en-1-on derivatives) represent a promising class of compounds with a simple structure, taking the possibility of extensive structural modifications that improve their natural anticancer properties. Their mechanism of action including the inhibition of tubulin assembly by binding to the colchicine binding domain resulting from their structural similarity to other active ligands that have the same molecular target (e.g. combretastatin A-4, CA-4). Our successful investigation on novel potent inhibitors of tubulin polymerization from group of CA-4 thioderivatives prompted us to extend our research on chalcone scaffold. Herein we present synthesis, molecular modelling studies, X-ray structural characteristics and biological evaluation of novel chalcone thioderivatives. Their antiproliferative activity was determined using panel of human cancer and normal cell lines, tubulin inhibition, cell cycle and pro-apoptotic analyses. The multidisciplinary research methodology supported by computer aided drug design methods, standard and high-resolution X-ray structural analysis combined with modelling of the multipole electron density distribution[2] enable to develop of a new, effective chemotherapeutics from the group of chalcone derivatives and for the better understanding of their interaction with tubulin at the molecular level.
Acknowledgments: The project was supported by research grant OPUS (UMO- 2015/17/B/ST4/03701) financed by Polish National Science Center.
[1] R. Mikstacka, T. Stefański, J. Różański, Cell. Mol. Biol. Lett., 2013, 18, 368. [2] A. Poulain-Paul, A. Nassour, C. Jelsch, B. Guillot, M. Kubicki, C. Lecomte, Acta Cryst. A, 2012, 68, 715.
220 The 10th Joint Meeting on Medicinal Chemistry 2017
P-145
OPIOID RECEPTOR ACTIVITY AND ANALGESIC POTENCY OF DPDPE PEPTIDE ANALOGUES CONTAINING A XYLENE BRIDGE
Azzurra Stefanucci,[a],* Giorgia Macedonio,[a] Ettore Novellino,[b] Sako Mirzaie,[c] Stefano Pieretti,[d] Paola Minosi,[d] Edina Szúcs,[e] Anna I. Erdei,[e] Ferenc Zador,[c] Sandor Benyhe[c] and Adriano Mollica [a]
[a] Dipartimento di Farmacia, Università di Chieti-Pescara “G. D’Annunzio”, Via dei Vestini 31, 66100 Chieti, Italy. [b] Dipartimento di Farmacia, Università di Napoli “Federico II”, Via D. Montesano, 49, 80131 Naples, Italy. [c] Department of Biochemistry, Islamic Azad University, Sanandaj, Iran. [d] Istituto Superiore di Sanità, Dipartimento del Farmaco, Viale Regina Elena 299, 00161, Rome, Italy. [e] Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, 6726, Szeged, Hungary. * [email protected]
Three cyclic analogues of DPDPE containing xylene bridge regioisomers (7a-c) have been synthesized and fully characterized as mixed δ/µ/κ-opioid receptors agonists.[1,2] The in vitro activity has been investigated showing a good affinity of 7a-c for both of them. In vivo biological assays revealed that 7b is the most potent cyclic analogue with the ability to maintain high level of analgesia after 60 and 90 minutes following i.c.v. and i.t. administrations respectively in Tail Flick test and long lasting analgesia after subcutaneous administration.
7b: kim = 34.9 nM k = 292.2 nM i [1] A. Mollica, G. Guardiani, P. Davis, S.-W. Ma, F. Porreca, J. Lai, L. Mannina, A.P. Sobolev, V.J. Hruby, J. Med. Chem., 2007, 50, 3138. [2] C. Marculescu, H. Kossen, R. E. Morgan, P. Mayer, S. A. Fletcher, B. Tolner, K. A. Chester, L. H. Jones, J. R. Baker, Chem. Comm., 2014, 50, 7139.
221 The 10th Joint Meeting on Medicinal Chemistry 2017
P-146
IDENTIFICATION OF NOVEL STAT3 INHIBITORS AND SYNTHESIS- ASSISTED ELUCIDATION OF MOLECULAR MECHANISM
Seungbeom Lee,[b] Changjin Lim,[a] Joonseong Hur[b] and Young-Ger Suh[a,b],*
[a] College of Pharmacy, Cha University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-Do, Republic of Korea [b] College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, Republic of Korea * [email protected]
A series of novel STAT3 inhibitors consisting of Michael acceptor as a typical electrophilic moiety has been identified through assays of the focused in-house library, which consist of a variety of scaffolds derived through a long-term medicinal chemistry program.[1] In addition, mode of action and structural feature of the identified STAT3 inhibitors responsible for the inhibitory activity were investigated. In particular, the enone analogs revealed promising inhibitory activities in the STAT3-driven luciferase expression in HeLa cells. We confirmed that enone moiety of the selected analogs, which possesses a less-hindered exo-olefin, is essential for direct interaction with the nucleophilic cysteine residue of STAT3 via Michael addition. The analogs also exhibited selective inhibition of STAT3 phosphorylation without affecting STAT1 phosphorylation.[2] It also exhibited cytostatic effect in human breast epithelial cells (MCF10A-ras), which supports the cancer cell-specific inhibitory properties. In order to investigate the mode of action for the selected analogs, STAT3 phosphorylation was confirmed by Western blot analysis using H-ras transformed MCF10A (MCF10A-ras), which seemed to serve as an adequate model for studies on mammary carcinogenesis. Intensive studies on the selected analogs including elucidation of their detailed inhibitory activities and development of more potent STAT3 inhibitors based on the preliminary SAR will be reported.
[1] D. Chang, H. An, K. Kim, H. H. Kim, J. Jung, J. M. Lee, N. Kim, Y. T. Han, H. Yun, S. Lee, G. Lee, S. Lee, J. S. Lee, J. Cha, J. Park, J. W. Park, S. Lee, S. G. Kim, J. H. Kim, H. Lee, K. Kim, and Y.-G. Suh, J. Med. Chem., 2012, 55, 10863. [2] K. Kim, S. Kim, Y. T. Han, S. Hong, H. An, D. Chang, T. Kim, B. Lim, J. Lee, Y. Surh, Y.-G. Suh, Bioorg. Med. Chem. Lett., 2015, 25, 5444.
222 The 10th Joint Meeting on Medicinal Chemistry 2017
P-147
HIGHLY REACTIVE DIENOPHILES FOR BIOORTHOGONAL TETRAZINE LIGATIONS
Dennis Svatunek, Maximilian Haider and Hannes Mikula*
Institute of Applied Synthetic Chemistry, Vienna University of Technology (TU Wien), Vienna, Austria * [email protected]
The tetrazine-TCO ligation, the reaction between 1,2,4,5-tetrazines and trans-cyclooctenes (TCO), is the fastest bioorthogonal reaction reported so far with second order rate constants of up to 3 300 000 M-1s-1.[1] High reactivity is of significance for reactions intended to be used in biological environments, which are commonly performed at very low concentration. The two-step reaction of an electron deficient tetrazine and TCO is initiated by an inverse electron demand Diels-Alder cycloaddition followed by a retro-Diels-Alder reaction under the loss of nitrogen. Highly reactivity TCOs are the conformationally strained trans-cyclooctenes s-TCO (1) and d-TCO (2) introduced by Fox and coworkers (Figure 1a).[1,2] They show incredibly high reaction rates, however, in vivo stability is limited. Within this work we aimed to improve the reactivity and stability of known trans-cyclooctene derivatives and to develop new TCOs with improved properties. Reactivity of proposed structures are first evaluated in silico using established DFT methods (M06- 2X/6-311+G(d,p)).[3,4] Most promising structures are selected and further investigated experimentally regarding their stability and reactivity. Explored structures include derivatives of known TCOs, for example bis-methylated s-TCO (3) and d-TCO (4) (Figure 1b), and trans-cyclooctenes with new structural features such as the bridged TCO 5 (Figure 1c).
Figure 1: a) Chemical structure of s-TCO (1) and d-TCO (2); b) Bis-methylated TCOs; c) Bridged TCO
DFT calculations show lowered free energies of activation for bis-methylated derivatives 3 and 4 in comparison to their parent compounds 1 and 2. The additional methyl groups are furthermore expected to be beneficial for stability. Computational investigation of the novel TCO 5 and similar structures suggests reactivities comparable to s-TCO (1). Results on quantum chemical calculations, the synthesis and evaluation of novel TCOs will be presented.
[1] A. Darko, S. Wallace, O. Dmitrenko, M. M. Machovina, R. a. Mehl, J. W. Chin, J. M. Fox, Chem. Sci., 2014, 5, 3770. [2] M. T. Taylor, M. L. Blackman, O. Dmitrenko, J. M. Fox, J. Am. Chem. Soc., 2011, 133, 9646. [3] C. Denk, D. Svatunek, S. Mairinger, J. Stanek, T. Filip, D. Matscheko, C. Kuntner, T. Wanek, H. Mikula, Bioconjug. Chem., 2016, 27, 1707. [4] C. Denk, D. Svatunek, T. Filip, T. Wanek, D. Lumpi, J. Fröhlich, C. Kuntner, H. Mikula, Angew. Chemie Int. Ed., 2014, 53, 9655.
223 The 10th Joint Meeting on Medicinal Chemistry 2017
P-148
SYNTHESIS AND CYTOTOXIC ACTIVITY OF NEW DERIVATIVE OF ISOTHIAZOLOPYRIDINE
Piotr Świątek,[a],* Agnieszka Matera-Witkiewicz,[b] Karolina Królewska-Golińska, Julia Kaźmierczak-Barańska, Marcin Cieślak and Barbara Nawrot[c]
[a] Department of Chemistry of Drugs, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211, 50-556 Wrocław, Poland [b] Screening Laboratory of Biological Activity Tests and Collection of Biological Material Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland [c] Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Lodz, Poland * [email protected]
A series of isothiazolopyridines of Mannich base type was synthesized. The structures of heterocycles were assigned on the bases of IR and 1H NMR data. The cytotoxicity of new compounds was determined on three neoplastic cell lines: HeLa (human cervix carcinoma), K562 (leukemia) and CFPAC (human pancreatic cancer cell line) by MTT assay as described in literature.[1] In the present screening program compound PS8 schowed the best cytotoxic activity.
O
N O N S N O N
Figure: PS8
In the screening test following survival rates were obtained:
HeLa K562 CFPAC 48H 72H 48H 72H 48H 72H 12% 8% 0% 0% - 1%
Because of high cytotoxic activity of PS8 on all three neoplastic cells lines, further cytotoxicity tests were performed using 6 different concentrations of the compound: 1mM, 1x10-1mM, 1x10-2mM, 1x10- 3 -4 -5 mM, 1x10 mM, 1x10 mM. After 72 hours a survival of the cancer cells was measured and IC50 values were calculated, yielding the following results: HeLa 30µM, K562 40µM and CFPAC 25µM. The cytotoxicity in HUVEC (human umbilical vein endothelial cells) as a reference/normal line was also determined. The IC50 = 6µM was obtained after 48 hours of incubation of HUVECs with PS8.
[1] M. Maszewska, J. Leclaire, M. Cieslak, B. Nawrot, A. Okruszek, A.-M. Caminade, J.-P. Majoral, Oligonucleotides, 2003, 13, 193.
224 The 10th Joint Meeting on Medicinal Chemistry 2017
P-149
STUDIES ON ARYL-SUBSTITUTED PHENYLALANINES: SYNTHESIS, ACTIVITY AND DIFFERENT BINDING MODES AT AMPA RECEPTORS
Ewa Szymańska,[a],* Birgitte Nielsen,[b] Darryl S. Pickering[b] and Tommy N. Johansen[b]
[a] Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland [b] Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark * [email protected]
Glutamate- and GABA-releasing neurons form two basic, excitatory and inhibitory systems responsible for neurotransmission in the mammalian central nervous system. Fast excitatory synaptic transmission in the CNS relies almost entirely on the neurotransmitter glutamate and its family of ion ligand-gated channel receptors (iGluRs). The family of iGluRs is divided into three functionally distinct subclasses: NMDA, AMPA and kainate receptors. Structurally, AMPA-receptors are cation-selective tetrameric heterooligomers formed by combinations of the highly homologous subunits GluA1-4, while kainate receptors are tetrameric assemblies of GluK1-5 subunits. The present project is a continuation of earlier studies on potent and selective competitive AMPA and/or KA receptors ligands among phenylalanine derivatives.[1-3] In order to map out molecular determinants for the competitive blockade of AMPA receptor subtypes, a series of racemic aryl- substituted phenylalanines was synthesized and pharmacologically characterized in vitro at native rat ionotropic glutamate receptors. The individual stereoisomers of selected compounds were further evaluated in radioligand binding assays at recombinant homomeric rat GluA2 and GluA3 receptors as well as in a TEVC electrophysiology assay at homomeric rat GluA2(Q)i receptor.
In the process of molecular modeling and docking to recently published X-ray structures of the glutamate ionotropic receptors binding sites,[2] two alternative antagonist binding modes at the GluA2 binding core were compare for the synthesized compounds. Structural factors important for pharmacological activity of individual enenantiomers were analyzed.
Acknowledgments: The financial support of the National Science Centre Poland (2014/15/B/NZ7/00908) is gratefully acknowledged.
[1] E. Szymanska, D. Pickering, B. Nielsen, T. Johansen, Bioorg. Med. Chem. 2009, 17, 6390. [2] E. Szymanska, K. Frydenvang, D.S. Pickering, C. Krintel, B. Nielsen, A. Kooshki, L.G. Zachariassen, L. Olsen, J.S. Kastrup, T.N. Johansen, J. Med. Chem., 2016, 59, 448. [3] E. Szymanska, P. Chalupnik, K. Szczepanska, A.M.C. Moral, D.S. Pickering, B. Nielsen, T.N. Johansen, K. Kiec-Kononowicz, Bioorg. Med. Chem. Lett., 2016, 26, 5568.
225 The 10th Joint Meeting on Medicinal Chemistry 2017
P-150
NOVEL AND EFFICIENT BICYCLIC GUANIDINE CATALYST FOR THE CYCLOTRIMERIZATION OF ISOCYANATES. A QUANTUM CHEMICAL STUDY.
Tana Tandarić and Robert Vianello
Computational Organic Chemistry and Biochemistry Group, Ruđer Bošković Institute, Zagreb, Croatia. * [email protected], [email protected]
Polyurethane foams are widely used polymers composed of organic units joined by carbamate (urethane) linkers.[1] Management of their physical properties represents significant challenge in the creation of new materials with desired properties. Since the cyclotrimerisation of organic isocyanates is one of the most sensitive steps in the whole process, identifying efficient catalysts for this chemical transformation represents an important and needed research goal. In this work we considered triazabicyclodecene (TBD) as a potential catalyst for the cyclotrimerization of isocyanates. We have investigated the reaction pathway involving a sequential addition of metyl-isocyanate (MIC) using well established quantum chemistry methods at the MP2/6– 311++G(2df,2pd)//M062X/6–31+G(d) level.[2] Our results show that the first MIC molecule is activated by the TBD catalyst through the nucleophilic attack of its imino nitrogen atom to strongly electrophilic carbon on MIC followed by the intramolecular MIC–TBD proton transfer, thus opening the possibility for the activation of another MIC molecule on the second nitrogen atom on TBD. After that, the two MIC systems combine to give a dimer, to be followed by the analogous formation of an open-chain trimer chemically bonded to TBD. The last step involves the cyclization of the trimer and the liberation of the final hexacyclic product concomitant with the regeneration of the TBD catalyst. The overall reaction pathway reveals that the investigated trimerization is thermodinamically a very ‡ favorable process (ΔrG = –34.3 kcal/mol) with reasonable reaction barrier (ΔG = 27.7 kcal/mol) in the THF solution. In addition, it provides a convincing insight to why dimerization is not favorable from both thermodynamic and kinetic points of view, being strongly in line with experimental observations. Compared to the uncatalyzed reaction, TBD lowers the activation barrier by 8.4 kcal/mol, thus increasing the reaction rate by the factor of 106. These significant results suggest TBD as a much efficient catalyst than some other systems proposed in the literature based on proazaphosphatranes.[3]
Figure: Schematic representation of a reaction involving three methyl-isocyanates (MIC) with the TBD catalyst.
[1] D. Heift, Z. Benkő, H. Grützmacher, A. R. Jupp, J. M. Goicoechea, Chem. Sci., 2015, 6, 4017. [2] I. Picek, R. Vianello, P. Šket, J. Plavec, B. Foretić, J. Org. Chem., 2015, 80, 2165. [3] J. N. Gibb, J. M. Goodman, Org. Biomol. Chem., 2013, 11, 90.
226 The 10th Joint Meeting on Medicinal Chemistry 2017
P-151
DESIGN AND SYNTHESIS OF DUAL G9A METHYLTRANSFERASE/LSD1 DEMETHYLASE OR SELECTIVE LSD1 INHIBITORS BY STRUCTURAL MANIPULATION OF THE QUINAZOLINE SCAFFOLD
Daniela Tomaselli,[a],* Alessia Lucidi,[a] Mariantonietta Forgione,[a] Gebremedhin Solomon Hailu,[a] Valentina Speranzini,[b] Biagina Marrocco,[b] Simona Pilotto,[b] Andrea Mattevi,[b] Dante Rotili[a] and Antonello Mai[a]
[a] Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy [b] Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy * [email protected]
In humans, histone methylation pattern results from the balance between lysine methylation and demethylation. The removal of methyl unit(s) is performed by two families of demethylases (KDMs) that differ for the reaction mechanism: LSD1/2 are FAD-dependent amine oxidases, while JmJC are iron/α-ketoglutarate dependent proteins.[1] LSD1 is able to catalyze demethylation of H3K4me1/2 and, in association with the co-repressor protein Co-REST, takes part in a multicomponent repressive complex including also REST and HDAC1/2.[2] LSD1 plays a crucial role in the epigenetic modulation of gene expression and represents a valuable target in cancer chemotherapy, since it is overexpressed in several types of tumors.[3] Our investigation of quinazolines as H3K9 methyltransferase/demethylase or DNMT inhibitors led us to identify MC3774, a Lys-mimicking derivative displaying dual G9a methyltransferase/LSD1 inhibition. In particular, MC3774 showed IC50 values of 1205 nM and 440 nM on G9a and LSD1 respectively. In MV4-11 leukemia cells, MC3774 showed antiproliferative activity with IC50 = 894 nM. The most interesting aspect of this investigation is about the inhibition mechanism. We designed MC3774 supposing that the insertion of the propanamine moiety could mimic the H3K4me2 moiety of the substrate bound within the active site. Surprisingly, the compound does not enter into the accessory pocket but binds the enzyme disposed with five copies in a stacked way obstructing the active site. The orientation of the molecules can be “face to face” or “head to tail”, and in both modes they interact with a cluster of negatively charged amino acidic residues.[4] This kind of non-covalent and reversible inhibition is typical for the interaction between quinazoline scaffold and the catalytic cleft of LSD1, in fact MC3774 does not inhibit G9a using the same stacking mode. Considering these observation, we worked on the synthesis of several analogs of the lead compound MC3774, modifying the quinazoline scaffold in position 2 with alkylamino functions of different length, variously substituted at omega position, and replacing the NH in position 4 with an oxygen atom or with N-CH3, or modifying the N-benzyl moiety with other aryl-alkyl functions, with the aim to increase the selectivity towards LSD1 and to improve the potency in AML cells of the compounds. The results are consistent with the inhibition mechanism. In fact, the insertion, on different position, of electron-rich functions, increase the potency on LSD1 and the disguise of proton donor groups determines the loss of the inhibitory activity on G9a.
[1] D. Rotili, A.Mai, Genes & Cancer, 2011, 2, 633. [2] S. Saleque, J. Kim, H. M Rooke, Mol. Cell., 2007, 27, 562. [3] J. W. Hojfeldt, K. Agger, K. Helin, Nat. Rev Drug Discov., 2013, 12, 917. [4] V. Speranzini et al., Sci. Adv., 2016, 2, 1.
227 The 10th Joint Meeting on Medicinal Chemistry 2017
P-152
HOMOLOGY MODELLING, STRUCTURE- AND LIGAND-BASED DRUG DESIGN OF NOVEL CALCIUM CHANNEL BLOCKERS WITH LEISHMANICIDAL ACTIVITIES
Carlos Henrique Tomich de Paula da Silva,[a],* Leonardo Bruno Federico,[a] Laura M. Alcântara,[b] Carolina B. Moraes,[b] Lucio H. Freitas-Júnior[b] and Joaquín M. Campos Rosa[c]
[a] School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil. [b] Laboratório Nacional de Biociências (LNBio) – Centro Nacional de Pesquisa em Energia e Materiais (CNPEM) – Campinas, Brazil. [c] Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de Granada, Spain * [email protected]
Nowadays, the biggest challenge for the chemotherapeutic treatments and which is responsible for many cases of failures in the leishmaniasis treatments is called multidrug resistance (MDR). MDR is not only related to a class of medication or to a specific target, but it can also be related to the multiple factors involved in this process. The pathways that affect the decrease of drug concentration in the intracellular environment are related to the decrease associated with the inflow of the carriers, e.g. a diminution via the ABC superfamily (ATP-binding cassette) through the efflux caused by the action of P-glycoprotein (MDR1). Within the ABC superfamily, the P-glycoprotein (P-gp) is the most widely studied class and the calcium channel blockers class is the first generation of P-gp modulators. Moreover, they interfere with the adhesion of the parasite to macrophages and this could be an important strategy to control the initial phase of leishmaniasis. In this work, we carried out the design of drug candidates addressed to a leishmanicidal activity through a potential calcium channel blockage, and not suffering the MDR phenomenon. We have used Ligand-Based Drug Design (LBDD), Structure-Based Drug Design (SBDD), pharmacokinetic and toxicological (ADME/Tox) predictions, as well as homology modeling of a L-type calcium channel. Resulting model was well evaluated as the top-ranked amongst three other models based on two other structures detected in a previous Blastp search. The two drug design approaches above mentioned were then used to perform virtual screening in different commercial compounds databases, totalizing up to 15 compounds selected for purchase. In silico validations of the approaches here used were initially performed using small “contaminated” (with known active ones) databases, and our drug candidates were then validated in vitro, showing interesting leishmanicidal activity as well as efficacy.
228 The 10th Joint Meeting on Medicinal Chemistry 2017
P-153
NOVEL D- GLUCOSAMINE N- PEPTIDYL DERIVATIVES ENDOWED WITH SELECTIVE ACTIVITY TOWARDS IKK alpha
V. Tudino,[a],* V. N. Madia,[a] F. Saccoliti,[a] G. Pupo,[a] R. Cocchiola,[b] A. Scotto D’Abusco,[b] R. Scandurra,[b] R. Costi[a] and R. Di Santo[a]
[a] Pasteur Institute – Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, “Sapienza” University of Rome, p.le Aldo Moro 5, 00185, Rome, Italy [b] Dipartimento di Scienze biochimiche “Alessandro Rossi Fanelli”, “Sapienza” University of Rome, p.le Aldo Moro 5, 00185, Rome, Italy * [email protected]
Osteoarthritis (OA) is a rheumatic disease which represents the major cause of disability in the adult population as well as a severe health burden with a significant economic impact. OA is the result of abnormal biomechanics and cell-derived and tissue-derived factors.[1] The NF-kB family of nuclear transcription factors is involved in the induction of inflammatory disorders, representing a potential therapeutic target in OA. It comprehends ubiquitously expressed proteins responsible for the regulation of a considerable number of genes. These transcription factors are sequestered in the unstimulated cell cytoplasm by inhibitor proteins called IkBs, forming inactive complexes. As a result of specific stimuli IkB is phosphorylated by IkB kinase (IKK) complex, leading to the dissociation of IkB from NF-kB which can migrate into the nucleus, activating the gene transcription. IKK includes three components: IKK, IKK and NF-Kb essential modulator (NEMO). IKK and IKK are implicated in the regulation of the expression of genes involved in the extracellular matrix remodeling and terminal differentiation of chondrocytes.[2,3] From a random screening of our in house library the compound RC510 (already known as substrate analog inhibitors of papain and cathepsin-B),[4] a D- glucosamine N-peptidyl derivative, showed selective activity towards IKK.[5] Following this result we decided to investigate the interactions of this compound with the target by conducting molecular docking studies, in order to speculate about the mechanisms by which it binds to IKK kinase domain. As docking molecular target we used a three-dimensional model of IKK, built by homology modelling. Docking experiment showed that RC510 interacts with ATP binding pocket mainly by the establishment of hydrogen bonds (with backbone atoms of Thr15 and Glu140 and with side chains of Thr15 and Asp94) and of hydrophobic interactions. From these results we decided to design and synthesize a novel series of D-glucosamine N-peptidyl derivatives in order to obtain compounds having an inhibitory activity towards IKK.
[1] L.J. Sandell, Nat. Rev. Rheumatol., 2012, 8, 77. [2] E. Zandi, D. M. Rothwarf, M. Delhase, M. Hayakawa, M. Karin, Cell, 1997, 91, 243. [3] S. Ghosh, M. Karin, N. Haven Cell, 2002, 109, S81. [4] C. Giordano, C. Gallina, V. Consalvi, R. Scandurra, E. J. Med. Chem., 1991, 26, 753. [5] A. Scotto D’Abusco, L. Politi, C. Giordano, R. Scandurra, Arthritis Res. Ther., 2010, 12, R18.
229 The 10th Joint Meeting on Medicinal Chemistry 2017
P-154
MEMANTINE ANALOGUES WITH ACTIVITY AS GLUTAMATE N-METHYL D-ASPARTATE RECEPTOR ANTAGONISTS
Andreea L. Turcu,[a] Daina Martínez-Falguera,[b] Francesc X. Sureda[b] and Santiago Vázquez[a],*
[a] Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, Barcelona, E-08028, Spain [b] Unitat de Farmacologia, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, C/St. Llorenç 21, Reus, 43201, Spain * [email protected]
Current treatments for Alzheimer’s disease (AD), the most common form of dementia, neither prevent nor reduce the progression of the disease.[1] Thus, new therapies are urgently needed. The N-Methyl-D-aspartate (NMDA) receptor antagonists act by protecting neurons from excessive pathological calcium influx, which leads to neuronal damage and finally to neuronal cell death, common features in neurodegenerative disorders such as AD. So far, memantine is the only NMDA uncompetitive receptor antagonist that has been approved for the treatment of AD.[2] In the last few years, our research group has synthesized and carried out the pharmacological evaluation of new memantine analogues with general structure 1. We found that this polycyclic amines were active as NMDA receptor antagonists, some of them with IC50 values similar to that of [3] memantine (IC50 = 1.5 µM) (Figure 1).
Figure 1: Compounds 1a-d and their activity as NMDA receptor antagonists
These results and the simplicity of the route led us to design and synthesize new derivatives with general structure 2, which pharmacological activities will be presented here (Figure 2).
Figure 2: Compounds 2a-h, new NMDA receptor antagonists
[1] J. Korabecny, F. Zemek, O. Soukup, K. Spilovska, K. Musilek, D. Jun, E. Nepovimova, K. Kuca, in Drug Design and discovery in Alzheimer’s Disease, Atta-ur-Rahman and Choudhary, M. I., ed.; Elsevier 2014, 3. [2] a) L. Devi, M. Ohno, Pharmacol. Biochem. Behav., 2016, 144, 60. b) W. Danysz, C. G. Parsons, British J. Phamacol., 2012, 167, 324. [3] E. Valverde, F. X. Sureda, S. Vázquez, Bioorg. Med. Chem., 2014, 22, 2678.
230 The 10th Joint Meeting on Medicinal Chemistry 2017
P-155
NOVEL THIAZOLES AS TRYPANOCIDAL AGENTS
Santiago Vázquez,[a],* Rosana Leiva,[a] Jèssica Rubí,[a] Martin C. Taylor,[b] Belén Pérez[c] and John M. Kelly[b]
[a] Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, Barcelona, E-08028, Spain [b] London School of Hygiene and Tropical Medicina, Department of Infectious and Tropical Diseases, Keppel Street, London WC1E 7HT, United Kingdom [c] Departament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de Barcelona, E- 08193, Bellaterra, Barcelona, Spain * [email protected]
The Trypanosoma protozoa infect humans and many domestic mammals causing severe mortality and significant economic burden. The human diseases related to these parasites are Human African trypanosomiasis (HAT, Sleeping sickness) caused by Trypanosoma brucei ssp. and Chagas disease caused by Trypanosoma cruzi. The existing therapies for both diseases exhibit serious side effects, require long treatment schedules and often fail to eliminate parasitemia.[1,2] Both diseases present clinically relevant neurological disorders. The second phase of the HAT –the neurological phase, is characterized by the presence of the parasite in the central nervous system (CNS).[3] In the case of Chagas disease, neurological alterations such as dementia are common in the chronic phase.[4] For these reasons, the design of new trypanocidal agents able to cross the blood-brain barrier (BBB) is of interest. Previous investigations have identified novel hydrazinylthiazoles as promising scaffolds having a low micromolar activity against T. cruzi.[5] Furthermore, adamantyl derivatives with submicromolar activity against T. brucei have been identified.[6] In light of these findings, we have combined both scaffolds to achieve potent, CNS-penetrant trypanocidal agents and to establish structure-activity relationships in a novel family of promising anti-Trypanosoma compounds. Preliminary results on the synthesis, structure-activity relationships of their trypanocidal activity and ability for BBB permeability will be presented.
[1] R. Brun, J. Blum, F. Chappuis, C. Burri, Lancet, 2010, 375, 148. [2] B. Perry, K. Sones, Science, 2007, 315, 333. [3] http://www.who.int/trypanosomiasis_african/en/ (accessed on 15th Feb 2017). [4] http://www.who.int/chagas/en/ (accessed on 15th Feb 2017). [5] M.V.O. Cardoso, L.R.P. de Siqueira, E.B. da Silva, L.B. Costa, M.Z. Hernandes, M.M. Rabello, R.S. Ferreira, L.F. da Cruz, D.R.M. Moreira, V.R.A. Pereira, M.C.A.B. de Castro, P.V. Bernhardt, A.C.L. Leite, Eur. J. Med. Chem., 2014, 86, 48. [6] I. Papanastasiou, A. Tsotinis, N. Kolocouris, S.R. Prathalingam, J.M. Kelly, J. Med. Chem., 2008, 51, 1496.
231 The 10th Joint Meeting on Medicinal Chemistry 2017
P-156
FLUORINATED PHENYLALANINE DERIVATIVES: VERSATILE BIOLOGICAL ACTIVITY
Martin Krátký,[a] Jarmila Vinšová,[a],* Šárka Štěpánková[b] and Jiřina Stolaříková [c]
[a] Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic [b] Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic [c] Laboratory for Mycobacterial Diagnostics and Tuberculosis, Regional Institute of Public Health in Ostrava, Partyzánské námĕstí 7, 702 00 Ostrava, Czech Republic * [email protected]
Unnatural amino acids are useful building blocks in medicinal chemistry. Replacement of the hydrogen atom with a hydrophobic and highly electronegative fluorine atom often results in significant changes in the properties of the parent molecule. Presence of a fluorine atom changes proteinogenic α-amino acids to unnatural (non-proteinogenic) species, thus influencing their biological behaviour. Phenylalanine with fluorine atom in the positions 2, 3 or 4 of the phenyl ring have affected activity of a wide range of proteins and enzyme with many potential medicinal applications including antiviral[1] or anti-cancer agents.[2] Inspired by these data, we designed and synthesized a novel series of aromatic esters and amides of ortho/meta/para DL-phenylalanine. A series of thirty novel N-acetylated fluorophenylalanine-based aromatic amides and esters was synthesized using N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide or phosphorus trichloride in pyridine. They were characterized by spectral methods and underwent a screening of their potential biological activity against Mycobacterium tuberculosis and three non-tuberculous mycobacterial strains, other bacteria (G+, G-), fungi and for their cytotoxicity (HepG2 cells). In general, the amidic derivatives avoided any significant antibacterial, antimycobacterial and antifungal properties. The majority of the esters exhibited a mild antimycobacterial activity against both tuberculous and non- tuberculous mycobacteria and several of them inhibited the growth of Gram-positive bacteria and a fungal strain (Trichophyton mentagrophytes). All prepared derivatives were evaluated on acetylcholinesterase and butyrylcholinesterase activity with IC50 values for AChE and BChE of 57.88- 130.75 µM and 8.25 to 289.0 µM, respectively. Some derivatives were comparable or superior to rivastigmine, an established drug. The modification of parent acids offers more active inhibitors of BChE but not AChE. IC50 values for BChE were within a broader concentration range when compared to AChE. One derivative produced a selective inhibition of BChE otherwise the inhibition is non-selective. With respect to the substitution of ester/amidic benzene nuclei, the introduction of NO2 and CH3 groups into aniline ring and CF3 moiety into phenol enhanced activity. Focusing on cytotoxicity, IC50 values for eukaryotic cell line were not sharply different from MIC obtained for prokaryotes. Contrarily, a range of investiPPgated derivatives provided a sufficient selectivity for butyrylcholinesterase.[3]
Acknowledgments: This work was supported by the Czech Science Foundation project No. 17- 27514Y.
[1] S.E. Webber, J.T. Marakovits, P.S. Dragovich, T.J. Prins, R. Zhou, S.A. Fuhrman, A.K. Patick, D.A. Matthews, C.A. Lee, B. Srinivasan, T. Moran, C.E. Ford, M.A. Brothers, J.E.V. Harr, J.W. Meador, R.A. Ferre, S.T. Worland, Bioorg. Med. Chem. Lett., 2001, 11, 2683. [2] X. Li, J. Wang, L. Zhang, W. Xu, Arch. Pharm. Chem. Life Sci. ,2011, 344, 494. [3]. M. Krátký, J Vinšová, Š. Štěpánková, K. Vorčáková, L. Navrátilová, F. Trejtnar, J. Stolaříková, Bioorg. Chem., 2017, accepted.
232 The 10th Joint Meeting on Medicinal Chemistry 2017
P-157
DISCOVERY OF THE FIRST-IN-CLASS CHEMICAL PROBES FOR THE SPINDLIN1 METHYL-LYSINE READER DOMAIN
M. Viviano,[a],* S. Castellano,[a,b] M. T. Bedford,[c] H. Li[d] and G. Sbardella[a]
[a] Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, I-84084 Fisciano, Salerno, Italy [b] Department of Medicine and Surgery, University of Salerno, Via Salvador Allende, I-84081 Baronissi, Salerno, Italy [c] The University of Texas, MD Anderson Cancer Center, Smithville, TX 78957, USA [d] Tsinghua University, Center for Structural Biology, Beijing 100084, P.R. China * [email protected]
Histone post-translational modifications (PTMs) have been proposed to constitute a “histone code”, which helps to organize genetic information at the chromatin level, and play a pivotal role in gene expression, cell differentiation, and development.[1] During the past decade, a wealth of “reader” modules have been characterized for histone PTM recognition, that function in a histone type- and site-specific manner.[2] In particular, the detection of methylated histone tail lysine residues by Tudor domains plays important roles in epigenetic control of gene expression and DNA damage response. Among them, Spindlin1 (SPIN1) is a protein of the SPIN/SSTY family implicated in the regulation of gametogenesis.[3] Furthermore, its overexpression perturbs the cell cycle, induces chromosome instability, and leads to tumorigenesis,[4-6] even if the molecular mechanisms remain poorly understood. Being interested in the development of novel small molecule modulators of epigenetic targets, here we report the identification of a compound (EML405) that acquired a novel interaction with the Tudor domain-containing protein Spindlin1. Structural studies revealed that the symmetric nature of EML405 allows it to simultaneously engage two of SPIN1’s Tudor domains (Figure), and also facilitated the rational synthesis of more selective SPIN1 inhibitors (EML631-633, Figure). The EML631-633 compounds engage SPIN1 in cells, block its ability to “read” H3K4me3 marks, and inhibit its transcriptional coactivator activity, paving the way for future progress in Spindlin1 biology and its therapeutic applications.
N N N
O
NH O NH O N N NH O N N N N N N N O O N N O N EML631 EML632 EML633 Figure: From structural studies of EML405 to new potent Spindlin1 inhibitors EML631-633.
[1] T. Jenuwein, C.D. Allis, Science, 2001, 293, 1074. [2] C. A. Musselman, M.E. Lalonde, J. Cote, T. G. Kutateladze, Nat. Struct. Mol. Biol., 2012, 19, 1218. [3] E. Staub, D. Mennerich, A. Rosenthal, Genome Biol., 2002, 3, 1. [4] P. Zhang, B. Cong, H. Yuan, L. Chen, Y. Lv, C. Bai, X. Nan, S. Shi, W. Yue, X. Pei, J. Cell. Physiol., 2008, 217, 400. [5] X. Su, G. Zhu, X. Ding, S. Y. Lee, Y. Dou, B. Zhu, W. Wu, H. Li, Genes. Dev., 2014, 28, 622. [6] H. Franz, H. Greschik, D.Willmann, L. Ozretic, C. A. Jilg, E. Wardelmann, M. Jung, R. Buettner, R. Schüle, Oncotarget, 2015, 6, 4773.
233 The 10th Joint Meeting on Medicinal Chemistry 2017
P-158
HYDRAZINO PEPTIDOMIMETICS AS MODULATORS OF PROTEIN-PROTEIN INTERACTIONS
Kristina Vlahoviček-Kahlina,[a] Luka Kavčič,[b] Marija Marković,[a] Janez Plavec,[b] Ivo Piantanida[a] and Ivanka Jerić[a],*
[a] Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia [b] National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia * [email protected]
Design and synthesis of peptidomimetics represent an important field in chemistry, pharmacology and material science, as they circumvent the numerous limitations of natural peptides. We aimed to develop solid-phase methodology for smooth incorporation of hydrazido derivatives of natural alpha- amino acids into peptide chain and study interaction of designed peptidomimetics with biomolecules. Modulation of protein–protein interactions (PPIs) have emerged as one of the main challenges in chemical biology and drug discovery.[1] Therefore, as a biological target, we chose a well-described p53-mDM2 model. Disruption of the p53-mDM2 interaction is an important goal for cancer therapy. To explore the utility of hydrazino-based peptidomimetics to interfere with these interaction, we designed a small library of compounds based on the biologically active octapeptide fragment of p53 protein (Figure). Three amino acids, Phe, Trp and Leu, directly participate in interaction, so we decided to replace two of them (Phe and Leu) and Tyr adjacent to Trp, with their hydrazino analogues. Prepared peptides were characterized by NMR spectroscopy. Detailed NMR analysis revealed presence of multiple conformations in D2O/DMSO solution, depending on number and position of hydrazino acids in a peptide sequence. Interaction between mDM2 protein and prepared peptides was assayed by fluorimetric titrations based on intrinsic fluorescence of both, mDM2 and peptides. For some peptides titration with mDM2 yielded non-additive change of fluorescence, allowing estimation of binding constants by multivariate least square analysis of complete titration spectra in HyperQuad programme.[2] For all peptide/mDM2 complexes similar, micromolar affinity was determined, pointing out that various introductions of hydrazine-moiety do not interfere significantly with binding.
Figure: Hydrazino-peptidomimetics for p53-mDM2 interaction inhibition study.
[1] P. Chene, ChemMedChem, 2006, 1, 400. [2] P. Gans, A. Sabatini and A. Vacca, Talanta, 1996, 43, 1739.; L. Alderighi, P. Gans, A. Lenco, D. Peters, A. Sabatini, A. Vacca, Coord. Chem. Rev., 1999, 184, 311.
234 The 10th Joint Meeting on Medicinal Chemistry 2017
P-159
SALICYLANILIDE MUTUAL PRODRUGS: SYNTHESIS AND BIOLOGICAL ACTIVITY
R. Vosátka,* M. Krátký, J. Vinšová
Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic * [email protected]
Tuberculosis (TB), particularly the development of drug-resistant forms (multidrug-resistant TB, extensively drug-resistant TB and recently reported totally drug-resistant TB), represents a serious global problem currently. According to the WHO report, about 1/3 of the world population is infected by latent TB. These alarming facts are reflected in an intensive search for new antimycobacterial drugs. Contemporary development is focused, e.g., on the unique steps in the biosynthesis of cell wall, the mapping of metabolic pathways or the identification of specific genes affecting virulence and latent state of Mycobacterium tuberculosis.[1] Salicylanilide (2-hydroxy-N-phenylbenzamide) derivatives belong to the promising agents. It has been reported that esterification of phenolic group to form its prodrugs with improved properties. This modification is able to enhance bioavailability, which is often a limiting factor for their activity, improve physicochemical properties (lipophilicity etc.) or reduce toxicity.[2] Salicylanilide-based esters have shown a high in vitro activity against both drug-sensitive and resistant TB strains with minimum inhibitory concentrations ≥0.125 µM.[3] In this study, salicylanilides were esterified by isonicotinic and pyrazine-2-carboxylic acids to obtain novel mutual prodrugs. Based on previous results, the design was focused on the compound with electron-withdrawing substituents (especially CF3 group) at aniline ring. This substitution pattern contributes to an increased efficacy against both M. tuberculosis and nontuberculous mycobacteria (Mycobacterium avium and Mycobacterium kansasii).[3] The synthesis of these esters involves two steps. The first step is the preparation of salicylanilides, which are obtained routinely by the reaction of appropriate salicylic acids with various anilines in the presence of PCl3 under microwave irradiation. The second step consists in a reaction with appropriate acyl chlorides in the presence of a tertiary base or Steglich esterification. Synthesized derivatives undergo in vitro evaluation against drug-sensitive M. tuberculosis H37Rv and atypical strains of M. avium and M. kansasii currently. The most active derivatives will be assayed against one extensively drug-resistant TB and five multidrug-resistant TB strains with different resistance patterns and for their cytotoxicity.
Acknowledgments: This work was supported by the Czech Science Foundation project No. 17- 27514Y.
[1] WORLD HEALTH ORGANIZATION. Global tuberculosis report 2016. http://apps.who.int/iris/bitstream/10665/250441/1/9789241565394-eng.pdf?ua=1 (4.2.2017) [2] J. M. Ferriz, J. Vinšová, Curr. Pharm. Des., 2010, 16, 2033. [3] M. Krátký, J. Vinšová, Curr. Pharm. Des., 2011, 17, 3494.
235 The 10th Joint Meeting on Medicinal Chemistry 2017
P-160
SYNTHESIS AND PHARMACOLOGICAL ACTIVITY IN A GROUP OF PHENOXYALKYL DERIVATIVES OF PIPERAZINE
Anna M. Waszkielewicz,[a],* Katarzyna Pańczyk,[a] Karolina Pytka,[b] Anna Rapacz,[b] Monika Głuch-Lutwin,[c] Agata Siwek,[c] Adam Bucki,[d] Marcin Kołaczkowski[d] and Henryk Marona[a]
[a] Department of Bioorganic Chemistry, Chair of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland [b] Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland [c] Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland [d] Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland * [email protected]
Central nervous system disorders such as anxiety, depression or epilepsy are important health challenges, and they are comorbid. Coexistence and common etiology include factors such as trauma or neurodegeneration.[2] The aim of our study was to design new phenoxyalkyl derivatives of piperazine for their potential anxiolytic, antidepressant and possibly anticonvulsant activity and to evaluate coexistence of observed activities in the group of compounds. The structure design was based on our former findings in a group of derivatives of 1- phenoxyalkyl-4-(2- methoxyphenyl)piperazine.[2] Ten new compounds have been designed and they were synthesized by aminolysis of appropriate phenoxyalkyl bromides, according to formerly published procedures. The final compounds were achieved in the form of hydrochlorides.[2] The compounds were evaluated for their affinities towards 5-HT1A, 5-HT2A, 5-HT6, 5-HT7, D2, and α1 receptors, and in functional assays, and they were subject to in vivo tests in mice, i.p. for their antidepressant-like (forced swim test), locomotor, anxiolytic-like (four-plate test) activities as well as – at higher doses – for anticonvulsant potential (MES) and neurotoxicity (rotarod). The most active compound was 1-(2-(2,5-dimethylphenoxy)ethyl)-4-phenylpiperazine dihydrochloride. It exhibits affinity and/or activity towards 5-HT1A receptor (Ki=35 nM, weak antagonist), 5-HT2A receptor (Ki=121 nM), 5-HT7 (Ki=130 nM, weak antagonist), and α1 (Ki=82 nM). Its anxiolytic-like properties were observed at 1.25 mg/kg and it is inactive in MES at 100 mg/kg. It was also subject to molecular modeling (docking), and mutagenicity (Ames test) and was found safe until 50 μg/plate. Within the title group of compounds an example of anticonvulsant agent was 1-(2,6-dimethylphenoxybutyl)-4- phenethylpiperazine hydrochloride (MES ED50 = 17.05 mg/kg, TD50 = 37.25 mg/kg). Among all tested compounds, anticonvulsant and anxiolytic activities have been observed, however, with no coexistence of both activities, since the active dose ranges did not cover.
The research was financed by the Polish National Science Centre, grant no. DEC- 2013/11/B/NZ7/04834.
[1] S. D. Silberstein, Headache, 2001, 41 S1, S11. [2] A. M. Waszkielewicz, K. Pytka, A. Rapacz, E. Wełna, M. Jarzyna, G. Satała, A. Bojarski, J. Sapa, P. Zmudzki, B. Filipek, H. Marona, Chem. Biol. Drug Des., 2014, 85, 326.
236 The 10th Joint Meeting on Medicinal Chemistry 2017
P-161
STRUCTURE-ACTIVITY RELATIONSHIP STUDY OF INTERVENOLIN, A NATURAL QUINOLONE WITH ANTI-TUMOR AND ANTI-HELICOBACTER PYLORI ACTIVITIES
Takumi Watanabe,[a],* Hikaru Abe,[a] Manabu Kawada,[b,c] Chiharu Sakashita,[a] Shun-ichi Ohba,[c] Hiroyuki Inoue,[c] Tomokazu Ohishi,[c] Tohru Masuda,[c] Chigusa Hayashi,[d] Masayuki Igarashi[d] and Masakatsu Shibasaki[a]
[a] Institute of Microbial Chemistry (BIKAKEN), Laboratory of Synthetic Organic Chemistry, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan [b] Institute of Microbial Chemistry (BIKAKEN), Laboratory of Oncology, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan [c] Institute of Microbial Chemistry (BIKAKEN), Numazu, 18-24 Miyamoto, Numazu-shi, Shizuoka 410-0301, Japan [d] Institute of Microbial Chemistry (BIKAKEN), Laboratory of Microbiology, 3-14-23 Kamiosaki, Shinagawa- ku, Tokyo 141-0021, Japan * [email protected]
Targeted therapy is one of the most active research subjects for treatment of cancer, which utilizes the chemotherapeutic agents that can modulate the growth signal of tumor cells. As long as the target is tumor relevant, the compounds are expected to be inert to normal tissues and display low toxicity. However, proteinous key players in the growth signal of tumor cells are more prone to mutate compared to those of normal cells, which is frequently causative of resistance. Therefore, we have been interested in the growth signal to affect tumor tissue transmitted from the adjacent stromal cells as a target of screening for anticancer agents; a novel natural product of microorganism origin, intervenolin, has been discovered.[1] Intervenolin has a 4-quinolone skeleton substituted with an iminodithiocarbonate moiety at the 1- position and a geranyl side chain at the 2-position; they are unusual substituents for 4-quinolones. In the present SAR study, various intervenolin analogs were prepared according to the synthetic procedure reported previously[2] to clarify that long aliphatic side chain at the 2-position was favorable for antiproliferative activity, and the substituent at the 1-position was able to alleviate the acute toxicity in many cases.[3] Intriguingly, several intervenolin derivatives exhibited potent anti-Helicobacter pylori activity comparable to that of clarithromycin with remarkable selectivity over other microorganisms.[3]
[1] M. Kawada, H. Inoue, S.-i. Ohba, M. Hatano, M. Amemiya, C. Hayashi, I. Usami, H. Abe, T. Watanabe, N. Kinoshita, M. Igarashi, T. Masuda, D. Ikeda, A. Nomoto, J. Antibiot., 2013, 66, 543. [2] H. Abe, M. Kawada, H. Inoue, S.-i. Ohba, A. Nomoto, T. Watanabe, M. Shibasaki, Org. Lett., 2013, 15, 2124. [3] H. Abe, Kawada, H. Inoue, S.-i. Ohba, T. Masuda, C. Hayashi, M. Igarashi, A. Nomoto, T. Watanabe, M. Shibasaki, Tetrahedron, 2013, 69, 7608.
237 The 10th Joint Meeting on Medicinal Chemistry 2017
P-162
DISCOVERY OF ISOQUINOLINOQUINAZOLINONES AS A NOVEL PPAR GAMMA ANTAGONISTS
Yifeng Jin,Younho Han, Daulat B. Khadka, Kwang Youl Lee and Won-Jea Cho*
College of Pharmacy, Chonnam National University, South Korea * [email protected]
Metabolic syndrome has undergone extensive investigation as it is an increasing medical problem worldwide. It is characterized by insulin resistance, hyperglycemia, dyslipidemia, obesity, fatty liver, and atherosclerosis. The peroxisome proliferator activated receptor γ (PPAR γ), a member of the steroid-thyroid hormone superfamily of ligand-activated transcription factors, has an important role in several metabolic diseases including adipocyte differentiation, lipogenesis, and glucose metabolism. Similar to other nuclear receptors, PPARγ shares a conserved modular domain structure, including a N-terminal activation function-1 (AF-1) and central DNA-binding domain (DBD). On the basis of helix 12 alteration, ligands can be divided into agonists and antagonists. Usually, the agonist of PPARγ such as rosiglitazone (an insulin-sensitizing agent) can stabilize H12 by interacting directly with Tyr473. While the antagonist of PPARγ, GW9662, forms covalent bond with Cys285 sulfur of PPARγ but lacks interaction with H12. To design novel inhibitors of PPARγ, GW9662 and berberine with PPARγ inhibitory activities were hybridized into isoquinolinoquinazolinones. We performed docking study in ligand binding domain (LBD) of the GW9662-PPARγ complex (PDB ID: 3B0R), and the designed molecule interacted in similar manner as GW9662 at the Y-shaped pocket of PPARγ. The designed molecule had H-bond with Cys285 and located away from H12. Isoquinolinoquinazolinones were simply synthesized by 2-step intermolecular cyclization reactions. The biological evaluation suggests that this new series of PPARγ antagonists may become effective agents for metabolic disorders.
[1] Y. Jin, Y. Han, D.B. Khadka, C. Zhao, K. Youl Lee, W.-J. Cho, Scientific Report 2016, 6, 34661.
238 The 10th Joint Meeting on Medicinal Chemistry 2017
P-163
SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF NEW S-TRIAZOLE DERIVATIVES
M. Wujec,[a],* A. Paneth,[a] Ł. Popiołek,[a] T. Plech,[a] Sz. Kosiek,[a] E. Kędzierska[b] and J. Kotlińska[b]
[a] Department of Organic Chemistry, Medical University, 4a Chodźki St., 20-093 Lublin, Poland [b] Department of Pharmacology and Pharmacodynamics, Medical University, 4a Chodźki St., 20-093 Lublin, Poland * [email protected]
Nowadays CNS disorders are among the most common. We have a various range of drugs but the treatment of central nervous system diseases, such as anxiety, analgesic, depression and epilepsy is still non satysfied. There is a need to search for new terapies; more effective and less toxic. Our erlier work showed that a large group of triazole derivatives showed very good anticonvulsant activity.[1-3] Additionally, some s-triazoles produced significant antinociceptive effect in the writhing syndrome test and in the hot plate test.[4-6] It is important to note, that all tested s-triazoles were devoid of neurotoxicity as they did not impair the mouse motor coordination and they did not affect the body temperature of mice. Considering the above, we have decided to obtain some new s-triazole with fluoro sustituted phenyl ring in position 3 of triazole scaffold with promissing CNS activity. First part of our experiments included: synthesis of nine s-triazoles with 2-fluorophenyl-, 3- fluorophenyl- and 4-fluorophenyl substituent in position 3 of triazole. The second one: the acute toxicity evaluation, motor coordination test, body temperature measurement, the thiopental induced sleeping time test and L-5-hydroxytryptophan-induced head-twitch test, which are generally accepted as basic in central activity investigations of new agents. Finnally, we were focused on potential antinociceptive, anticonvulsant, antidepressant and anxiolytic activity of title compounds.
[1] T. Plech, B. Kaproń, J. Łuszczki, A. Paneth, A. Siwek, M. Kołaczkowski, M. Żołnierek, G. Nowak, Eur. J. Med. Chem., 2014, 86, 690. [2] T. Plech, J. Łuszczki, M. Wujec, J. Flieger, M. Pizoń, Eur. J. Med. Chem., 2013, 60, 208. [3] J. Łuszczki, T. Plech, M. Wujec, Pharmacol. Rep., 2012, 64, 970. [4] A. Siwek, M. Wujec, M. Dobosz, E. Jagiełło-Wójtowicz, A. Kleinrok, A. Chodkowska, P. Paneth, Phosphorus Sulfur Silicon Relat. Elem., 2008, 183, 2669. [5] A. Siwek, M. Wujec, M. Dobosz, E. Jagiełło-Wójtowicz, A. Chodkowska, A. Kleinrok, P. Paneth, Centr Eur. J. Chem., 2008, 6, 47. [6] J. Listos, S. Talarek, J. Orzelska, S. Fidecka, M. Wujec, T. Plech, Naunyn-Schmiedeberg’s Arch. Pharmacol., 2014, 387, 367.
239 The 10th Joint Meeting on Medicinal Chemistry 2017
P-164
DEVELOPMENT OF THE METHOD FOR HPLC ASSAY OF THE LIMОNIUM GMЕLINII DRY EXTRACT
G. Е. Zhussupova, D. T. Kassymova and A. I. Zhussupova*
Al-Farabi Kazakh National University * [email protected]
Phаrmасеutiсаl prоduсt whеn intrоduсed into mеdiсinе must mееt аll thе rеquirеmеnts аnd еnsurе thе sаfеty аnd еffiсiеnсy оf its usе, and validation is one of the basic parts of GMP rules enabling the production of consistently high-quality medicinal products. Thе substаnсе оbtаinеd frоm thе grass оf Limоnium gmеlinii contains epigallocatechin gallate in the free form and in the form of monomer units of condensed tannins. It is known that epigallocatechin gallate is superior to other forms of monomeric flavan-3-ols for the antioxidant activity, which decreases in the series: epigallocatechin, epicatechin gallate and epicatechin. High antitumor activity of epigallocatechin gallate has been shown as well. That is why the epigallocatechin gallate was selected as an active substance for the assay of Limоnium gmеlinii dry extract by HPLC. The method has to be designed and validated firstly. The use of gradient elution, where the stationary phase (A) was diluted acid – 0.5-0.2% trifluoroacetic acid (method 1), acetic acid (method 2) and phosphoric (method 3) acid, and as a mobile phase B was acetonitrile, did not lead to satisfactory results. The best separation of the components was achieved with isocratic elution, where mobile phase consists of water: acetonitrile: acetic acid in a ratio of 89:10:1. A retention time equal to 5.109 minutes was obtained for a standard of epigallocatechin gallate, while 5.100 minute retention for the studied plant extract. By calculation based on peaks areas the content of epigallocatechin gallate in isolated extract was estimated as 35.89%. It is supposed that the contribution to a high content of epigallocatechin gallate cannot be simply connected to its monomeric form, but is also due to the polymeric forms of condensed tannins. Designed by HPLC analysis conditions in the long term can be used to standardize the test dry extract and drugs obtained on its basis.
240 The 10th Joint Meeting on Medicinal Chemistry 2017
P-165
STRUCTURE-ACTIVITY AND MECHANISTIC STUDY OF INHIBITORY EFFECTS OF POLYSUBSTITUTED PYRIMIDINES ON PROSTAGLANDIN E2 PRODUCTION
Zdeněk Zídek,[a],* Zlatko Janeba,[b] Petr Jansa,[b] Miloslav Kverka,[a] Eva Kmoníčková,[a] Filip Kalčic[b] and Viktor Kolman[b]
[a] Department of Pharmacology, Institute of Experimental Medicine, The Czech Academy of Sciences, Vídeňská 1083, 14220 Prague 4, Czech Republic [b] Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences, Flemingovo nám. 2, 16610 Prague 6, Czech Republic * [email protected]
Pyrimidines possess multiple biological activities and thus have become an important source of drugs used for the treatment of diseases, such as viral, bacterial and fungal infections, cancer and Parkinson disease.[1] The aim of our studies was to examine possible beneficial effects of pyrimidine derivatives on inflammation. We have synthesized a series of novel polysubstituted pyrimidines and analysed their interaction with production of prostaglandin E2 (PGE2) implicated in etiology of various inflammatory processes. The test compounds differed at combinations of distinct substituents at the positions C2, C4, C5 and C6 of the pyrimidine ring (Table). Effects of compounds on production of PGE2 were determined under the in vitro conditions using mouse peritoneal cells. They were cultured (2x106/ml) in the presence of bacterial lipopolysaccharide (LPS; 10 ng/ml) and pyrimidines. Supernatant concentration of PGE2 was assayed by ELISA after 5 h of culture. We have found that pyrimidines are the structure-dependent inhibitors of PGE2 production. The C4,6- (bis)chloro compounds with hydrogen or methyl substituents at the C5 position (groups I-III) are devoid of the inhibitory effects. The intrinsic PGE2-inhibitory activity has only been acquired by the replacement of the C5-hydrogen and C5-methyl with C5-butyl. Irrespective of the length of aliphatic substituent at the C5 position, all compounds with phenyl, p-methylphenyl or p-methoxyphenyl (instead of chlorine) at both or just one of the C4 and C6 positions (groups IV-VIII) are strong inhibitors of PGE2 production. Their IC50s range between 1 to 5 µM. The tested pyrimidines do not interfere with the transductional (MAP kinases p38, ERK1/2, JNK) and transcriptional (mRNA expression of cyclooxygenases COX-1 and COX-2) pathways of PGE2 production. Pharmacodynamic profile of PGE2 inhibition has indicated post-translational mechanism of pyrimidine action. However, they do not suppress the enzyme activity of COX-1 and COX-2. Mechanism of action of pyrimidines thus differs from that of the non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin, aspirin and celecoxib, recognized and clinically used PGE2 inhibitors that bind to the active centre of COX enzymes.
gr. positions: C2 C4 C6 C5 I amino chlorine chlorine hydrogen/ methyl/ butyl II dimethylamino(methylenamino) chlorine chlorine hydrogen/ methyl/ butyl III formylamino chlorine chlorine hydrogen/ methyl/ butyl IV amino phenyl phenyl hydrogen/ methyl/ butyl V amino methylphenyl methylphenyl hydrogen/ methyl/ butyl VI amino methylphenyl chlorine hydrogen/ methyl/ butyl VII amino methoxyhenyl methoxyhenyl hydrogen/ methyl/ butyl VIII amino methoxyhenyl chlorine hydrogen/ methyl/ butyl
Acknowledgments: The research was supported by grant TE01020028.
[1] T.P. Selvam, C.R. James, P.V. Dniandev, S.K. Valzita, Res. Pharm., 2012, 2, 1.
241 The 10th Joint Meeting on Medicinal Chemistry 2017
P-166
DESIGN AND ANTIMYCOBACTERIAL EVALUATION OF COMPOUNDS COMBINING PYRAZINAMIDE AND PARA-AMINOBENZOIC ACID
Jan Zitko[a],* and Martin Doležal[a]
[a] Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, Hradec Králové, 500 05, Czech Republic * [email protected]
According to the latest WHO Global Tuberculosis Report, estimated 10.4 million people worldwide developed active tuberculosis (TB) in 2015. In 2015, TB was the causative agent of 1.4 million deaths, including 0.4 million deaths in people with HIV/TB co-infection. This ranks TB the second leading cause of death from infectious diseases, following HIV. On contrary to positive trends in global epidemiology of TB, the widespread of drug-resistant TB is threatening the TB control policy. The basic regimen for non-complicated, non-resistant TB is a cocktail of first-line antituberculars (rifampicin, isoniazid, ethambutol and pyrazinamide) administered for six months. Such prolonged administration is a draw-back with the respect to side effects and compliance. Therefore, there is an urgent need for the development of new TB drugs, preferably with not yet exploited mechanism of action. Pyrazinamide (PZA) exerts synergistic effects with rifampicin and is active against dormant subpopulation of mycobacteria. The draw-backs of PZA are its narrow spectrum of activity (M. tuberculosis only), frequent resistance, and hepatotoxicity. However, the aforementioned valuable clinical properties of PZA, its simple structure as well as supposed multi-target activity, make PZA a good starting point for the development of new antituberculars. In recent years, the perception of PZA and its metabolite pyrazinoic acid (POA) has changed from a non-specific cytosol acidifier to a multi-target inhibitor of specific mycobacterial enzymes and processes. Although p-aminosalicylic acid (PAS) as an antitubercular drug was considered obsolete and was used only in developing countries, it has experienced resurrection due to its usability in combination therapy of resistant TB. Recent studies indicate that PAS interferes with folate pathway in mycobacteria. [1] Compound 1 combining PZA and PAS fragments, exerted a micromolar in vitro activity against M. tuberculosis H37Rv and was non-toxic against several mammalian cell lines.[2] In this study, we took 1 as a reference compound and designed and prepared derivatives with modified substitution on the phenyl ring and/or esterification of the carboxylic group. The series showed quite tight SAR which pointed out the necessity of the p-aminosalicylic fragment for substantial antimycobacterial activity.
Acknowledgments: The research was supported Czech Science Foundation project No. 17- 27514Y.
[1] J. Zheng, E. J. Rubin, P. Bifani, V. Mathys, V. Lim, M. Au, J. Jang, J. Nam, T. Dick, J. R. Walker, K. Pethe, L. R. Camacho, J. Biol. Chem., 2013, 288, 23447. [2] J. Zitko, B. Servusova, P. Paterova, J. Mandikova, V. Kubicek, R. Kucera, V. Hrabcova, J. Kunes, O. Soukup, M. Dolezal, Molecules, 2013, 18, 14807.
242 The 10th Joint Meeting on Medicinal Chemistry 2017
P-167
BIOLOGICAL ACTIVITY OF NOVEL PRIMAQUINE-CINNAMIC ACID CONJUGATES OF THE ACYLSEMICARBAZIDE TYPE
K. Pavić,[a] K. Ester,[b] M. Kralj,[b] D. Schols,[c] D. Hadjipavlou-Litina,[d] E. Pontiki[d] and B. Zorc[a],*
[a] Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovačića 1, Zagreb, Croatia [b] Ruđer Bošković Institute, Bijenička cesta 54, Zagreb, Croatia [c] Rega Institute for Medical Research, Katholieke Universiteit Leuven, Herestraat 49, Leuven, Belgium [d] Faculty of Health Sciences, School of Pharmacy, Aristotles University of Thessaloniki, Thessaloniki, Greece * [email protected]
Considering the individual biological and medicinal importance of primaquine (PQ) and cinnamic- acid derivatives (CADs), we wanted to explore biological significance of novel conjugates combining both moieties in single entities. Here we report the results of antiproliferative, antiviral and antioxidative evaluation of new PQ-CAD hybrids 1a-k in which PQ and CADs were connected by acylsemicarbazide groups, built from the PQ amino group, CONHNH spacer and the carbonyl group originating from the CADs.[1]
Their antiproliferative activity was evaluated in vitro on five types of human tumor cell lines: lymphoblastic leukemia (CEM), cervical carcinoma (HeLa), lung carcinoma (NCI-H460), colon carcinoma (SW 620), breast carcinoma (MCF-7) and murine lymphocytic leukemia (L1210), and compared with the standard anticancer drugs and PQ. All new hybrids were more or less active against all the tested cell lines in low micromolar concentrations and very active against MCF-7. Compounds bearing methoxy, chloro or benzodioxole substituents showed high selectivity and activity against MCF-7 in micromolar scale and p-CF3 in nanomolar concentration. Most of them bear substituents in para position. Compounds 1a–k were evaluated against a broad variety of viruses (herpes simplex virus type 1 (KOS), herpes simplex virus 2 (G), herpes simplex virus 1 TK–(KOS) ACVr, vaccinia virus, adeno virus 2 and human coronavirus (229E) in HEL cell cultures) and their activities were compared with reference drugs. CF3 derivatives showed selective antiviral activity against human coronavirus at concentrations which did not alter normal cell morphology. Two different antioxidant assays were used to evaluate antioxidant potentials of PQ-CADs: interaction with DPPH free radical and AAPH. For the majority of derivatives, DPPH-reducing ability was concentration and time dependent. CF3, dimethoxy and chloro derivatives showed the highest DPPH-reducing ability, while unsubstituted, methoxy, benzodioxole, p-Cl and m-CF3 derivatives exerted the highest anti-lipid peroxidation activity (83–89%). Dimethoxy derivative was the most potent LOX inhibitor.
Acknowledgments: This work has been fully supported by the Croatian Science Foundation under the project number IP-09-2014-1501.
[1] K. Pavić, I. Perković, P. Gilja, F. Kozlina, K. Ester, M. Kralj, D. Schols, D. Hadjipavlou-Litina, E. Pontiki, B. Zorc, Molecules, 2016, 21, 1629.
243 The 10th Joint Meeting on Medicinal Chemistry 2017
P-168
ANTIMYCOBACTERIAL SCREENING OF FOUR SERIES OF PRIMAQUINE DERIVATIVES
Josef Jampílek,[a] Sarka Pospíšilová,[a,b] H. Michnová,[a,b] Kristina Pavić,[c] Ivana Perković[c] and Branka Zorc[c],*
[a] Faculty of Pharmacy, Comenius University, Odbojárov 10, Bratislava, Slovakia [b] Faculty of Veterinary Medicine, University of Veterinary and Pharmaceutical Sciences, Palackého 1, Brno, Czech Republic [c] Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovačića 1, Zagreb, Croatia * [email protected]
Primaquine (PQ) is a well known antimalarial drug active against all species of parasite causing human malaria, including multi-resistant P. falciparum strains. Primaquine has been also identified as orally administrated drug capable of inhibiting M. tuberculosis growth.[1] In several papers, we have described preparation of almost hundred various PQ derivatives and their evaluation as potential antiproliferative, antioxidative, antimalarial, antimicrobial and antiviral agents.[2-7] Here we report the results of antimycobacterial screening of four groups of PQ derivatives: amides 1a-k, ureas 2a-s, semicarbazides 3a-c and bis-ureas 4a-u.
Antimycobacterial evaluation was performed in vitro against three different Mycobacterium species: M. tuberculosis H37Ra ATCC 25177 (MTB), well characterised clinical isolates of M. avium complex CIT19/06 (MAC), and M. avium subsp. paratuberculosis CIT03 (MAP). The results were compared with PQ diphosphate and the standard antitubercular drugs isoniazid (INH), rifampicin (RIF) and ciprofloxacin (CPX). Most of the compounds of series 1 and 2 showed high activity against MAP, comparable or even higher than the relevant drug CPX, and weak or no activity against the other two bacteria. Cinnamic acid amide 1a and bis-CF3 cinnamic acid amide 1k were active against all three Mycobacterium species comparable or slightly higher than the reference drugs. PQ urea derivatives 2f-p with hydroxyl, halogen and particularly trifluoromethyl substituted benzene ring exerted very strong antimycobacterial activity towards all three tested bacteria, stronger than PQ and the reference drugs. In general, meta substituted derivatives were more active than analogues para derivatives. The benzene substituted ureas were also more active than urea derivatives with cycloalkyl or hydroxyalkyl moieties. Semicarbazide 3a showed similar activity as PQ, while the other two semicarbazides were inactive. In general, bis-urea derivatives were less active than the analogues urea derivatives sharing the same scaffold, differing only in the spacer type. Out of 21 evaluated bis- urea derivatives only p-Cl, m-CF3 phenyl derivative 4p, benzhydryl derivatives 4t and 4u and bis-PQ derivative 4s showed high activity, higher than the all three reference drugs.
This work has been fully supported by the Croatian Science Foundation under the project number IP-09-2014-1501 and by the Slovak Research and Development Agency, Grant No. APVV-0516- 12.
[1] K. E. A. Lougheed et al., Tuberculosis (Edinb.), 2009, 89, 364. [2] G. Džimbeg et al., Eur. J. Med. Chem., 2008, 43, 1180. [3] M. Šimunović et al., Bioorg. Med. Chem., 2009, 17, 5605. [4] I. Perković et al., J. Enzyme Inhib. Med. Chem., 2013, 28, 601. [5] K. Pavić et al., Eur. J. Med. Chem., 2014, 86, 502. [6] I. Perković et al., Eur. J. Med. Chem., 2016, 124, 622. [7] K. Pavić et al., Molecules, 2016, 21, 1629.
244 The 10th Joint Meeting on Medicinal Chemistry 2017
P-169
INSIGHTS INTO ANTIOXIDANT AND CYTOSTATIC ACTIVITY OF THE NOVEL PRIMAQUINE UREIDOAMIDES
Branka Zorc,[a],* Kristina Pavić,[a] Dimitra Hadjipavlou-Litina,[b] Eleni Pontiki,[b] Marijeta Kralj[c] and Katja Ester[c]
[a] Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovacica 1, Zagreb, Croatia [b] Faculty of Health Sciences, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece [c] Ruđer Bošković Institute, Bijenička cesta 54, Zagreb, Croatia * [email protected]
In the last decade our research group has designed and prepared almost a hundred of various primaquine (PQ) derivatives and evaluated their cytostatic and antioxidant activity. Many compounds from the different series of PQ derivatives showed prominent cytostatic and/or antioxidant activity.[1– 6] The latest series of compounds synthesized by our group are PQ hybrids of ureidoamide type bearing amino acid moiety in the central part of the structure.[7] Although they were primarily designed as potential antimalarial drugs, we wanted to explore their cytostatic and antioxidant activities as well.
The antioxidant properties of novel PQ hybrids 1a-g were investigated using two different assays: interaction with DPPH free radical and AAPH. DPPH-reducing ability of the ureidoamide derivatives 1a-g was very low possibly due to stereochemical reasons. However, all derivatives significantly inhibited lipid peroxidation (77–99%) with the exception of the compound 1a (15%), the only derivative of an aliphatic amino acid. In the latter experiment AAPH was used as a free radical initiator to follow oxidative changes of linoleic acid to conjugated diene hydroperoxide. Compound 1c was the most potent (99%). Furthermore, all tested compounds, except of 1a again, appeared to be potent LOX inhibitors (40–71 μΜ). Derivative 1c was the most potent LOX inhibitor with an IC50 value of 40 μΜ followed by 1e and 1f. It seems that the presence of the chloride atom in the molecule, and not its position, influence the inhibition. The antiproliferative activity of the compounds 1a-g was evaluated in vitro on three types of human tumor cell lines: NCI-H460, MCF-7 and SW620. In general, most of the compounds displayed weak, and only several compounds, along with PQ, showed moderate antiproliferative activity on all tested cell lines. Compound 1e showed the strongest activity against SW620, and moderate against other tested cell lines. Compounds 1d and 1e were generally the most active. The weak antiproliferative activity of the novel PQ hybrids 1a-g favours the hypothesis that the general cytotoxicity is not the reason for their prominent antimalarial activity against erythrocytic stages of P. falciparum.[8]
Acknowledgments: This work has been fully supported by the Croatian Science Foundation under the project number IP-09-2014-1501.
[1] G. Džimbeg et al., Eur. J. Med. Chem., 2008, 43, 1180. [2] M. Šimunović et al., Bioorg. Med. Chem., 2009, 17, 5605. [3] I. Perković et al., J. Enzyme Inhib. Med. Chem., 2013, 28, 601. [4] K. Pavić et al., Eur. J. Med. Chem., 2014, 86, 502. [5] I. Perković et al., Eur. J. Med. Chem. 2016, 124, 622. [6] K. Pavić et al., Molecules, 2016, 21, 1629. [7] K. Pavić et al., 25th Croatian Meeting of Chemists and Chemical Engineers, Poreč, 2017. [8] B. Zorc et al., 10th Joint Meeting on Medicinal Chemistry, Dubrovnik, 2017.
245 The 10th Joint Meeting on Medicinal Chemistry 2017
P-170
NITROGEN BASICITY AFFECTS ALDOSE REDUCTASE INHIBITION IN A SERIES OF 5-CARBOXYMETHYLATED TETRAHYDROPYRIDOINDOLES: STRUCTURE-ACTIVITY RELATIONSHIPS AND MOLECULAR MODELING
Jana Ballekova,* Marta Soltesova Prnova, Milan Stefek and Magdaléna Májeková
Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Dubravska cesta 9, 841 04 Bratislava, Slovakia * [email protected]
Aldose reductase (ALR2) is an important target in diabetic complications and inflammatory pathologies. However, safe ALR2 inhibitors should be selective against aldehyde reductase (ALR1) involved in the detoxification of reactive aldehydes. Substituted pyridoindoles represent an interesting group of compounds with a plethora of biological activities. In our previous study,[1] tetrahydropyridoindoles carboxymethylated in position 8 were identified as aldose reductase inhibitors with mild efficacy and selectivity yet with significant antioxidant activity as an additional biological activity. In this study we proceeded with optimization of the tetrahydropyridoindole scaffold by shifting the carboxymethyl pharmacophore from position 8 to position 5, with the aim to improve aldose reductase inhibitory efficacy and selectivity. Commercial databases were screened for the presence of tetrahydropyridoindoles carboxy-methylated in position 5 (Fig.1). Experimental set of eight compounds was created and subjected to experimental testing of their inhibitory potency against ALR2. Selectivity in relation to the closely related rat kidney ALR1 was determined. Mild inhibition characterized by IC50 in µM range was recorded for the compound 8 with the isopropyl substituent in the position 2. This alkylated tertiary nitrogen is characterized by a rather high basicity (pKa ~ 10.4) with complete protonization at physiological pH. On the other hand, ALR2 inhibition activity of the low basicity derivatives 3-7 (pKa ~ -1 to -3) is characterized with IC50 values in low an medium nanomolar region. Among the compounds studied, 2-(2-(ethoxycarbonyl)-8-methoxy-3,4- dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid (3) was identified as the most promising inhibitor of ALR2, with IC50 ~ 12.6 nM and selectivity factor relative to ALR1 around 750. Docking 3 to ALR2 revealed an interaction network responsible for the high affinity and selectivity. In ex vivo experiment, sorbitol accumulation in isolated rat eye lenses was significantly inhibited by 3 in the presence of high glucose, starting at a concentration as low as 0.1 μM. This finding indicates the ready uptake of 3 by the eye lens tissue followed by inhibition of the cytosolic ALR2. In streptozotocin-induced diabetic rats, compound 3 administered intragastrically (i.g., 50 mg/kg/day) for five consecutive days significantly inhibited sorbitol accumulation in red blood cells and the sciatic nerve. This result points to a ready uptake of 3 after its i.g. administration into the central compartment, its supply to the peripheral nerves and inhibition of ALR2-mediated sorbitol accumulation. Molecular obesity indices, ADMET parameters predicted along with water solubility point to an excellent „lead-likeness” of compound 3, with prospects of further structure optimizations.
Supported by grants: APVV-15-0455; SAS-TUBITAK JRP 2015/7, VEGA 2/0033/14 and VEGA 2/0041/15.
[1] M. Stefek, et al. Bioorg. Med. Chem. 2008, 16, 4908.
246 The 10th Joint Meeting on Medicinal Chemistry 2017
P-171
CAN THE BCHE POLYMORPHISM AFFECT THE INHIBITION POTENCY OF CARBAMYLATING AND REVERSIBLE INHIBITORS FROM EVERYDAY LIFE?
Anita Bosak* and Zrinka Kovarik
Institute for Medical Research and Occupational Health, Zagreb, Croatia * [email protected]
Butyrylcholinesterase (BChE) serves as a co-regulator of cholinergic neurotransmission because it can efficiently hydrolyse the neurotransmitter acetylcholine, which is primarily the role of acetylcholinesterase (AChE). Recently, BChE and its impact on the development and progression of Alzheimer's disease have become increasingly important and the inhibition of BChE appears to be of interest in treating diseases with symptoms of reduced neurotransmitter levels.[1] However, one should keep in mind that today, more than 56 mutations of the human BCHE gene have been identified and different catalytic properties or lower enzyme levels than of usual BChE have been confirmed for several BChE variants. Ample evidence demonstrates that individuals with the unusual BChE polymorphism respond differently to anti-AChEs; e.g. individuals homozygous for atypical BChE (carries the BCHE mutation D70G) can experience prolonged apnea if the muscle relaxant succinylcholine and mivacurium are administered and individuals with silent BChE are more susceptible to organophosphorus compounds than that of usual BChE.[2] This study evaluated the inhibition of atypical and fluoride-resistant BChE (carries BCHE mutations T243M or G390V) variants with the aim of relating the BChE polymorphism by two groups of compounds that differ in the mode of binding to BChE. One group were ligands such as certain - adrenergic agonists and flavonoids that bind to the enzyme with noncovalent interactions. The second group contained inhibitors like carbamate derivatives of bronchodilatators terbutaline (bambuterol), metaproterenol and isoproterenol, which covalently bind to the catalytic serine in the active site of the enzyme. Our results have shown that all of the tested compounds reduced human BChE activity and therefore can affect their use as drugs or food supplements. All three of the tested carbamates had an about 50 and 100 times higher inhibition potency for usual BChE than for atypical and fluoride-resistant BChE, respectively.[3] Similarly, the tested 2-agonists showed the highest inhibition potency towards usual BChE, while atypical and fluoride-resistant variants were up to 26 and 2.8 times (depending on structure), respectively, less inhibited than usual BChE. However, in the case of flavonoids, we showed that no significant change in their inhibition potency exists in view of the BCHE polymorphism.[4] Therefore, our results emphasize that in the case of carbamates and 2-agonists, individuals - carriers of atypical BChE variants will be less affected compared to the usual variant. This is especially important for drugs for which BChE is a key enzyme in the metabolism.
Acknowledgments: Supported by the Croatian Science Foundation (4307).
[1] A. Tasker, E.K. Perry, C.G. Ballard, Expert Rev. Neurother. 2005, 5, 101. [2] O. Lockridge, P. Masson, Neurotoxicology 2000, 21, 113-126. [3] A. Bosak, I. Gazić Smilović, G. Šinko, V. Vinković, Z. Kovarik, J. Med. Chem. 2012, 55, 6716M. [4] Katalinić, A. Bosak, Z. Kovarik, Food Technol. Biotechnol. 2014, 52, 64.
247 The 10th Joint Meeting on Medicinal Chemistry 2017
P-172
ANTIMALARIAL SCREENING OF PRIMAQUINE DERIVATIVES AGAINST ERYTHROCYTIC STAGE OF P. falciparum
B. Zorc,[a],* K. Pavić,[a] F. Supek,[b] J. Levatić[c] and M. Kaiser[d]
[a] Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovačića 1, Zagreb, Croatia [b] Ruđer Bošković Institute, Bijenička cesta 54, Zagreb, Croatia [c] Jožef Stefan Institute, Jamova cesta 39, Ljubljana, Slovenia [d] Swiss Tropical and Public Health Institute, 4051 Basel, Switzerland * [email protected]
World malaria report 2016 of the World Health Organization tracks a dramatic decline in the global malaria burden over last 15 years, primarily due to more efficient drugs and better mosquito control. Despite the remarkable progress in fighting malaria, updated estimates indicate that there were still 212 million cases of malaria in 2015 alone, leading to 429 000 deaths.[1] Primaquine (PQ), an 8- aminoquinoline antimalarial drug, is active against all species of parasite causing human malaria, including multi-resistant Plasmodium falciparum strains. In order to overcome PQ drawbacks and drug resistance, various PQ derivatives have been synthesized and evaluated. Here we report the results of antimalarial screening of six groups of PQ derivatives: amides 1a-k, ureas 2a-k, semicarbazides 3a,b, acylsemicarbazides 4a-k, bis-ureas 5a-v and ureidoamides 6a-g synthesized by our research group[2-8]. Antimalarial evaluation was performed in vitro against erythrocytic stage of drug sensitive P. falciparum NF54 strain and compared with the standard antimalarial drugs. The cytotoxicity of the compounds was tested on a cell line derived from rat skeletal myoblasts (L-6).
PQ amide derivatives 1d and 1e with two or three methoxy substituents on cinnamic acid residue, urea derivatives 2i and 2j with chlorobenzhydryl or trityl substituent and urea 2k with two PQ residues, PQ-cinnamic acid semicarbazide 4e with three methoxy groups, and trityl bis-urea 5r showed the highest activity and the lowest cytotoxicity. Practically all ureidoamides 6a-g excerted high selectivity index (cytotoxicity/activity ratio), but the best results showed 6e, a benzhydryl derivative of p-chlorophenylglycine. Due to their high activity and low cytotoxicity compounds 6e and 5r may be considered as potential scaffolds for development of more effective and safer drugs for malaria treatment. This work has been fully supported by the Croatian Science Foundation under the project number IP-09-2014-1501.
[1] http://www.who.int/malaria/publications/world-malaria-report-2016/report/en/ [2] G. Džimbeg et al., Eur. J. Med. Chem. 2008, 43, 1180. [3] M. Šimunović et al., Bioorg. Med. Chem. 2009, 17, 5605. [4] I. Perković et al., J. Enzyme Inhib. Med. Chem. 2013, 28, 601. [5] K. Pavić et al., Eur. J. Med. Chem. 2014, 86, 502. [6] I. Perković et al., Eur. J. Med. Chem. 2016, 124, 622. [7] K. Pavić et al., Molecules 2016, 21, 1629. [8] K. Pavić et al., 25th Croatian Meeting of Chemists and Chemical Engineers, Poreč, 2017.
248 The 10th Joint Meeting on Medicinal Chemistry 2017
INDEX
A Benaki, D...... 53 Abad, Paloma ...... 178 Benedec, Daniela ...... 91 Abakumova, T. O...... 73 Benedetto Tiz, Davide ...... 63 Abe, Hikaru ...... 60, 237 Benyhe, Sandor ...... 221 Albarghouti, Ghassan...... 65 Ber, A. P...... 158 Alcalde, E...... 109 Beus, Maja ...... 205 Alcântara, Laura M...... 228 Biała, Grażyna ...... 132 Alencar, Nelson ...... 178 Bidon-Chanal, Axel ...... 74 Alente, S...... 172 Binnie, Margaret ...... 74 Aligiannis, N...... 53 Birkus, Gabriel ...... 47 Allu, Senkara Rao...... 44 Bist, Ganesh ...... 111 Altomare, Cosimo ...... 75 Blank, Michael ...... 67 Altucci, L...... 83, 172 Bobanović, Kristina ...... 147 Amić, Ana ...... 77, 78 Bochicchio, Anna ...... 104 Amić, Dragan ...... 77, 78 Boček, Ida ...... 217 Anderluh, Marko ...... 141 Boháč, Andrej ...... 42 Andreadou, Ioanna ...... 152 Bojarski, Andrzej J...... 68, 117, 155, 213 Angeli, A...... 62 Bojko, Barbara ...... 220 Angiulli, G...... 210 Boka, V. I...... 53 Anna, Munder ...... 177 Borcea, Anca-Maria ...... 89 Annunziato, G...... 62 Bosak, Anita ...... 247 Argyros, Orestis ...... 165 Bősze, Szilvia ...... 146 Arie, Gruzman ...... 177 Boura, Evzen ...... 47 Arvidsson, Per I...... 116, 179, 216 Brea, J. Manuel ...... 99, 100 Aytemir, M. D...... 79 Brea, José ...... 75 Azoulay-Ginsburg, Salome ...... 80 Brennan, Paul ...... 37 Azuaje, Jhonny ...... 75 Brkljača, Zlatko ...... 145 Azzam, Amina...... 135 Bronner, Christian ...... 70 Bruno, A...... 62 B Brus, Boris ...... 39 Babić, Maja Stipković ...... 113 Bucki, Adam ...... 236 Bacsa, Ildikó ...... 173 Baek, Seung Yeop ...... 190 C Baijnath, Sooraj ...... 202, 216 Cadavid, María I...... 75 Baiocco, P...... 210 Cahard, Dominique ...... 139 Baji, Ádám ...... 81, 112 Campos Rosa, Joaquín M...... 228 Balabasquer, M...... 156 Cannalire, Rolando ...... 64 Ballekova, Jana ...... 56, 201, 246 Capasso, C...... 62 Balogh, Balázs ...... 82 Car, Željka ...... 119 Balzano, A. L...... 83 Carbajales, Carlos ...... 75 Bampali, Konstantina ...... 38, 72, 124 Carev, Ivana ...... 85, 90 Ban, Nenad ...... 31 Carloni, Paolo ...... 104 Barančoková, Michaela ...... 63 Carlsen, Peter N...... 44 Baranyai, Zsuzsa ...... 32, 146 Casey, P.J...... 156 Barashkin, A. A...... 86 Castellano, S...... 83, 175, 207, 233 Barbaraci, Carla ...... 178 Castro, Marian...... 132 Barreca, Maria Letizia ...... 64 Cecchetti, Violetta ...... 64 Bartenschlager, Ralf...... 115 Cellamare, Saverio ...... 75 Bartolini, Manuela ...... 206 Çetin Atalay, Rengül ...... 102 Basarić, Nikola ...... 97, 121, 144 Chalupská, Dominika ...... 47 Baumlová, Adriana ...... 47 Chang, Minsun ...... 136 Bautista, José M...... 178 Chatzisideri, Theodora ...... 93 Bazina, Linda ...... 84 Chinthakindi, Praveen K...... 179 Bedford, M. T...... 233 Chmielewska, Ewa ...... 94, 133, 192 Bekić, Sofija S...... 214 Cho, Won-Jea ...... 238 Bektašević, Mejra ...... 85 Choi, Ji Won ...... 125 Beloglazkina, A. A...... 86, 148 Choi, Sun ...... 95 Beloglazkina, E. K...... 73, 86, 148, 158, 197 Christoffels, Alan ...... 162
249 The 10th Joint Meeting on Medicinal Chemistry 2017
Cieślak, Marcin J...... 66, 96, 180, 224 E Cindrić, Maja ...... 120 Edward, Korshin ...... 177 Cindrić, Matej ...... 97 Efentakis, Panagiotis ...... 152 Cintulova, Daniela ...... 98 Efrat, Shtriker ...... 177 Cirrincione, Girolamo...... 35 Egieyeh, Samuel ...... 162 Cocchiola, R...... 229 Ejiri, Hiromi ...... 118 Codony, Sandra ...... 99, 100 Emmanouilidis, Leonidas ...... 51 Cokarić Brdovčak, Maja ...... 61 Eraković Haber, Vesna ...... 58 Colotti, G...... 210 Ercan, A...... 79 Coluccia, A...... 191, 203 Erdei, Anna I...... 221 Coluccia, Addolorata Maria Luce ...... 153 Erdmann, Ralf...... 51 Coluccia, Antonio ...... 153, 154 Erdoğan, Merve ...... 105, 110 Condakes, Matthew L...... 44 Ernst, Margot ...... 38, 72, 124 Contu, Michela ...... 82 Esposito, F...... 161 Corona, A...... 161 Esquena, J...... 109 Costantino, G...... 62 Estè, J. A...... 191 Costi, R...... 161, 203, 210, 229 Ester, Katja ...... 243, 245 Cotman, Andrej Emanuel ...... 139 Crespan, E...... 203 F Crespo, Abel ...... 75 Fallon, I...... 109 Cummins, Carolyn ...... 176 Famiglini, V...... 191 Cushman, I...... 156 Famiglini, Valeria ...... 154 Cvetanović, Aleksandra ...... 182, 183 Federico, Leonardo Bruno...... 228 Čipčić Paljetak, Hana...... 120, 195 Felicetti, Tommaso ...... 64 Ćelić, Andjelka S...... 214 Felici, Antonio ...... 63 Feoli, A...... 175 D Filatov, V. E...... 148 D’Abusco, A. Scotto ...... 229 Fiorillo, A...... 210 D’Alba, F...... 62 Forgione, Mariantonietta ...... 227 Dahmoune, Amina ...... 135 Forné, I...... 83 Damjanović, Ana ...... 182 Frakolaki, Efseveia ...... 115 Damjanović-Vratnica, Biljana ...... 101, 196 Franci, G...... 83 Dawidowski, Maciej ...... 51 Frank, Éva ...... 36, 81, 112, 114 de Andrade Ramos, Giselle ...... 206 Fraser, Paul E...... 206 de Melo, Eduardo B...... 168, 169 Freitas-Júnior, Lucio H...... 228 de Oliveira Miranda, Camila ...... 176 Fukuzaki, Takehiro ...... 44 Dejmek, Milan ...... 47 Furač, Lidija ...... 147 Demirci, Aslı ...... 102 Denk, Christoph ...... 103, 215 G Denya, Ireen ...... 129 García-Celma, M. J...... 109 Desantis, Jenny...... 104 Garrido, Vanesa ...... 63 Di Muccio, T...... 210 Gaurina Srček, Višnja ...... 182 Di Santo, R...... 161, 210, 229 Gavriil, Efthymios-Spyridon ...... 157 Diallinas, George ...... 157 Gazivoda Kraljević, Tatjana ...... 113 Dimitrakis, Spyridon ...... 157 Gelmi, M. L...... 159 Dimitrić Marković, Jasmina M...... 77, 78 Gerasi, Maria ...... 200 Dinarès, I...... 109 Getter, Tamar ...... 80 Djaković, Lara ...... 61 Giannakopoulou, Erofili ...... 115 Dobiaš, Juraj ...... 42 Giannouli, Vasiliki ...... 165 Doğruer, Deniz S...... 105, 110 Gielara-Korzańska, Agnieszka ...... 220 Doležal, Martin ...... 242 Gikas, E...... 53 Dorocka-Bockowska, B...... 87 Gil, A...... 156 Downs, Jessica Ann ...... 70 Ginalska, Grazyna ...... 199 Drabczyk, Anna...... 106, 107, 149, 163 Ginex, Tiziana ...... 100 Drabczyk, Anna K...... 126 Glamočlija, Una ...... 186 Dreier, D...... 108 Glavaš-Obrovac, Ljubica ...... 113 Drenjančević, Domagoj ...... 113 Głuch-Lutwin, Monika ...... 236 Drynda, Angelika ...... 160 Gobec, Martina ...... 211 Durmaz, İrem ...... 102 Gobec, Stanislav ...... 39, 48, 211 Duszkiewicz, Roksana ...... 69 Gobin, Ivana ...... 61 Dutkiewicz, Zbigniew ...... 220 Golemac, Anja ...... 90 Dzamova, Pavlina ...... 46 Gopal, Nirmala D...... 202 Dziuk, Błażej ...... 192 Góra, Małgorzata...... 184
250 The 10th Joint Meeting on Medicinal Chemistry 2017
Govender, Kimberleigh B...... 179 Jäntsch, K...... 108 Govender, Thavendran ...... 71, 116, 179, 202, 216 Jaśkowska, Jolanta ...... 106, 107, 126, 127, 149, 163, 212 Gramiccia, M...... 210 Jeong, Hui Rak ...... 128, 138 Grandi, N...... 161 Jeremić, Svetlana ...... 78 Grbčić, Petra ...... 164, 204 Jerić, Ivanka...... 145, 234 Gredičak, Matija ...... 145 Jin, Yifeng ...... 238 Green, William D...... 44 Johansen, Tommy N...... 225 Grolik, Barbara ...... 220 Jójárt, Rebeka ...... 173 Gruzman, Arie ...... 67, 80 Joubert, Jacques ...... 129, 134 Jovanović-Šanta, Suzana S...... 214 H Juárez-Jiménez, Jordi ...... 178 Ha, Jae Du ...... 122 Jukić, Marijana ...... 113 Hadian, Kamyar ...... 51, 104 Jung, Da Woon ...... 130, 137 Hadjipavlou-Litina, Dimitra ...... 243, 245 Jung, U.-K...... 88 Haider, Maximilian ...... 223 Jung, Y.-S...... 88 Hailu, Gebremedhin Solomon ...... 227 Jung, Young Hoon ...... 190 Hamel, Ernest ...... 153 Jurak, Igor ...... 61 Han, S. B...... 88 Jurić, Snježana ...... 131 Han, Younho ...... 238 Jurin, Mladenka ...... 85 Handzlik, Jadwiga ...... 117, 155 Hanquet, Gilles ...... 42 K Hapko, V. V...... 73 Kaczor, Agnieszka A...... 132, 199 Harej, Anja ...... 61, 174, 186 Kafarski, Paweł ...... 94, 133, 192 Hayashi, Chigusa...... 60, 237 Kaiser, M...... 248 Hayashi, Yuko ...... 118 Kaiser, Marcel ...... 51 Herman, Bianka Edina...... 173 Kalčic, Filip ...... 241 Hirai, Yoshiro ...... 118 Kalel, Vishal ...... 51 Hiscott, John ...... 154 Kamiński, Krzysztof ...... 52, 184 Hlaváč, Matúš...... 42 Kang, Chung Hyo ...... 122 Hog, Daniel T...... 44 Kang, Yong Gu ...... 125 Hogendorf, Adam ...... 220 Kania, Emilia ...... 220 Holy, M...... 108 Kapp, Erika ...... 134 Horak, Ema...... 147 Karagiannis, Dimitrios ...... 152 Hranjec, Marijana ...... 120, 195, 217 Karakaya, G...... 79 Hu, X...... 159 Karczmarzyk, Zbigniew ...... 199 Humpa, Otakar ...... 170 Karminski-Zamola, Grace ...... 120, 195, 204 Hur, Joonseong ...... 222 Karpov, N. A...... 86 Husak, Antonija ...... 121 Kassymova, D. T...... 240 Husnjak, Koraljka ...... 131 Katila, Pramila ...... 111 Hwang, Jong Yeon ...... 92, 122 Katirtzi, Anastasia ...... 46 Hyeon, Changbong ...... 95 Katsamakas, Sotirios ...... 93 Kavčič, Luka ...... 234 I Kawada, Manabu...... 60, 237 Igarashi, Masayuki ...... 60, 237 Kaźmierczak-Barańska, Julia ...... 66, 96, 180, 224 Ihmof, A...... 83 Kędzierska, E...... 239 Ilari, A...... 210 Kelavić, Ana ...... 90 Ilaš, Janez ...... 63 Kelly, John M...... 189, 231 Inoue, Hiroyuki ...... 60, 237 Kessal, Fetta ...... 135 Inoue, Motomu ...... 185 Khadka, Daulat B...... 238 Ionuţ, Ioana ...... 91, 123, 167 Kieć-Kononowicz, Katarzyna ...... 117, 155 Iorio, Maria Teresa ...... 124 Kijkowska-Murak, Urszula ...... 209 Ivanković, Siniša ...... 166 Kikelj, Danijel...... 63 Kılıç, Burcu ...... 105, 110 J Kim, C...... 88 Jakas, Andreja ...... 145 Kim, Hee-Doo ...... 136 Jakimov, Dimitar ...... 151 Kim, Hyeon Jeong ...... 125 Jakubec, Pavol ...... 44 Kim, Hyeon Ji ...... 125 Jampílek, Josef ...... 244 Kim, Hyoung Rae ...... 92 Jandourek, Ondrej ...... 46 Kim, J. W...... 88 Janeba, Zlatko ...... 241 Kim, Jin Han ...... 130, 137 Jang, Bo Ko ...... 125 Kim, Pilho ...... 92 Janowska, Dominika ...... 188 Kim, Si Won ...... 125 Jansa, Petr ...... 241 Kim, Sun Yeung...... 128
251 The 10th Joint Meeting on Medicinal Chemistry 2017
Kim, Sun Young ...... 138 Lambrinidis, George ...... 152, 157 Kiricsi, Mónika ...... 81 Lameira, Jerónimo ...... 178 Kiss, Anita ...... 140 Lamut, Andraž ...... 63 Kiss-Faludy, Réka ...... 114 Langlois-Mercier, Audrey ...... 44 Kišić, Andrea ...... 139 Lankri, David ...... 65 Kitamura, Yoshiaki ...... 44 Lazarides, Theodore ...... 93 Klebe, Gerhard ...... 33 Łażewska, Dorota ...... 117, 155 Klimek, Katarzyna ...... 199 Lee, Chong Ock ...... 92, 122 Klisuric, Olivera...... 151 Lee, Dong Ho ...... 122 Kliza, Katarzyna ...... 131 Lee, Eung-Seok ...... 111 Kmoníčková, Eva ...... 241 Lee, Gary ...... 47 Knapp, Stefan ...... 70 Lee, J. Y...... 88 Knez, Damijan ...... 39, 48 Lee, Jae Yeol ...... 128, 130, 137, 138 Koczurkiewicz, Paulina ...... 187 Lee, Jin-Ching ...... 154 Kohyama, Aki ...... 171 Lee, Seungbeom ...... 222 Kołaczkowski, Marcin ...... 236 Lee, Sun Young ...... 136 Kolarič, Anja ...... 141 Lee, Yerim ...... 125 Kolb, Peter ...... 132 Lee, Yoonji ...... 95 Kolcarkova, Lucie ...... 46 Leiva, Rosana ...... 74, 99, 100, 231 Kolman, Viktor ...... 241 Lešnik, Samo ...... 48 Kolonko, Marta ...... 51 Levatić, J...... 248 Konc, Janez ...... 48 Li, H...... 233 Konecna, Klara ...... 46 Li, Quan...... 171 Korshin, Edward ...... 80 Lim, Changjin ...... 222 Korzanski, Artur ...... 220 Linares, María ...... 178 Kosiek, Szymon ...... 188, 239 Login, Cezar ...... 91 Kossakowski, Jerzy ...... 66, 96 López-Rodríguez, M.L...... 156 Kostakis, Ioannis K...... 165 Lougiakis, Nikolaos ...... 157, 165, 200 Košak, Urban ...... 39 Loza, María Isabel ...... 75, 99, 100 Koteliansky, V. E...... 73, 158, 197 Luca, V. De ...... 62 Kotlińska, J...... 239 Lucidi, Alessia ...... 227 Kotovskii, G. A...... 86 Lučić, Bono ...... 77, 78 Kovačević, Tatjana ...... 142 Lukaszewska-Kuska, M...... 87 Kovarik, Zrinka...... 143, 247 Luque, F. Javier ...... 74, 100, 178 Kralj, Damir ...... 145 Kralj, Marijeta ...... 97, 120, 144, 147, 217, 243, 245 M Kraljević Pavelić, Sandra ...... 61, 164, 174, 186, 204 Macchia, Marco...... 54 Krátký, Martin ...... 32, 146, 232, 235 Maccioni, Elias ...... 82 Krauss, Sybille ...... 104 Macedonio, Giorgia ...... 221 Krištafor, Svjetlana ...... 147 Machulkin, A. E...... 158 Krivokapić, Slađana...... 101 Macut, H...... 159 Królewska, Karolina ...... 66, 96, 180 Mączyński, Marcin ...... 160 Królewska-Golińska, Karolina ...... 224 Maček-Hrvat, Nikolina ...... 143 Kruger, Gert ...... 216 Madia, V. N...... 161, 203, 210, 229 Kruger, Hendrik G...... 116, 179, 202 Maga, G...... 191, 203 Kruk-Słomka, Marta ...... 132 Mai, Antonello ...... 172, 227 Kubicki, Maciej ...... 220 Majchrowski, R...... 87 Kucerova-Chlupacova, Marta ...... 46 Májeková, Magdaléna ...... 56, 201, 246 Kucia, Urszula ...... 69 Majellaro, Maria ...... 75 Küçükgüzel, İlkay ...... 102 Majka, Zbigniew ...... 126, 127 Kukushkin, M. E...... 86, 148 Majouga, A. G...... 73, 86, 148, 158, 197 Kułaga, Damian ...... 106, 107, 126, 149, 163 Maklakova, S. Yu...... 7 3, 197 Kumar, A. Sanjeeva ...... 179 Malan, Sarel F...... 129, 134, 162 Kunin, M. A...... 86 Malatesti, Nela ...... 61 Kuntner-Hannes, Claudia ...... 103 Malinowska, Magdalena ...... 106, 107, 126, 149, 163 Kuran, Bożena ...... 66, 96 Manfroni, Giuseppe ...... 64 Kurczab, Rafał...... 68, 117, 150, 155, 212, 213, 220 Manikoth Ayyathan, Dhanoop ...... 67 Kuzminac, Ivana ...... 151 Maračić, Silvija ...... 164 Kverka, Miloslav ...... 241 Marakos, Panagiotis ...... 157, 165, 200 Kwon, Youngjoo ...... 111 Marasović, Maja ...... 166 Marc, Gabriel ...... 89, 123, 167 L Marín-Ramos, N...... 156 La Regina, G...... 191 Marković, Marija ...... 234
252 The 10th Joint Meeting on Medicinal Chemistry 2017
Marković, Snežana D...... 198 Muñoz-Torrero, Diego ...... 178 Marković, Zoran ...... 77, 78 Murár, Miroslav...... 42 Marona, Henryk ...... 187, 236 Murković Steinberg, Ivana ...... 147 Marrocco, Biagina ...... 227 Myers, Andrew G...... 44 Martin Kleiner, Irena ...... 97, 120, 217 Myrianthopoulos, Vassilios ...... 70, 115 Martinet, Nadine ...... 70 Martínez-Falguera, Daina...... 230 N Martín-Fontecha, M...... 156 Naccarato, Valentina ...... 153 Martins, João Paulo A...... 168, 169 Naesens, Lieve...... 115 Marvanová, Pavlína ...... 170 Naicker, Tricia ...... 116, 179, 202, 216 Masci, D...... 191 Napiórkowska, Mariola ...... 66, 96, 180 Masci, Domiziana ...... 154 Nastasă, Cristina ...... 91, 181 Mäser, Pascal ...... 51 Nastić, Nataša ...... 182, 183 Massari, Serena ...... 104 Nawrot, Barbara ...... 66, 96, 180, 224 Masuda, Tohru ...... 237 Nebbioso, A...... 172 Matera-Witkiewicz, Agnieszka ...... 224 Nencka, Radim ...... 47 Matić, Josipa ...... 121 Ngcobo, Bongani ...... 216 Matijašić, Mario ...... 120, 195 Nielsen, Birgitte ...... 225 Matosiuk, Dariusz ...... 209 Nikolić, Andrea ...... 151 Matovina, Mihaela ...... 131 Novakov, Vesna ...... 183 Matsuura, Nobuyasu ...... 185 Novaković, Irena ...... 186 Matsuya, Yuji...... 171 Novellino, Ettore ...... 221 Mattevi, Andrea ...... 227 Novotortsev, V. K...... 148 Matthes, Frank ...... 104 Nowakowska, Angelika ...... 117 Mátyus, Péter ...... 82 Nujić, Krunoslav...... 142 Mazzone, R...... 172 McBride, Andrew ...... 74 O Meglić, Karlo ...... 119 Obmińska-Mrukowicz, Bożena ...... 160 Mejdrová, Ivana ...... 47 Obniska, Jolanta ...... 184 Mernyák, Erzsébet ...... 36, 173 Odehnalová, Klára ...... 170 Mertlíková-Kaiserová, Helena ...... 47 Odžak, Renata ...... 84 Mesić, Milan...... 142 Offermann, Nina...... 104 Messore, A...... 203 Ohba, Shun-ichi ...... 60, 237 Meščić, Andrijana ...... 174 Ohishi, Tomokazu ...... 60, 237 Miazga-Karska, Małgorzata ...... 199 Oikawa, Tsutomu ...... 185 Michnová, H...... 244 Olga, Viskind ...... 177 Mihovilovic, Marko D...... 38, 72, 98, 108, 124 Öncül, S...... 79 Mihovilović, Moris ...... 113 Ondar, E. E...... 197 Mikros, Emmanuel ...... 53, 70, 115, 152, 157 Oniga, Ilioara ...... 89 Mikstacka, Renata ...... 220 Oniga, Ovidiu...... 89, 91, 123, 167, 181, 219 Mikula, Hannes ...... 57, 103, 215, 223 Opletalova, Veronika ...... 46 Milite, C...... 83, 175, 207 Ortega, F.J...... 156 Miloš, Mladen ...... 166 Ortega-Gutiérrez, S...... 156 Minosi, Paola...... 221 Osada, Hiroyuki ...... 185 Minovski, Nikola ...... 141 Osmanović, Amar ...... 186, 218 Miošić, Mande...... 113 Oyarzábal, Julen ...... 99, 100 Mirzaie, Sako ...... 221 Miszczyk, Patrycja...... 192 P Miyazawa, Masahiro...... 118 Padhye, Subhash ...... 186 Mlinarič-Raščan, Irena ...... 211 Padrtová, Tereza ...... 170 Mlinarić-Majerski, Kata ...... 144 Pae, Ae Nim...... 125 Młynarz, Piotr...... 133 Palma, Luca Di ...... 178 Mohar, Barbara ...... 139 Pamreddy, Annapurna ...... 202 Mok, Hui Yeon ...... 190 Pańczyk, Katarzyna ...... 187, 236 Mokrý, Petr ...... 170 Paneth, A...... 239 Mollica, Adriano ...... 221 Paneth, Agata ...... 188 Moodley, Chivonne ...... 216 Pantović, Snežana...... 101, 196 Moraes, Carolina B...... 228 Papadakis, Georgios ...... 200 Morawiak, Maja ...... 199 Pardali, Vasiliki ...... 189 Motojima, Atsuko ...... 185 Pardo, L...... 156 Mótyán, Gergő ...... 112, 114 Park, Chi Hoon...... 92 Müller, Christin...... 47 Park, Chi-Hoon ...... 122 Müller, Susanne ...... 70 Park, Hyun-Ju ...... 190
253 The 10th Joint Meeting on Medicinal Chemistry 2017
Park, Jong-Hyun ...... 125 Ražić, Slavica ...... 182 Park, Ki Duk ...... 125 Regina, Giuseppe La ...... 153, 154 Pârvu, Alina ...... 181 Rescigno, D...... 175, 207 Passacantilli, S...... 191 Ribić, Rosana ...... 119, 208 Paurević, Marija ...... 208 Roca, Sunčica ...... 186 Pavić, Kristina ...... 243, 244, 245, 248 Rodriguez, Ana ...... 51 Pedrys, Anna ...... 69 Rodriguez, Yoel...... 201 Pękala, Elżbieta ...... 187 Roig, F...... 109 Pellay, François-Xavier ...... 90 Roje, Marin ...... 85 Pellegrino, S...... 159 Rosińska, Agata ...... 209 Pérez, Belén ...... 99, 100, 231 Rossetti, Giulia ...... 104 Pérez-Benavente, Susana ...... 178 Roškarić, Petra ...... 217 Perić, Mihaela ...... 120, 195 Rotili, Dante ...... 227 Perin, Nataša ...... 195 Rožman, Kaja...... 48 Perković, Ivana ...... 244 Rubí, Jèssica ...... 231 Peroković, V. Petrović ...... 119 Rybka, Sabina ...... 184 Perović, Andrej ...... 196 Ryng, Stanisław ...... 160 Perović, Svetlana ...... 101, 196 Pescatori, L...... 203 S Petri, Edward T...... 214 Saccoliti, F...... 161, 203, 210, 229 Petrov, R. A...... 73, 197 Sáez, Elena ...... 99, 100 Petrov, S. A...... 197 Saito, Tomio ...... 185 Petrović, Vladimir P...... 198 Sakač, Marija N...... 151, 214 Petrović, Zorica D...... 198 Sakashita, Chiharu ...... 60, 237 Philips, M.R...... 156 Salihović, Mirsada...... 218 Piantanida, Ivo ...... 41, 121, 234 Saltykova, I. V...... 158, 197 Pickering, Darryl S...... 225 Samia, Boualem...... 135 Pieretti, Stefano ...... 221 Sampedro, Cristina ...... 178 Pieroni, M...... 62 Sampson, Samantha L...... 134 Pilotto, Simona ...... 227 Santo, R. Di...... 203 Pîrnău, Adrian ...... 89, 167 Sarli, Vasiliki ...... 49, 93 Pitucha, Monika ...... 199 Sarno, F...... 83 Pizarro, Javier ...... 99, 100 Satała, Grzegorz ...... 68, 106, 107, 117, 126, 149, 155 Plačková, Pavla ...... 47 Sattler, Michael ...... 51 Plavec, Janez ...... 234 Savić, Marina ...... 151 Plech, T...... 239 Sbardella, G...... 50, 83, 175, 207, 233 Plech, Tomasz...... 188 Scandurra, R...... 229 Polanski, Jaroslaw ...... 69 Scherman, Daniel ...... 181 Politeo, Olivera ...... 85, 90 Schiffrer, Eva Shannon ...... 211 Pont, Caterina ...... 178 Schilling, Judith...... 104 Pontiki, E...... 243 Schliebs, Wolfgang ...... 51 Pontiki, Eleni ...... 245 Schmidt, Tuanny P...... 168 Popiołek, Ł...... 239 Schneider, Gyula ...... 36, 140, 173 Popowicz, Grzegorz M...... 51 Schnürch, Michael ...... 38, 72 Poso, Antti ...... 132 Schols, Dominique ...... 174, 243 Pospíšilová, Sarka ...... 244 Schorp, Kenji ...... 104 Pouli, Nicole ...... 157, 165, 200 Schorpp, Kenji ...... 51 Pricopie, Andreea ...... 89 Scipione, L...... 210 Procházková, Eliška...... 47 Sedić, Mirela ...... 164, 204 Prokopowicz, Monika ...... 133 Seiple, Ian B...... 44 Ptiček, Lucija ...... 204 Seira, Constantí ...... 74 Pujol, Eugènia...... 99, 100 Sergeeva, O. V...... 73 Pupo, G...... 161, 203, 210, 229 Shibasaki, Masakatsu ...... 60, 237 Pym, Alexander ...... 216 Shin, Su Jeong ...... 125 Pytka, Karolina ...... 236 Shokhen, Michael ...... 67 Shrestha, Aarajana ...... 111 R Shubely, Moran ...... 67 Racané, Livio ...... 204 Siebert, David Chan Bodin...... 38, 72 Radošević, Kristina...... 182, 183 Silia, Boumrar ...... 135 Raić, Sanda ...... 90 Silva, Andrea G...... 132 Raić-Malić, Silvana ...... 113, 164, 174 Silvestri, R...... 191 Rajić Džolić, Zrinka ...... 205 Silvestri, Romano ...... 153, 154 Rapacz, Anna ...... 184, 236 Simeone, Xenia...... 72
254 The 10th Joint Meeting on Medicinal Chemistry 2017
Simijonović, Dušica ...... 198 Škrijelj, Nihada ...... 218 Singh, Sanil D...... 216 Špirtović-Halilović, Selma ...... 186, 218 Sitte, H. H...... 108 Šprung, Matilda ...... 84 Sitte, Harald H...... 98 Šramel, Peter ...... 42 Siwek, Agata ...... 236 Štajner, Lara ...... 145 Skonieczka, Katarzyna...... 220 Štěpánková, Šárka ...... 232 Skvortsov, D. A...... 86, 148 Šuvak, Anđelo ...... 61 Slivac, Igor ...... 182, 183 Švajger, Urban ...... 48, 141 Śliwa, Paweł ...... 126, 212, 213 Švarc-Gajić, Jaroslava ...... 182, 183 Słoczyńska, Karolina ...... 187 Smith, Ana Sunčana ...... 145 T Smith, David ...... 145 Tabarrini, Oriana ...... 104 Smolíček, Maroš ...... 42 Tafani, M...... 172 Soares Romeiro, Luiz A...... 176, 206 Tamaian, Radu ...... 219 Sobczak, Milena ...... 66, 96 Tammela, Päivi ...... 63 Sohr, Barbara ...... 215 Tamvakopoulos, Constantin ...... 165 Sola, Irene ...... 178 Tandarić, Tana ...... 119, 226 Soldo, Barbara ...... 84 Tanghe, Scott ...... 51 Soltesova Prnova, Marta ...... 56, 201, 246 Tarantino, D...... 159 Son, Han Pyo ...... 190 Targowska-Duda, Katarzyna M...... 132 Song, Yun Seon ...... 136 Taylor, Martin C...... 189, 231 Sosič, Izidor ...... 211 Teklezgi, Belin G...... 202 Sotelo, Eddy ...... 75 Terán, Hugo Gutiérrez de ...... 75 Sova, Matej ...... 48 Thapa Magar, Til Bahadur ...... 111 Sović, Irena...... 204, 217 Thysiadis, Savvas ...... 93 Speranzini, Valentina ...... 227 Tiperciuc, Brîndușa ...... 89, 91, 123, 167, 181, 219 Srček, Višnja Gaurina ...... 183 Tir, Nora ...... 208 Stana, Anca ...... 91, 219 Tkocz, Aleksandra ...... 69 Starčević, Kristina ...... 195, 217 Tomaselli, Daniela ...... 227 Stathopoulou, K...... 53 Tomašič, Tihomir ...... 63, 141 Stefanachi, Angela ...... 75 Tomich de Paula da Silva, Carlos Henrique ...... 228 Stefano, Sabatini ...... 64 Tomić, Srđanka ...... 119, 208 Stefanski, Tomasz ...... 220 Torrecillas, I.R...... 156 Stefanucci, Azzurra ...... 221 Tramontano, E...... 161 Stefek, Milan ...... 56, 201, 246 Tripsianes, Kostas ...... 51 Stelmasiński, Michał ...... 155 Trotsko, Nazar ...... 188 Stepanić, Višnja ...... 174, 195 Tschammer, Nuška ...... 141 Stephan, Michel ...... 139 Tsvelikhovsky, Dmitry ...... 65 Stepić, Robert...... 145 Tudino, V...... 161, 210, 229 Stevaert, Annelies ...... 115 Turcu, Andreea L...... 230 Steven, Chessler ...... 177 Turło, Jadwiga ...... 40 Stojković, Ranko ...... 166 Stolaříková, Jiřina ...... 232 U Strunin, Dmytro ...... 47 Ueno, Yurie ...... 185 Sugimoto, Kenji ...... 171 Ukrainczyk, Marko ...... 145 Suh, Young-Ger ...... 222 Urbanczyk-Lipkowska, Zofia ...... 199 Supek, F...... 248 Uzelac, Lidija ...... 97, 144, 147 Supuran, C. T...... 62 Sureda, Francesc X...... 230 V Svatunek, Dennis ...... 103, 223 Valverde, Elena ...... 99, 100 Świątek, Piotr ...... 224 Vassilaki, Niki ...... 115 Syce, James ...... 162 Vázquez, Santiago ...... 74, 99, 100, 230, 231 Szabó, Nóra ...... 32, 146 Vázquez-Carrera, Manuel ...... 99, 100 Szczpinski, Filip ...... 44 Veljović, Elma ...... 186, 218 Szécsi, Mihály ...... 36, 173 Verbanac, Donatella ...... 120, 195 Szilvia, Bősze ...... 32 Vianello, Robert...... 55, 119, 226 Szúcs Edina...... 221 Vinšová, Jarmila...... 32, 146, 232, 235 Szymańska, Ewa ...... 225 Viviano, M...... 207, 233 Šála, Michal ...... 47 Vlahoviček-Kahlina, Kristina ...... 234 Šapčanin, Aida ...... 218 Vlase, Laurian ...... 89 Šarić, Maria ...... 90 Vodnar, Dan C...... 89, 167, 219 Šćepanović, Valentina ...... 196 Vorobyeva, N. A...... 86, 148 Škalamera, Đani ...... 144 Vos, Margaretha de ...... 134
255 The 10th Joint Meeting on Medicinal Chemistry 2017
Vosátka, R...... 235 Yoon, Hong Bin ...... 130, 137 Vullo, D...... 62 Youl Lee, Kwang ...... 238 Yun, Chang-Soo ...... 92 W Wanek, Thomas...... 103, 215 Z Waszkielewicz, Anna M...... 187, 236 Zador, Ferenc ...... 221 Watanabe, Takumi ...... 60, 237 Zaręba, Przemysław ...... 127 Weber, Jan ...... 47 Zatsepin, T. S...... 73 Weber, Stephanie ...... 104 Završnik, Davorka ...... 186, 218 Webster, Scott P...... 74 Żelaszczyk, Dorota ...... 187 Więcek, Małgorzata ...... 117, 155 Żesławska, Ewa...... 187 Wietrzyk, Joanna ...... 94, 133, 192 Zhang, Ziyang ...... 44 Wilkovitsch, Martin ...... 103 Zhou, Xiang ...... 44 Wimmer, Laurin ...... 98, 124 Zhussupova, A. I...... 240 Wojtowicz, Natalia ...... 133 Zhussupova, G. Е...... 240 Wölfling, János ...... 36, 114, 140, 173 Zidar, Nace ...... 45, 63 Woś, Maciej ...... 199 Zídek, Zdeněk ...... 241 Wright, Peter M...... 44 Ziebuhr, John ...... 47 Wu, Ling ...... 206 Zitko, Jan ...... 242 Wujec, Monika ...... 188, 239 Zoidis, Grigoris ...... 34, 115, 189 Wybrańska, Iwona ...... 66 Zorbaz, Tamara ...... 143 Wysocki, Waldemar ...... 199 Zorc, Branka ...... 205, 243, 244, 245, 248 Zupkó, István ...... 36, 112 Y Zwergel, C...... 172 Yabu, Kazuo...... 44 Zyk, N. V...... 73, 86, 148, 158 Yeon, Seul Ki...... 125 Žarković, Jelena ...... 90 Yin, Shuqiang...... 171 Živanović, Marko N...... 198 Yokoyama, Hajime ...... 118
256 The 10th Joint Meeting on Medicinal Chemistry 2017
PARTICIPANTS
Dragan Amić Maria Ermitas Alcalde Hendrik Gerhardus Kruger Ana Amić Margot Ernst Marta Kučerová-Chlupáčová Stana Anca-Daniela Tommaso Felicetti Maxim Kukushkin Marko Anderluh Éva Frank Damian Kulaga Giannamaria Annunziato Vesna Gabelica Marković Rafal Kurczab João Paulo Ataide Martins Tatjana Gazivoda Kraljević Ivana Kuzminac Mutlu Aytemir Erofili Giannakopoulou Giuseppe La Regina Salome Emma Azoulay Stanislav Gobec Heather Lambert Ginsburg Nirmala Gopal George Lamprinidis Sooraj Baijnath Thavendran Govender Dorota Lažewska Ádám Baji Christopher Graham Eung Seok Lee Damir Bakoš Soo Bong Han Cynthia Leigh Schreiber Jana Ballekova Jadwiga Handzlik Rosana Leiva Balázs Balogh Denise Harding Pasquale Linciano Konstantina Bampali Yoshiro Hirai Gavin Logie Nenad Ban John Hogg Cristian Cezar Login Michaela Barančoková Young Hoon Jung Maria Luz Lopez Rodriguez Paola Barraja Marijana Hranjec Nikolaos Lougiakis Nikola Basarić Antonija Husak Marco Macchia Linda Bazina Jong Yeon Hwang Aleksei Machulkin Sofija Bekić Ioana Andrada Ionut Helena Macut David Chan Bodin Siebert Maria-Teresa Iorio Marcin Mączyński Anca-Maria Borcea Pavol Jakubec Valentina Noemi Madia Istvan Borza Boko Jang Raimund Maier Anita Bosak Jolanta Jaskowska Magdaléna Májeková Danielle Bradshaw Hui Rak Jeong Maria Majellaro Paul Brennan Ivanka Jerić Svetlana Maklakova Ivana Carev Jacques Joubert Sarel Malan Theodora Chatzisideri Dawoon Jung Nela Malatesti Ewa Chmielewska Snježana Jurić Magdalena Malinowska Won Jea Cho Agnieszka Kaczor Silvija Maračić Sun Choi Pawel Kafarski Panagiotis Marakos Marcin Cieślak Krzysztof Kaminski Maja Marasović Matej Cindrić Erika Kapp Gabriel Marc Daniela Cintulova Grace Karminski-Zamola Ksenija Markešić Girolamo Cirrincione Manabu Kawada Pavlina Marvanová Sandra Codony Julia Kaźmierczak-Barańska Dariusz Matosiuk Gabriele Costantino Danijel Kikelj Yuji Matsuya Victoria Coulthard Heedoo Kim Péter Mátyus Maciej Dawidowski Jin Han Kim Roberta Mazzone Asli Demirci Sun Young Kim Erzsébet Mernyák Christoph Denk Anita Kiss Milan Mesić Jenny Desantis Andrea Kišić Andrijana Meščić Roberto Di Santo Gerhard Klebe Marko Mihovilovic Patrizia Diana Anja Kolarič Emmanuel Mikros Martin Doležal Sanja Koštrun Hannes Mikula Barbara Dorocka Bobkowska Matea Kovač Ciro Milite Anna Karolina Drabczyk Zrinka Kovarik Camila Miranda Oliveira Dominik Dreier Marijeta Kralj Patrycja Miszczyk Werner Embrechts Damir Kralj Florian Montel Vesna Eraković Haber Martin Krátký Gergö Mótyán Merve Erdogan Svjetlana Krištafor Diego Muñoz Torrero Branka Ergović Karolina Królewska-Golińska Vassilios Myrianthopoulos
257 The 10th Joint Meeting on Medicinal Chemistry 2017
Tricia Naicker Eugènia Pujol Nataša Štefanac Danijel Namjesnik Taylor Quinn Tana Tandarić Mariola Napiórkowska Livio Racané Brindusa Georgeta Tiperciuc Cristina Mariana Nastasa Miroslava Radečić Daniela Tomaselli Natasa Nastic Silvana Raić-malić Srđanka Tomić-Pisarović Barbara Nawrot Zrinka Rajić Džolić Antoni Torrens Jover Radim Nencka Giselle Ramos De Andrade Dmitry Tsvelikhovsky Jolanta Obniska Rosana Ribić Valeria Tudino Tsutomu Oikawa Agata Rosińska Andreea Larisa Turcu Ovidiu Oniga Deniz S. Dogruer Jadwiga Turlo Ana Gil Ordoñez Giuseppe Saccomanni Mario Varasi Amar Osmanović Vasiliki Sarli Santiago Vazquez Tereza Padrtova Gianluca Sbardella Robert Vianello Katarzyna Pańczyk Eva Shannon Schiffrer Jarmila Vinšová Agata Paneth Michael Schnürch Monica Viviano Snežana Pantović Emily Ann Shangle Kristina Vlahoviček-Kahlina Vasiliki Pardali Moran Shubely Rudolf Vosátka Sara Passacantilli Carlos Silva Ines Vujasinović David Peralta Pawel Śliwa Shouming Wang Nataša Perin Barbara Sohr Anna Waszkielewicz Ivana Perković Matej Sova Takumi Watanabe Svetlana Perović Irena Sović János Wölfling Byron Peters Tomasz Stefanski Monika Wujec Rostislav Petrov Azzurra Stefanucci Chang Soo Yun Vladimir Petrović Višnja Stepanić Davorka Završnik Ivo Piantanida Youngger Suh Aizhan Zhussupova Marco Pieroni Dennis Svatunek Nace Zidar Monika Pitucha Piotr Świątek Zdenek Zidek Jaroslaw Polanski Ewa Szymanska Grigorios Zoidis Nicole Pouli Marta Šoltésová Prnová Branka Zorc
258 The 10th Joint Meeting on Medicinal Chemistry 2017
259