2ND ALPINE WINTER CONFERENCE ON MEDICINAL AND SYNTHETIC CHEMISTRYTim ST. ANTON, AUSTRIA | JONCKERS JANUARY 19 – 23, 2020 JANSSENwww.alpinewinterconference.org PHARMACEUTICA Prof. Erick

BOOK OF ABSTRACTS

SCIENTIFIC ORGANISING COMMITTEE

Klemens HOEGENAUER (Novartis Institutes for BioMedical Research, Switzerland) Karl Heinz KRAWINKLER (Novartis Institutes for BioMedical Research, Switzerland) Antonia F. STEPAN (F. Hoffmann-La Roche, Switzerland)

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ALPINE20-BookAbstracts-Covers.indd 1 20/12/19 17:18 CONTENT

SPEAKERS & ORAL COMMUNICATIONS - Biographies and Abstracts 3

POSTERS - Frontiers of Synthetic Chemistry 73

POSTERS - Structure and Biophysics - Companions for Medicinal Chemistry 89

POSTERS - Protein Degradation: New Rules for Drug Discovery 93

POSTERS - Innovation and Inspiration from Natural Products 95

POSTERS - Accelerating Drug Discovery by Intelligence Augmentation 107

POSTERS - Drug Discovery Tales 113

POSTERS - Others 133

LIST OF ABSTRACTS 143

LIST OF AUTHORS 149

LIST OF PARTICIPANTS 155

2 SPEAKERS & ORAL COMMUNICATIONS

Biographies and Abstracts

3 Sarah E. REISMAN California Institute of Technology, United States

arah E. Reisman earned a BA in Chemistry from Connecticut College in 2001, and her Ph.D. in Schemistry from Yale University in 2006, under the direction of Prof. John L. Wood. From 2006– 2008, Sarah worked as an NIH fellow with Prof. Eric Jacobsen at Harvard University, and then joined the faculty at the California Institute of Technology where she is now a Professor of Chemistry and a Heritage Medical Research Institute Investigator.

er laboratory seeks to discover, develop, and study new chemical reactions within the Hcontext of natural product total synthesis.

4 KL01 NECESSITY IS THE MOTHER OF INVENTION: NATURAL PRODUCTS AND THE CHEMISTRY THEY INSPIRE

Sarah E. Reisman

California Institute of Technology, Division of Chemistry and Chemical Engineering, 1200 E. California Blvd, MC 101-20, Pasadena CA 91125, [email protected]

The chemical synthesis of natural products provides an exciting platform from which to conduct fundamental research in chemistry and biology. Our group is currently pursuing the synthesis of a number of structurally complex natural products, including the diterpenoids perseanol and talatisamine. The densely-packed arrays of heteroatoms and stereogenic centers that constitute these polycyclic targets challenge the limits of current technology and inspire the development of new synthetic strategies and tactics. This seminar will describe the latest progress in our methodological and target-directed synthesis endeavors.

5 Li DI Pfizer, United States

r Li Di has over 25 years of experience in the pharmaceutical industry including Pfizer, DWyeth and Syntex. She is currently a research fellow at Pfizer, Groton, CT.

er research interests include the areas of drug metabolism, pharmacokinetics, drug-drug Hinteractions, absorption, transporters, and blood–brain barrier.

he has over 145 publications including two Sbooks and presented over 85 invited lectures. he is a recipient of the Thomas Alva Edison Patent Award, the New Jersey Association for SBiomedical Research Outstanding Woman in Science Award, the Wyeth President’s Award and Peer Award for Excellence.

6 PL01 STRUCTURAL ATTRIBUTES INFLUENCING UNBOUND TISSUE DISTRIBUTION

Li Di

Pfizer Worldwide Research and Development, 280 Shennecossett Rd, CT 06340 Groton, United States

Free drug concentrations in the tissues are essential to develop pharmacokinetic / pharmacodynamic relationships, estimate therapeutic index, and predict dose for disease targets residing in tissues. Unbound tissue-to-plasma partition coefficient (Kpuu) is a useful parameter to understand asymmetry tissue distribution and guide structural modification to enhance or restrict tissue exposure. As the literature information on tissue K puu is scarce and human data is difficult to obtain, rat in vivo tissue Kpuu data of 56 structurally diverse compounds were generated in white adipose, brain, heart, liver, and skeletal muscle. Selective tissue distribution was observed for certain compounds, demonstrating the feasibility of targeting or restricting drug exposure in certain tissues through rational drug design. Structural attributes governing Kpuu in each tissue were identified, such as: (1) Compounds with high TPSA and hydrogen binding capacity tend to be impaired in the brain; (2) Strong acids tend to be restricted for muscle penetration, while compounds with high passive permeability tend not to be impaired in the muscle; (3) Large lipophilic acids tend to be enriched in the liver, potentially due to active uptake by OATPs; and (4) Compounds with low lipophilicity tend to be impaired in the adipose. The rank ordering of the median tissue Kpuu values was: liver (4.5) > heart (1.8) > adipose (1.2) > skeletal muscle (0.6) > brain (0.05), with liver being most enriched and brain most impaired. Multiple mechanisms can impact Kpuu including passive permeability, uptake and efflux transport, metabolism and tissue bulk flow. The structural attributes identified provide valuable insights on design principles for asymmetric tissue distribution to improve efficacy or reduce toxicity.

7 Martin HAYES AstraZeneca, Sweden

artin Hayes is currently Biocatalysis Leader in Hit Discovery, part of Discovery Sciences Mat AstraZeneca in Gothenburg, Sweden. He has over 25 years of industrial experience in drug discovery and development in large pharma and biotech with research interests in biocatalysis, biotransformation, natural products chemistry, analytical chemistry, structure elucidation and drug design. MH has held roles as a Team Leader, Design Leader and Project Leader at AstraZeneca, GlaxoSmithKline and Xenova. He led preclinical biotransformation studies on the P2Y12 blockbuster Brilinta/Brilique and DMPK design efforts for the FLAP inhibitor AZD5718 for atherosclerosis, currently in Phase 2. He is Industrial Lead for small molecule development and member of the Prosperity Partnership Management Board for the EPSRC/ BBRSC PP Grant to establish a new Centre for Biocatalytic Manufacture of New Modalities (CBNM) at Manchester University (2018-2023). He was PI on the Marie Curie FP7 funded P4FIFTY project (2013- 2017).

e has published over 35 papers in peer- reviewed journals, holds 14 patents and was Hmade a Fellow of the Royal Society of Chemistry in 2000. Martin worked with Prof Tom Simpson FRS at the University of Bristol on mechanistic aspects of fungal polyketide chain assembly, followed by a postdoctoral fellowship with Prof Bryan Jones at University of Toronto.

8 PL02 METABOLISM OF STRAINED RINGS: TALES OF THE UNEXPECTED

Martin Hayes

Hit Discovery, Discovery Sciences , Biopharmaceuticals R&D, AstraZeneca, Gothenburg

Strained rings and in particular combinations of strained spiro-ring systems are commonly used motifs used in drug discovery in lead generation and optimization programmes. Often ring systems of this type are utilized to modulate physicochemical properties e.g. solubility, pKa and/or DMPK properties such as in vitro metabolic stability (Clint) or permeability (P-app). Recent work from our group has highlighted the unexpected importance of the long-studied enzyme microsomal epoxide hydrolase in the in vitro clearance of simple and spiro-oxetane rings to form diol metabolites. This metabolic pathway has been demonstrated on two distinct structural series from in-house lead optimization programmes. An homology model based on the mEH crystal structure from Bombyx mori was used in attempts to rationalize substrate binding. It may be possible to use oxetane-based design elements to reduce dependency on CYP mediated clearance. Further studies on spiro oxetanyl-azetidines have revealed the importance of soluble glutathione transferases in the clearance of the MCHr1 antagonist AZD1979. Human recombinant GSTs including GST A1, A2-2, M1a, M2-2, T1-1 all catalyzed the formation of ring opened metabolites. Interestingly MetID studies using a combination of HRMS and NMR revealed ring opening in the spiro oxetanyl-azetidine containing AZD1979 took place on the azetidine, leaving an intact oxetane. Various downstream oxetane containing metabolites from GS-conjugate processing were also characterized. Compounds in this series show no GSH conjugation in regular HLM catalyzed GSH ‘trapping’ assays. In-house database searching indicated this metabolic pathway operating on simple azetidines.

9 Falgun SHAH Merck Sharp & Dohme, United States

r Falgun is currently an Associate principal scientist and computational ADME & toxicology Ddomain lead within the discovery chemistry group at Merck, West Point.

is interest lies in applying machine learning and data mining approaches to identify Hpotential ADME and safety liabilities within chemotypes.

is current role involves influencing medicinal chemistry project teams to utilize in silico HADMET approaches during post-HTS work- up to enable them to bring high-quality chemical series forward. Prior to Merck, Falgun worked in compound safety prediction group at Pfizer for 4.5 years where he deployed in silico and informatics approaches to identify new mechanisms of organ toxicities in particularly drug-induced liver injury and cardiotoxicity. He has over 25 publications in peer- reviewed journals and multiple invited presentations. Falgun is trained as a pharmacist and holds a Ph.D. in medicinal/computational chemistry.

10 PL03 LEVERAGING IN SILICO ADMET PROFILES AND ANCILLARY PHARMACOLOGY TO INFLUENCE PRIORITIZATION OF HIT SERIES WITH HIGHER PROBABILITY OF SUCCESS

Falgun Shah

MERCK SHARP & DOHME, 320 Bent St, MA 02141 Cambridge, United States

Evaluation of High-throughput screening (HTS) technologies has enabled screening of millions of compounds for biological activity against the target of interest. However, a major challenge remains with hit series prioritization in HTS campaigns with higher hit rates. How can we enable a better decision on which hit series to prosecute with high probability of success? How can we select a high-quality hit series with increased likelihoods of finding a lead candidate? We have developed a process that utilizes a battery of in-house quantitative structure activity relationship (QSAR) models to generate in silico Absorption Distribution Metabolism Excretion Toxicity (isADMET) profile and ancillary pharmacology to identify associated poly-pharmacology to enable more complete characterizations of HTS chemical matter. These profiles allow teams to quickly assess hit series for desirable ADMET properties and off-target(s) profile or find intrinsic liabilities that may require significant optimization. Presentation will focus on to discuss several prospective examples to substantiate the value of this approach.

11 Simone SCHADT F. Hoffmann-La Roche, Switzerlan

imone Schadt, PhD, DABT, ERT, is a Senior Principal Scientist, heading the biotransformation section Sat Roche Innovation Center Basel (Switzerland). Simone is a biochemist by training, with a major in organic chemistry and immunology, from the University of Tübingen (Germany). She graduated in 2007 with a PhD in biochemistry and analytical chemistry (Prof. Roderich D. Süssmuth) from Technical University of Berlin (Germany) with a thesis on the mode of action of a novel antibiotic. After graduating, she started her career as a postdoctoral fellow in the field of reactive metabolites and drug induced liver injury, then became a lab head in the drug metabolism group at Boehringer Ingelheim (Biberach, Germany). In 2011, she joined the drug metabolism group at Roche, and was promoted to group head drug metabolism in 2012 and to section head biotransformation in 2018. In 2019, she took over additional responsibility for coordinating ADME activities in a Matrix role.

er current focus is on biotransformation and ADME of small molecules, oligonucleotides Hand therapeutic proteins.

12 PL04 PREDICTING ADME - REALITY, VISION OR FANTASY?

Simone Schadt, Kenichi Umehara

F. Hoffmann-La Roche, Grenzacherstrasse 124, 4070 Basel, Switzerland

Predicting the ADME properties of compounds, such as oral absorption, bioavailability, brain penetration, or clearance, would provide information about the human dose size and frequency early on. In this talk, we would like to share our own experience with predicting the ADME properties of compounds. Among others, we will share case examples of biotransformation predictions as well as predictions of the rate-determining step in hepatic elimination.

13 Richmond SARPONG University of California, United States

ichmond Sarpong is a Professor of Chemistry at the University of California Berkeley where Rhe and his group specialize in synthetic organic chemistry.

ichmond completed his undergraduate studies at Macalester College in St. Paul, MN and his Rgraduate work was carried out with Prof. Martin Semmelhack at Princeton. He conducted postdoctoral studies at Caltech with Prof. Brian Stoltz.

t Berkeley, Richmond’s laboratory focuses on the synthesis of bioactive complex Aorganic molecules, with a particular focus on secondary metabolites that come from marine or terrestrial flora and fauna.

f all his professional accomplishments, Richmond is most proud of the students with Owhom he has worked.

14 PL05 BREAK-IT-TO-MAKE-IT STRATEGIES FOR COMPLEX MOLECULE SYNTHESIS

Richmond Sarpong

University of California, Berkeley, Department of Chemistry, 841-A Latimer Hall, CA 94720 Berkeley, United States

Natural products continue to inspire and serve as the basis of new medicines. They also provide intricate problems that expose limitations in the strategies and methods employed in chemical synthesis. Several strategies and methods that rely on C–C bond cleavage and a re-stitching of the carbon addends (i.e., break-it-to-make-it strategies) and their application to natural products synthesis and the preparation of pharmaceutically relevant molecules will be presented.

References 1) Kuroda, Y.; Nicacio, K. J.; da Silva, I. A.; Leger, P. R.; Chang, S.; Gubiani, J. R.; Deflon, V. M.; Nagashima, N.;Rode, A.; Blackford, K.; Ferreira, A. G.; Sette, L. D.; Williams, D. E.; Andersen, R. J.; Jancar, S.; Berlinck, R. G. S.; Sarpong, R. Nat. Chem. 2018, 10, 938. 2) Roque, J. B.; Kuroda, Y.; Göttemann, L. T.; Sarpong, R. Science, 2018, 361, 171. 3) Roque, J. B.; Kuroda, Y.; Göttemann, L. T.; Sarpong, R. Nature, 2018, 564, 244.

15 David NICEWICZ University of North-Carolina at Chapel Hill, United States

ave Nicewicz completed his Chemistry B.S. (2000) and M.S. (2001) degrees at the DUniversity of North Carolina, Charlotte. He then moved to the University of North Carolina, Chapel Hill where he completed his Ph.D. with Prof. Jeffrey S. Johnson in 2006. David then was a Ruth L. Kirschstein Postdoctoral Fellow with Prof. David W. C. MacMillan. In 2009, Dave began his independent career at the UNC Chapel Hill, where his laboratory has focused on organic photoredox catalysis for the development of novel chemical reactivity.

e has received awards from UNC (Ruth Hettleman Prize for Artistic and Scholarly HAchievement), industry (Boehringer Ingelheim; Amgen; Eli Lilly), private foundations (Packard Fellowship in Science and Engineering; Camille Dreyfus Teacher-Scholar Award) and international recognition (The 13th Hirata Award, Nagoya University).

n 2015, he was promoted to Associate Professor, Iand then Full Professor in 2018.

16 PL06 NEW AVENUES IN SYNTHESIS ENABLED BY ORGANIC PHOTOREDOX CATALYSIS

David Nicewicz

UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL, Chapel Hill, United States

Single electron pathways are prevalent in numerous biosynthetic pathways that are crucial to life on our planet. As synthetic chemists, we seek to harness the power of these open-shell processes to achieve uncommon but valuable chemical reactivity. To this end, my laboratory is interested in accessing single electron pathways via the use of organic photoredox catalysis. This seminar will highlight the recent synthetic methods developed by my laboratory, C-H functionalization reactions of aromatic and aliphatic compounds as well as catalysis of the nucleophilic aromatic substitution of methoxyarenes. Where, applicable, data in support of mechanistic hypotheses will be presented.

17 Tobias RITTER Max-Planck-Institut für Kohlenforschung, Germany

obias Ritter received his undergraduate education in Braunschweig (Germany), TBordeaux (France), Lausanne (Switzerland), and Stanford (US). He has performed undergraduate research with Prof. Barry M. Trost at Stanford, obtained his PhD working with Prof. Erick M. Carreira at ETH Zurich in 2004, and was a postdoc with Prof. Robert H. Grubbs at Caltech. In 2006, Tobias was appointed as Assistant Professor in the Department of Chemistry and Chemical Biology at Harvard, promoted to Associate Professor in 2010, and to Professor of Chemistry and Chemical Biology in 2012. Since 2015 he is director at the Max-Planck-Institut für Kohlenforschung in Germany, since 2018 as the Managing Director, and holds additional faculty appointments at RWTH Aachen and Massachusetts General Hospital, Boston.

he Ritter lab focuses on late-stage functionalization chemistry, with a focus on Tfluorination methods and their application to molecular imaging.

n 2011, Tobias founded SciFluor LifeScience, a clinical pharmaceutical company in Cambridge, IMassachusetts.

18 PL07 LATE-STAGE FUNCTIONALIZATIONS

Tobias Ritter (1,2,3)

1) Max Planck Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim, Germany, [email protected] 2) RWTH Aachen University University, Department for Chemistry, Landoltweg 1, 52074 Aachen, Germany 3) Massachusetts General Hospital, Department of Radiology, 55 Fruit Street, Boston, MA 02114 USA

Late-stage functionalization reactions should reliably functionalize already complex molecules to quickly access value-added molecular diversity. Late-stage functionalization is desirable in many areas of discovery such as in drug or agrochemical development and a requirement in other areas such as the synthesis of positron-emission tomography (PET) tracers. I will describe the development of novel, modern highly selective reactions in late-stage functionalization, as well as their application in transition-metal-catalyzed and photoredox reactions, with a focus on the synthesis of 18F and 19F containing complex small molecules. In particular, I will describe the development of a broadly useful new C-H functionalization reaction to create molecular complexity for applications in catalysis, drug discovery, and medicine.

19 Philipp HERETSCH Free University of Berlin, Germany

hilipp Heretsch was born in Lippstadt, Germany, in 1982. He obtained his PhD degree from PUniversität Leipzig (supervisor: Prof. A. Giannis) in 2009. After a postdoctoral stay with Prof. K.C. Nicolaou at The Scripps Research Institute, La Jolla, California, and at Rice University, Houston, Texas, he was appointed assistant professor at Freie Universität Berlin in 2015.

hilipp Heretsch has been working on total synthesis of biologically active natural products Psince the beginning of his career. His group is now interested in radical C−C-bond manipulation strategies in the context of the synthesis of complex abeo-steroids, guided by biosynthetic hypotheses as well as designing flow reactors for specific use in natural product synthesis.

20 PL08 A RADICAL WAY TO ABEO-STEROIDS

Philipp Heretsch, Robert C. Heinze, Fenja L. Duecker

Free University of Berlin, Takustr. 3, 14195 Berlin, Germany

In recent years, the strategic manipulation of non-activated C–H bonds has become an important tool in facilitating and streamlining the synthesis of complex natural products. In many cases, selective methods are now at our disposal to access bioactive natural products efficiently and economically, thus completely avoiding – or at least reducing – the number of protecting group operations and non-strategic redox manipulations. A class of natural products that lends itself rather readily to said strategies are the terpenes. Among them, and of special interest to our research, are the abeo-steroids: highly oxidized steroids with at least one C–C bond scission, accompanied by rearrangement of the tetracyclic framework. While the comparably high oxidation levels of abeo-steroids can be addressed synthetically by C–H manipulation methods, their rearranged frameworks require other synthetic tools. This talk will highlight, at the example of our recent work in the field, that radical rearrangement cascades can be used to achieve those necessary C–C bond manipulations. Unveiling radical rearrangement processes can additionally shed light on the potential biosynthesis of these natural products.

References 1) R.C. Heinze, P. Heretsch, J. Am. Chem. Soc. 2019, 141, 1222–1226. “Translation of a Polar Biogenesis Proposal into a Radical Synthetic Approach: Synthesis of Pleurocin A/Matsutakone and Pleurocin B“. 2) R.C. Heinze, D. Lentz, P. Heretsch, Angew. Chem. Int. Ed. 2016, 55, 11656–11659. “Synthesis of Strophasterol A Guided by a Proposed Biosynthesis and Innate Reactivity”.

21 Katharina DUERR University of Oxford, United Kingdom

he Duerr group at the Structural Genomics Consortium Oxford uses structural methods T(X-ray crystallography and single-particle cryo- Electron microscopy) to determine the molecular architecture of human ion channels, transporters, enzymes and other integral membrane proteins relevant to various disease conditions and human therapies. This structural work provides valuable insights into the molecular interactions of these proteins with their native substrates, small molecule drugs or therapeutic antibodies and provides a framework to develop mechanistic models for their functional activity, which are then further tested in functional experiments.

rior to joining the SGC in 2016, Katharina has been a postdoctoral researcher in the lab of PEric Gouaux at OHSU (Portland, OR), studying the structure and function of ionotropic glutamate receptors.

22 PL09 MEMBRANE PROTEINS AT THE SGC: CHALLENGES AND SUCCESS STORIES

Katharina Luise Dürr

Structural Genomics Consortium, University of Oxford, Old Road Research Campus Research Building, , Off Roosevelt Drive, OX3 7DQ, Oxford, UK

The workflows at the Structural Genomics Consortium (SGC) are characteristic for an institution at the interface between academia and industry: the SGC is a not-for-profit public-private partnership to accelerate drug discovery through open access research by 250+ scientists, located at 6 sites (Toronto, Oxford, Frankfurt, Chapel Hill, Stockholm and Campinas) across the globe. It has built an international collaborative network spanning nine pharmaceutical partners, over 300 leading academic labs and several biotech companies. A major focus of the SGC is the structure determination of medically relevant human and parasite proteins, with a track record of over 500 novel human soluble proteins, 30 protein-protein complexes and over 10 human integral membrane proteins (IMPs). Membrane protein structural biology is exclusively carried out at the largest site located in Oxford, with a total of more than 20 scientists dedicated to production of integral membrane proteins (IMPs) for structural studies by cryo-EM and X-ray crystallography. Here, we describe the “IMP pipeline” and some of the changes that were introduced into the workflows to enable structural studies by cryo-EM. Examples of ongoing projects and pharma collaborations illustrate the advantages over membrane protein crystallography, but also highlight new challenges and limitations of structure-aided drug discovery using cryo-EM. We also demonstrate how we can contribute to drug discovery and tool generation for membrane protein targets when structure determination is not feasible by either method.

23 Matthias FRECH MERCK, Germany

atthias is heading the department for Molecular Interaction and Biophysics (MIB) Mat Merck-Serono since 2008. Integrated into the “Small Molecule Platform”, the group is responsible for molecular interaction studies and protein crystallographic work, to generate insight into the mode of action by combining various biophysical methods. Fragment based lead discovery, thermodynamic signatures, interaction kinetics and protein structure are the current data packages which support the drug discovery process at Merck- Serono with biophysics. Prior to that position, he was responsible for a protein chemistry group working with different biophysical methods combined with the protein purification and analysis for structural studies and high throughput screening campaigns.

efore joining Merck, he was working on protein kinases and their biochemical characterization Ba post doctoral fellow at the Friedrich Miescher Institute, part of the Novartis Research organisation,. As EMBO fellow he worked on nucleotide exchange factors and adaptor proteins in the p21ras signalling pathway at the CNRS Institute de Pharmacologie Moleculaire et Cellulaire in the technology park of Sophia Antipolis near Nice/ France. He accomplished his doctoral work in the department of Biophysics at the Max Plank Institute in Heidelberg focusing on molecular interaction studies of small p21ras like proteins.

24 Abstract not yet available

25 Wolfgang JAHNKE NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH, Switzerland

olfgang Jahnke is a Director and leading scientist in the Protein Sciences department Wat Novartis in Basel, Switzerland, where he is responsible for the development and application of NMR spectroscopy and other biophysical methods for lead discovery at Novartis. Wolfgang received his PhD with Prof. Horst Kessler at the Technische Universität München. He worked with Peter Wright at the Scripps Research Institute in La Jolla, California, before joining Novartis. In his 20 years at Novartis, Wolfgang has helped to pioneer the application of protein NMR spectroscopy and fragment-based approaches in drug discovery.

is contributions were internally and externally recognized by the Novartis Leading Scientist Haward, the Novartis President’s Award for the discovery of ABL001, and the Industrial Investigator Award by the Swiss Chemical Society.

olfgang has co-authored more than 80 scientific publications and patents, and has Wco-edited two books on fragment-based lead discovery.

26 PL11 DISCOVERY OF ABL001, AN ALLOSTERIC INHIBITOR OF BCR-ABL: FRAGMENTS, BIOPHYSICS, STRUCTURE AND CHEMISTRY

Wolfgang Jahnke

NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH, Basel, Switzerland

The team effort that led to the discovery and early development of ABL001 will be described. Discovery of ABL001 started with a fragment-based screen using NMR spectroscopy and X-ray crystallography. An NMR-based conformational assay was needed to understand the requirements for functional inhibition of fragments. Structure-based design and medicinal chemistry finally resulted in the clinical candidate ABL001, which is currently in phase III trials of chronic myelogenous leukemia. Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1. Schoepfer J, et al. Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1. J Med Chem. 2018 Sep 27;61(18):8120-8135. doi: 10.1021/acs.jmedchem.8b01040 Jahnke W, et al. Binding or bending: distinction of allosteric Abl kinase agonists from antagonists by an NMR-based conformational assay. J Am Chem Soc. 2010 May 26;132(20):7043-8. doi: 10.1021/ja101837n.

27 Stuart FRANCIS Cancer Research UK Beatson Institute, United Kingdom

tuart studied Medicinal Chemistry at the University of Sussex before working at Celltech SChiroscience for 2 years working on integrins and kinases against inflammatory targets. He subsequently joined Organon, in 2003 which latterly became MSD, at Newhouse for 9 years working on a number of GPCR targets including Cannabinoids and aminergics.

ince 2011, he has worked on several kinase and Protein Protein Interactions (PPI) projects Swith a particular interest in fragment screening and Protacs to help validate novel and challenging oncology targets.

28 OC01 DISCOVERY OF SMALL MOLECULE FASCIN 1 INHIBITORS USING FRAGMENT-BASED DRUG DISCOVERY

Stuart Francis (1), Charles Parry (1), Daniel Croft (1), Alexander Schuttelkopf (1), Angelo Pugliese (1), Jen Konzcal (1), Laura Macdonald (1), Mokdad Mezna (1), Nikki Paul (2), Andrea Gohlke (7), Chris Gray (6), Gillian Goodwin (5), Andrew Pannifer (3), Martin Drysdale (4), Laura Machesky (2), Heather McKinnon (1), Justin Bower (1)

1) Drug Discovery, Cancer Research UK Beatson Institute, Switchback Road, Glasgow G61 1BD, UK 2) Migration, Invasion & Metastasis Laboratory, Cancer Research UK Beatson Institute, Switchback Road, Glasgow G61 1BD, UK 3) Medicines Discovery Catapult, Alderly Edge, Cheshire, SK10 4TG, UK 4) Broad Institute, Cambridge, MA 02142, US 5) Antibody Analytics Ltd. BioCity Scotland, Bo'ness Road, Newhouse, Lanarkshire, ML1 5UH, UK 6) GE Healthcare, Glasgow 7) AstraZeneca, Chesterton, Cambridgeshire, United Kingdom

Fascin 1 binds and cross-links filamentous actin (F-actin) into parallel bundles that are used in the formation of dynamic cellular protrusions (such as lamellipodia and filopodia) used during cell migration, and in the formation of invadopodia used by tumor cell lines to degrade the tumor extracellular matrix (ECM). Fascin 1 is overexpressed in a range of aggressive and invasive tumors and is believed to play a critical role in cancer cell metastasis. Utilising our in-house fragment collection (~1000 compounds) coupled with biophysical assays and X-ray crystallography, we identified novel fascin 1 inhibitors binding in multiple ligand binding sites. The best of the binders in "site 2" had nannomolar affinity in biochemical and biophysical binding assays and also demonstrated functional activity by causing a large conformational twist of one of the domains. 1 The best of this series of compounds was BDP-13176 (Kd=85nM, IC50=240nM) with activity in a number of cell based invasion assays including both 2D and 3D cultures, demonstrating the potential of fascin inhibition as a valid target for preventing invasion and metastasis.

References 1) Francis et al. (2019) Structure-based design, synthesis and biological evaluation of a novel series of isoquinolone and pyrazolo[4,3-c]pyridine inhibitors of fascin 1 as potential anti-metastatic agents. Biorg Med Chem Lett 8,1023-1029 29 Andy PHILLIPS C4 Therapeutics, United States

ndy Phillips is President and Chief Executive Officer of C4 Therapeutics, a biotech company Athat is developing a new class of small molecules that direct the machinery of the ubiquitin- proteasome system to selectively degrade disease- relevant proteins for therapeutic benefit.

efore joining C4 Therapeutics, Andy was Senior Director, Center for Development of BTherapeutics at the Broad Institute of MIT and Harvard, where he led overall therapeutic efforts and provided strategic leadership for a number of major partnerships. Previously, he was a Full Professor of Chemistry at Yale University, where he received the ACS Cope Scholar Award for his research accomplishments, which included the development of small molecules aimed at modulating ‘undruggable’ targets. Prior to this, he was a Full Professor of Chemistry and Biochemistry at the University of Colorado at Boulder, where his efforts in complex molecule synthesis and targeting protein-protein interactions garnered a number of awards, including an Alfred P. Sloan Research Fellowship, an Eli Lilly Grantee Award, and a National Science Foundation CAREER Award.

ndy received a B.Sc. (Hons) in biochemistry and a Ph.D. in biochemistry and chemistry Afrom the University of Canterbury in New Zealand and completed a postdoctoral fellowship in organic chemistry at the University of Pittsburgh.

30 PL12 TARGETED PROTEIN DEGRADATION

Andrew J. Phillips

C4 Therapeutics, 490 Arsenal Way, MA 02472 Watertown, United States

Targeted protein degradation has emerged as an exciting new approach for drug discovery. This talk will provide a brief background to the technology and how degraders work before covering two case studies in therapeutic applications of targeted protein degradation.

31 Georg WINTER Research Center for Molecular Medicine of the Austrian Academy of Sciences, Austria

eorg Winter, PhD, obtained his degree from the Medical University of Vienna, working Gon elucidating the mechanism of action of anti-neoplastic drugs under the supervision of Prof. Giulio Superti-Furga. He specialized on proteomics- as well as chemical genetics approaches to identify drug resistance mechanisms and synergistic drug combinations. He continued his training in chemical biology, working as a postdoctoral fellow with Dr. James Bradner the Dana Farber Cancer Institute/ Harvard Medical School. Supported by an EMBO fellowship, he developed the first generalizable pharmacologic solution to in vivo target protein degradation (Winter et al., Science 2015). He was recruited as a CeMM Principal Investigator in June 2016 where his research is now focused on using the unique molecular pharmacology of targeted protein degradation to understand and disrupt fundamental principles of transcription and gene control aberrantly regulated in human cancers.

eorg Winter (co-) authored 30 manuscripts including publications in Science, Nature and GNature Chemical Biology. is interdisciplinary research lab is supported by several national and international grants Hincluding an ERC Starting grant. Dr. Winter’s contribution to the field of targeted protein degradation was acknowledged via multiple prices and awards, including the Eppendorf Award and the Elisabeth Lutz Award of the Austrian Academy of Sciences.

32 PL13 CHEMICAL GENOMICS APPROACHES TO TARGETED PROTEIN DEGRADATION

Georg Winter

Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090 Vienna, Austria

Targeted protein degradation (TPD) is a novel paradigm in pharmacology that promises to overcome challenges of conventional drug discovery strategies. Structural determinants of TPD are beginning to emerge, segregating requirements that are unique to different kind of degraders such as heterobifunctional degraders (PROTACs) or monovalent molecular glue degraders. Comparatively, mechanisms determining the cellular response to small-molecule degraders remain poorly understood. Here, we set out to systematically delineate effectors required for targeted protein degradation and to further analyze involved protein surfaces at high functional resolution. We conducted genome-scale CRISPR/Cas9 screens, deep mutagenesis of relevant protein interface, and targeted hybrid-capture sequencing of candidate genes in thousands of spontaneously resistant haploid human leukemia cells. Our data highlights putative mechanisms of resistance to both types of small molecule degraders, as well as strategies to potentially overcome them.

33 Christian STEINEBACH University of Bonn, Germany

hristian Steinebach completed his undergraduate studies in Pharmacy (state Cexamination) at the University of Bonn, Germany. In 2015, he became a licensed Pharmacist and got the Carl-Friedrich-Mohr award. He received his MSc in Drug Development in 2016. Since then he is performing his PhD studies in Pharmaceutical Chemistry supervised by Prof. Michael Gütschow at the Pharmaceutical Institute in Bonn. In 2018, he successfully applied for a PhD-related scholarship from the Bonn International Graduate School of Drug Sciences.

is scientific work is devoted to the Medicinal Chemistry of Proteolysis Targeting Chimeras H(PROTACs), to the design and synthesis of bioactive molecules acting by a new modality of targeted degradation of disease-causing proteins, in particular protein kinases.

34 OC02 FOUR E3 LIGASES, ONE TARGET: TOWARDS NOVEL CDK6 PROTACS

Christian Steinebach (1), Yuen Lam Dora Ng (2), Izidor Sosič (3), Stefanie Lindner (2), Jan Krönke (2), Michael Gütschow (1)

1) University of Bonn, Pharmaceutical Institute, An der Immenburg 4, D-53121 Bonn, Germany 2) University Hospital Ulm, Department of Internal Medicine III, Albert-Einstein-Allee 23, D-89081 Ulm, Germany 3) University of Ljubljana, Faculty of Pharmacy, SI-1000 Ljubljana, Slovenia

Cyclin-dependent kinases 4 and 6 (CDK4/6) are key orchestrators of transcription and cell cycle regulation. Dysregulation of the cell cycle, fuelled by up-regulated and over-activated CDKs, significantly contributes to uncontrolled cellular proliferation, which is a fundamental hallmark of cancer. However, anticancer therapies based on ATP competitive inhibition of CDK4/6 fail to discriminate between both isoforms and disregard kinase-independent functions in tumour development. As a moonlighting protein, CDK6 is further transcriptionally regulating processes such as differentiation and inflammation.1) Proteolysis targeting chimeras (PROTACs) represent a new paradigm in pharmacological intervention of a given target protein. PROTACs are heterobifunctional small-molecules, in which a target protein ligand is chemically fused to an E3 ligase ligand. The induced proximity between the target and the E3 ligase enables the formation of a ternary complex, ubiquitin transfer and proteasomal degradation.2) We and others sought for a selective chemical knockdown of CDK6. In previous examples, PROTACs were assembled based on the dual selective CDK4/6 inhibitors palbociclib, ribociclib or abemaciclib, and the E3 ligase ligand thalidomide.3) In some cases, the degradation of Ikaros (IKZF1) and Aiolos (IKZF3),4) well-established targets of imide-based PROTACs,5) was observed. To further fine-tune the degradation potency and selectivity, we thoroughly explored the CDK6 degradation space through hijacking of four different E3 ligases (VHL, CRBN, MDM2, and IAP). With our array of different E3 ligase ligand-CDK inhibitor combinations we successfully generated CDK6-selective degrader molecules (Fig. 1) that not only target the kinase activity but also silence kinase-independent functions. The results raise the intriguing possibility to assemble the mosaic of CDK6-specific functions via a PROTAC-mediated knockdown. We propose that our degraders represent multipurpose tools in the fight against cancer and to study CDK6 biology in even greater detail.

Fig. 1: Western blot analysis to show the degradation potency of PROTAC 27. MM1S cells were treated for 16 h with the compounds at the indicated concentrations. VH298, monomeric VHL-ligand; CDK-VHL(-), VHL non-binding heterobifunctional negative control.

References 1) Sánchez-Martínez et al., Bioorg. Med. Chem. Lett. 2019, 29, 126637. 2) Maniaci et al., Curr. Opin. Chem. Biol. 2019, 52, 145–156. 3) Jiang et al., Angew. Chem. 2019, 58, 6321–6326. 4) Krönke et al., Science 2014, 343, 301–305. 5) Steinebach et al., Chem. Commun. 2019, 55, 1821–1824.

35 Lawrence G. HAMANN Bristol-Myers Squibb Corporation, United States

arry Hamann is currently Corporate Vice President and Global Head of Chemistry at Celgene, with Lresponsibility for Medicinal and Computational Chemistry, Biochemistry, Structural and Chemical Biology and Screening. In > 27 years in drug discovery he has led teams responsible for more than 17 clinical stage compounds, including the FDA approved DPP4 inhibitor saxagliptin (Onglyza™) for type 2 diabetes, and first-in-class HCV NS5A inhibitor daclatasvir (Daklinza™) for hepatitis C. Prior to Celgene, Larry was Executive Director, Global Discovery Chemistry at Novartis, overseeing programs in oncology, neuroscience, respiratory, cardiovascular, and rare genetic disease. Previously, Larry was at Bristol- Myers Squibb and Ligand Pharmaceuticals.

arry holds a BS in Chemistry from the University of Detroit and a PhD in Organic Chemistry from Lthe University of Michigan.

36 KL02 EXPANDING THE DRUGGABLE GENOME THROUGH CEREBLON-MEDIATED PROTEIN DEGRADATION

Lawrence G. Hamann

Bristol-Myers Squibb Corporation, Cambridge, MA, USA

The FDA approved drug lenalidomide is indicated for the treatment of a variety of hematologic malignancies, including multiple myeloma and myelodysplastic syndrome. Lenalidomide, as well as the analogs pomalidomide and thalidomide bind to the protein cereblon, which is part of the CRL4-CRBN E3 ubiquitin ligase complex that catalyzes the transfer of ubiquitin to mark target proteins for degradation. Cereblon modulating drugs bind to the surface of cereblon to form a ‘hotspot’ for protein-protein interactions triggering the recruitment of proteins to the CRL4 E3 ubiquitin ligase complex where they can be ubiquitinated and subsequently degraded. This means of engaging cereblon has diverged into two parallel fields: 1) direct cereblon modulators capable of directing degradation of certain proteins containing a degron motif, sometimes referred to as molecular glue, and 2) heterobifunctional degraders which tether a target binding moiety through a linker to a cereblon binding moiety to engage proteins which do not contain this degron motif. The degron can be found in more than a thousand proteins, including in families such as zinc finger transcription factors that had been generally considered undruggable prior to the discovery of the mechanism of action of cereblon modulators. The evolution of our mechanistic understanding of this powerful emergent modality for drug discovery and the implications of these findings for future drug discovery in the targeted degradation space will be discussed, including recent clinical molecules CC-90009 for treatment of acute myeloid leukemia, and CC-92480 for treatment of relapse refractory multiple myeloma.

37 Karl GADEMANN University of Zürich, Switzerland

arl Gademann (1972) was educated at ETH Zürich and Harvard University, where he worked Kwith Prof. Dieter Seebach, Prof. Eric N. Jacobsen, and Prof. Erick M. Carreira. His previous professorial appointments include the EPFL in Lausanne and the University of Basel, where he served as full professor and dean of research. He has been elected to the board of the Swiss Academy of Sciences, and is affiliated to the NCCR Molecular Systems Engineering. In Summer 2015, Karl Gademann moved to the University of Zürich, where he serves as the chair of the department of chemistry. In addition, he also performs duties as a research councillor to the Swiss National Science Foundation.

is work has been recognized by a number of international awards, including the Latsis prize, Hthe Novartis Early Career Award, the Ruzicka Medal, The Liebig Lecture by the German Chemical Society, and the European Young Investigator Award.

38 PL14 CAPTURING BIOLOGICAL ACTIVITY IN NATURAL PRODUCT FRAGMENTS: SUCCESS AND LIMITATIONS

Karl Gademann

Department of Chemistry, University of Zurich, Zurich, Switzerland

Natural products have had an immense influence on science and have directly led to the introduction of many drugs. Organic chemistry, and its unique ability to tailor natural products through synthesis, provides an extraordinary approach to unlock the full potential of natural products. In this presentation, an approach based on natural product derived fragments is presented that can successfully address some of the current challenges in drug discovery. These fragments often display significantly reduced molecular weights, reduced structural complexity, a reduced number of synthetic steps, while retaining or even improving key biological parameters such as potency or selectivity. Both success stories and also limitations of this approach will be presented and critically discussed.

References 1) E. A. Crane, K. GAdemann, Angew. Chem. Int. Ed. 2016, 55, 3882 – 3902

39 Tanja GAICH University of Konstanz, Germany

anja Gaich received her PhD in Chemistry at the University of Vienna (2009, Prof. Dr. J. Mulzer) TShe then moved on as a post-doctoral research fellow to the Scripps Research Institute La Jolla CA (Prof. P. S. Baran, 2009-2010). In 2010, she started her independent career at the Leibniz University Hannover (mentorship Prof. Dr. M. Kalesse), and was funded by the “Fonds der chemischen Industrie” and the Alexander von Humboldt Foundation with the “Sofja Kovalevskaja prize”. Since July 2015 she is a full professor of Organic Chemistry at the University of Konstanz.

er research interests contain the total synthesis of bioactive natural products and the synthesis Hand design of chiroptical molecular switches.

40 PL15 CONCISE SYNTHESIS OF COMPLEX TAXANE DITERPENE CANATAXPROPELLANE BY PHOTOCHEMICAL DEAROMATIZATION

Fabian Schneider, Konstantin Samarin, Simone Zanella, Tanja Gaich

University of Konstanz, Department of Chemistry, Universitätsstrasse 10, 78467, Konstanz, Germany

Canataxpropellane belongs to the medicinally very important taxane diterpene family. The most prominent congener Taxol®is a blockbuster drug and one of the most commonly used anti-cancer agent in clinics today. Canataxpropellane exhibits a novel taxane skeleton with an unparalleled molecular complexity. Unfortunately, its isolation from natural sources is inefficient to the extent, that biological evaluations are rendered impossible. Here, we describe the first total synthesis of canataxpropellane from inexpensive starting materials in 26 chemical transformations and 19 isolated synthetic intermediates. Taxane diterpenes (1-3) are a medicinally vital family of natural products, exhibiting potent anti-cancer activity, and are isolated from slow growing evergreen shrubs (genus Taxus) commonly known as yews. Ever since, different Taxus species have been screened for their constituents and a vast number of more than 500 taxanes were isolated until the end of 2009 (1). Their structures are classified into 11 groups based on their carbon ring systems (1). Amongst them, canataxpropellane (2) was isolated from Taxus Canadensis (4),and constitutes a member of the “complex taxane”-group (Fig. 1B). This highly oxygenated diterpene is one of the most convolute and complex natural products that have ever been isolated. Just as it’s sibling Taxol®and all other taxane diterpenes, it suffers from extremely inefficient sourcing from its natural producer, thus preventing biological and pharmaceutical investigations to this day. The talk will detail the first and optical active synthesis of canataxpropellane (2), and discuss the pitfalls and challenges of the synthetic route.

References 1) Y.-F. Wang, Q.-W. Shi, M. Dong, H. Kiyota, Y.-C. Gu and B. Cong, Chem. Rev. 111, 7652-7709 (2011). 2) E. Baloglu and D. G. I. Kingston, J. Nat. Prod. 62, 1448-1472 (1999). 3) D. Schinzer, in Organic Synthesis Set DOI: 10.1002/9783527620784.ch36a, pp. 335-347 (2008). 4) M. C. Wani, H. L. Taylor, M. E. Wall, P. Coggon and A. T. McPhail, J. Am. Chem. Soc. 93, 2325-2327 (1971). 41 Christopher VANDERWAL University of California, United States

hris Vanderwal was born in Germany (to Canadian parents). At the age of nearly five, Cyoung Chris moved with his parents to Ottawa, Canada, where he attended school, up to and including university (BSc in Biochemistry, MSc in Chemistry from the University of Ottawa). Chris moved to sunny San Diego, where he earned his PhD under the supervision of Erik Sorensen at Scripps in 2003. Chris then moved back to the cold as a Jane Coffin Childs Postdoctoral Fellow at Harvard University in the lab of Eric Jacobsen. Chris enthusiastically joined the Chemistry Department faculty at UC Irvine in 2005. In 2011, Chris was promoted to Associate Professor of Chemistry with tenure, and was named a UCI Chancellor’s Faculty Fellow. In 2013, Chris was promoted to Professor.

42 PL16 SYNTHESIS OF COMPLEX ANTIPLASMODIAL ISOCYANOTERPENES

Christopher Vanderwal

University of California, Department of Chemistry, Natural Sciences II, CA 92697 Irvine, United States

The isocyanoterpene family of marine natural products are structurally unusual for the presence of isonitrile functional groups, and they demonstrate potent antiplasmodial activity. Therefore, synthesis programs that are able to generate these targets, structural analogues, and related chemical probe molecules, could lead to new directions in antimalarial chemotherapy. Our laboratory has developed a unified approach to many of the most potent natural products. This strategy has yielded short syntheses of kalihinol B and diisocyanoadociane, as well as many related compounds. The development of our successful strategy toward these targets, and some preliminary data on their biological activity, will be discussed.

43 Simon WILLIAMS Syngenta, Switzerland

imon Williams did his undergraduate education in natural sciences at the University of Cambridge Sand continued to do a PhD on the synthesis of marine natural products with Prof. Ian Paterson. He spent a further year as a postdoc in the Paterson group before moving to the University of Zurich to work with Prof. Karl Gademann on antibiotic natural products. At the end of 2018 he started his current position as a team leader in research chemistry at Syngenta in Stein (Switzerland).

44 OC03 TOTAL SYNTHESIS OF CHIVOSAZOLE F

Simon Williams (1,2), Jialu Jin (1), Jennifer Kan (1), Munyuen Li (1), Lisa Gibson (1), Ian Paterson (1)

1) University of Cambridge, Lensfield Road, Cambridge, UK 2) Present address: Syngenta Crop Protection, Schaffhauserstrasse 101, Stein, Switzerland

The total synthesis of the polyene macrolide chivosazole F is presented. The chivosazoles are myxobacterial natural products that inhibit actin polymerisation and the interaction of actin-binding proteins with actin.1,2 Their complex unsaturated architecture presents a formidable challenge to the synthetic chemist to control the geometry of nine olefins and ten stereogenic centres. To achieve the synthesis an ambitious strategy based on a multicomponent Stille coupling was developed that permitted the construction of almost the entire carbon backbone of the molecule in a single operation. A short series of delicate manipulations installed the most sensitive of the olefins and the macrocycle was completed with a final, intramolecular, Stille coupling.3

References 1) Irschik, H., Jansen, R., Gerth, K., Hofle, G., Reichenbach, H. J.Antibiot. 1995, 48 ,962 2) Wang, S., Gegenfurtner, F. A., Crevenna, A. H., Ziegenhain, C., Kliesmete, Z., Enard, W., Müller, R., Vollmar, A. M., Schneider, S., Zahler, S., J. Nat. Prod. 2019, 82, 1961 3) Williams, S., Jin, J., Kan, S. B. J., Li, M., Gibson, L., Paterson, I., Angew. Chem. Int. Ed. 2017, 56, 645

45 Bartosz A. GRZYBOWSKI Ulsan National Institute of Science & Technology, South Korea

artosz A. Grzybowski graduated summa cum laude from Yale University in 1995 and received Bhis Ph.D. in chemistry from Harvard in 2000. After a postdoctoral fellowship at Harvard, he joined the faculty of Northwestern University in 2003 and in 2009 became Kenneth Burgess Professor of Physical Chemistry and Chemical Systems’ Engineering. From 2009 he directed the DoE Non-Equilibrium Research Center at Northwestern. In late 2014, he moved to UNIST where he is now a Distinguished Professor of Chemistry and also a Group Leader at the IBS Center for Soft and Living Matter. He is also Professor at the Institute of Organic Chemistry, Polish Academy of Sciences.

is current research interests include chemical networks and systems, automated synthetic Hplanning, theory of organic synthesis, applications of AI to chemistry, autocatalysis, and “thinking” materials.

46 PL17 ORGANIC SYNTHESIS ON A COMPUTER: SHOULD MEDICINAL CHEMISTS CARE?

Bartosz Grzybowski

Ulsan National Institute of Science & Technology, Ulsan, South Korea

Although making new chemicals is the backbone of chemical and pharmaceutical industries, designing novel and efficient synthetic routes remains a challenging process, especially if more complex molecules are to be made. Given that planning of a synthetic route can be tedious, chemists have strived – for over five decades now – to accelerate the process by teaching computers the art of synthetic design. However, despite numerous and often ingenious approaches being pursued, there have been no examples of syntheses of non-trivial targets first planned by the machine and then successfully executed in the laboratory. With enormous improvements in computers’ performance, with the modern methods of machine learning and graph theory and with carefully encoded reaction mechanisms, we have been able to develop the so-called Chematica (SynthiaTM) platform that is finally capable of completely automated and chemically correct design of synthetic pathways leading to arbitrary targets, including not only drugs but also complex natural products. In my talk, I will first discuss the theoretical basis of the program that emerged over many years of concerted effort, and then talk about an all-important validation effort in which this software designed, without human supervision, syntheses leading to numerous targets diverse both in terms of structure and complexity – these computer designed routes were later executed in the laboratory and in all cases offered significant improvements on previous approaches or identified efficient routes to targets for which previous synthetic attempts proved unsuccessful. With these results, I will also discuss the ability of the computer to discover *new* synthetic knowledge (ranging from previously unreported tactical combinations to new reaction types), and how this computer-driven discovery can feed back into automated synthetic design, ultimately benefitting the community of synthetic and medicinal chemists.

47 Timothy CERNAK University of Michigan, United States

im Cernak was born in Montreal, Canada in 1980. He obtained a B.Sc. in Chemistry from TUniversity of British Columbia Okanagan and there studied the aroma profile of Chardonnay wines. Following PhD training in total synthesis with Prof. Jim Gleason at McGill University, Tim was a FQRNT Postdoctoral Fellow with Tristan Lambert at Columbia University. In 2009, Tim joined the Medicinal Chemistry team at Merck Sharp & Dohme in Rahway, New Jersey. There he developed technologies for miniaturized synthesis and late- stage functionalization. In 2013, Tim moved to Merck’s Boston site. In 2018, Dr Cernak transitioned from industry to academia and launched a lab at the University of Michigan in Ann Arbor as an Assistant Professor of Medicinal Chemistry.

he Cernak Lab is exploring an interface of Tchemical synthesis and data science.

48 PL18 EXPLORING AN INTERFACE OF SYNTHESIS AND DATA SCIENCE

Tim Cernak

University of Michigan, Department of Medicinal Chemistry, 930 N University, 48104 Ann Arbor, United States

Coupling reactions are important tools in the arsenal of the medicinal chemist. A wide diversity of commercially available building blocks provide the ability to sample diverse pockets of chemical space using coupling reactions. Current practice favors the use of a narrow subset of coupling reactions with a broad diversity of building blocks. We endeavor to explore an approach that uses a narrow subset of building blocks, and a broad diversity of coupling reactions. Towards this objective, we will report in this poster the development of a novel esterification reaction, which operates through C–N bond activation. This unorthodox reaction was discovered and optimized using high-throughput experimentation. High-throughput synthesis revealed an interplay of substrate and reaction conditions. This poster will detail our discovery and development of this new esterification reaction using high-throughput and automated synthesis.

49 Matthias ZENTGRAF Boehringer Ingelheim, Germany

atthias did his PhD with Prof. Klebe and joined the Computational Chemistry group Mof Boehringer Ingelheim in Biberach in 2006. In 2010 he became team lead of one of the Computational Chemistry teams with a focus on respiratory diseases. Since 2017 he is “Head of Computational Chemistry“.

50 PL19 ACCELERATING R&D WITH AUGMENTED INTELLIGENCE

Matthias ZENTGRAF

BOEHRINGER INGELHEIM, Biberach an der Riss, Germany

Excellence in molecular design is a key business capability of every research driven Pharma Company. Modern digital tools, machine learning and so-called artificial intelligence hold the promises to bring molecular design to an even higher level of quality and enable a more stringent prioritization of compounds for synthesis. Boehringer Ingelheim has implemented a digital molecular design platform to provide scientists live access to contextual experimental data and in-silico predictions during their molecular design sessions and idea prioritization discussions. We will show how computational tools can accelerate NCE drug discovery projects.

51 David SPIEGEL Yale University, United States

avid Spiegel, MD, PhD is a Professor at Yale University with appointments in the Ddepartments of Chemistry and Pharmacology. He is also the Chief Scientific Advisor and co-founder of Kleo Pharmaceuticals, and serves as Founding Scientific Advisor to Kymera Therapeutics.

he central focus of Professor Spiegel’s research has been the development of novel, small Tmolecule-based strategies for manipulating and regulating human immunity and other biological processes.

ver the course of his career, Dr. Spiegel has co-authored more than 50 peer-reviewed Opublications and has obtained over a dozen patents.

52 PL20 USING SMALL MOLECULES TO ENGINEER AND EXPLORE HUMAN IMMUNITY

David SPIEGEL

YALE UNIVERSITY, New Haven, United States

Research in the Spiegel Laboratory utilizes techniques and insights from organic chemistry to modulate and/or create immunological function. This talk will describe our lab’s recent efforts in this field, which range from complex molecule synthesis to the creation of novel paradigms in immunotherapy. Specific topics to be discussed will include: (1) investigations into advanced glycation end-products (AGEs) – a class of complex, non-enzymatic post-translational modifications of proteins with effects on immune function; (2) rational design and biological characterization of immunomodulatory small molecules.

53 Brian SAFINA Bolt Biotherapeutics, United States

rian Safina, Ph.D., serves as vice president for Bolt Biotherapeutics, where he leads chemistry Band bioconjugation toward developing novel immuno-oncology therapeutics. He joined Bolt in 2018 with over a decade of medicinal chemistry experience at Genentech.

r Safina has made significant contributions to the discovery of multiple clinical candidates Din the areas of oncology, immunology and neuroscience.

r Safina holds a Ph.D. in organic chemistry from the University of California, San Diego, Dwhere he worked in the laboratories of K.C. Nicolaou.

54 PL21 DISCOVERY OF TUMOR-TARGETED TLR7/8 IMMUNE-STIMULATING ANTIBODY CONJUGATES (ISAC): A NEW CLASS OF IMMUNO-ONCOLOGY THERAPEUTICS

Brian Safina

BOLT BIOTHERAPEUTICS, 640 GALVESTON DR, REDWOOD CITY, CA 94063, USA

The clinical success of cancer immunotherapies has reinvigorated the discovery for novel immune stimulants. Selective activation of the innate immune system to generate an adaptive immune response has long been a goal for drug discovery. Systemically delivered small molecule Toll-like receptor (TLR) agonists have been vigorously pursued in the clinic but have suffered from undesirable side-effects, mainly attributed to the inherent mode of action. To overcome these liabilities, we developed an immune-stimulating antibody conjugate (ISAC) platform. ISACs are tumor-targeting monoclonal antibodies that systemically deliver a powerful innate immune-stimulating agent directly to the tumor microenvironment. Pre-clinical data will be presented demonstrating an adaptive immune response leading to durable T cell mediated tumor clearance and surveillance through TLR7/8 agonism. The structure-based design of novel TLR7/8 agonists will be presented. Optimization of TLR7/8 potency, selectivity and linker chemistry will be described in the context of ISAC potency and in vivo efficacy. Bolt’s approach to this new class of immuno-oncology therapeutics demonstrates the promise of the ISAC platform.

55 Vadim DUDKIN Janssen Discovery Sciences, United States

adim Dudkin is Senior Director and Head, RNA & Targeted Therapeutics group within Janssen VDiscovery Sciences, Johnson and Johnson. adim is responsible for leading research teams at La Jolla, CA, Spring House, PA, and South VSan Francisco, CA sites focusing on nucleic acid therapeutics including oligonucleotides and large nucleic acids as well as intracellular and tissue specific targeted modalities. In his previous role at Janssen, Vadim was leading research at Centyrex internal venture. Vadim joined Janssen from Merck, where he was engaged in small molecule, vaccine and siRNA discovery.

56 PL22 INTRACELLULAR AND TISSUE SPECIFIC TARGETING OF THERAPEUTIC MODALITIES

Vadim Dudkin

Janssen Discovery Sciences, 10021 Lansdale, United States

Unlocking the full potential of novel therapeutic modalities including nucleic acid medicines, nanoparticles, and targeted small molecules requires development of strategies for efficient and functional delivery to target cells, especially outside of the liver. The presentation will focus on the discovery and characterization of protein targeting ligands capable of driving receptor mediated uptake and methods of covalent conjugation to nanoparticles and oligonucleotides. Characterization of capacity and kinetics of intracellular uptake of conjugate systems applicable across modality spectrum is described. As a platform application, receptor dependent functional delivery of siRNA has been demonstrated in vitro and in vivo with 5’RACE assay confirming RNAi mechanism of mRNA silencing.

57 Valerie QDEGARD Silverback Therapeutics, United States

alerie Odegard, Ph.D., is the Chief Scientific Officer of Silverback Therapeutics. She has Vover 15 years of experience in immunotherapy drug development across multiple therapeutic areas. Prior to Silverback, Dr Odegard served as Vice President of R&D at Juno Therapeutics, where she was responsible for advancing novel cellular immunotherapies into clinical development. Prior to Juno, she held research leadership positions at Novo Nordisk and Trubion Pharmaceuticals, where she oversaw the discovery and preclinical development of therapeutics for oncology and inflammatory conditions.

r Odegard received her Ph.D. in Immunobiology Dfrom Yale University.

58 PL23 SBT6050, A HER2-DIRECTED TLR8 IMMUNOTAC™ THERAPEUTIC, IS A POTENT HUMAN MYELOID CELL AGONIST WITH TUMOR-LOCALIZED ACTIVITY

Ty Brender, Jamie Brevik, Damion Winship, Heather Metz, Monica Childs, Brenda Stevens, Li-Qun Fan, Hengyu Xu, Ben Setter, Jeffery Adamo, Jenny R. Chang, Michael R. Comeau, Phil Tan, Robert DuBose, Yvette Latchman, Peter Baum, Sean W. Smith, Valerie Odegard

Silverback Therapeutics, Seattle, United states

Clinical development of systemically administered myeloid cell agonists has been hindered by acute toxicities due to peripheral activation of the targeted cell types. Intratumoral administration, the route of delivery typically used for innate immune/myeloid cell agonists, is limited by tumor accessibility and a dependence on abscopal responses. SBT6050, a novel therapeutic comprised of a potent toll-like receptor (TLR) 8 agonist conjugated to a HER2-directed monoclonal antibody, is designed for systemic delivery with tumor-localized activation of human myeloid cells. Unlike other endosomal TLRs, such as TLR7 and TLR9, TLR8 is highly expressed in the human myeloid cells prevalent in tumors, including conventional DCs and macrophages. Agonism of TLR8 in human myeloid cells activates a broad spectrum of anti-tumor immune mechanisms. These activities cannot be replicated by potent agonists for other endosomal TLRs or with clinical agents that only weakly engage TLR8, such as resiquimod. Studies with human immune cells show that SBT6050 potently induces, in a HER2-dependent manner, multiple anti-tumor immune activities, including proinflammatory cytokine and chemokine production, inflammasome activation, direct activation of DCs and indirect T and NK cell cytolytic activity. This activity is dependent upon the ability of the Fc domain of the antibody to engage Fcγ receptors on the surface of myeloid cells, facilitating delivery of the TLR8 agonist payload. Our data indicate the favorable profile of SBT6050 is likely due to activation of endosomal TLR8 by efficient delivery of the TLR8 agonist in conjugate form and TLR8’s unique expression profile. Systemic delivery of a SBT6050 surrogate in mice shows robust single agent efficacy in multiple mouse tumor models. In contrast to observations with small molecule TLR agonists, the SBT6050 surrogate does not induce peripheral cytokine production in mice at effective dose levels, consistent with the localized activity of the molecule. Collectively, these data support the development of SBT6050 for patients with HER2-expressing tumors. More broadly, the data presented here describe a novel therapeutic modality that allows for systemic administration of immune modulators with tissue-localized activity.

59 Vishal VERMA Genentech, United States

ishal Verma obtained his BA from Northwestern University in 2003 and his PhD Vfrom Stanford University in labs of Professor Paul Wender in 2008. He started his drug discovery career at Schering-Plough/Merck and contributed to multiple programs targeting HCV. In 2012, he joined Genentech and has worked on a variety of therapeutic areas including antibody-drug conjugates for oncology & infectious disease and small molecule programs targeting pain, Gram-negative infectious disease, oncology and immunology, contributing to multiple clinical candidate programs.

60 OC04 DISCOVERY OF GDC-0334: A POTENT AND ORALLY BIOAVAILABLE CLINICAL CANDIDATE FOR THE INHIBITION OF TRPA1

Vishal Verma

Discovery Chemistry, Genentech, 1 DNA Way, 94080 South San Francisco, United States

The non-selective cation channel transient receptor potential ankyrin 1 (TRPA1) has been proposed as an irritant sensor of noxious exogenous and chemicals. It is expressed predominantly in primary afferent nociceptive neurons. Of recent interest, multiple genetic studies have been reported that suggest a TRPA1-dependent role in asthma. In the course of our efforts to obtain potent, selective and orally bioavailable inhibitors of TRPA1, we pursued a strategy employing techniques such as increasing potency in an LLE manner, saturating or removing aryl rings, utilizing prodrugs, consideration of crystal packing as well as a large focus on crystal form characterization at an early stage. Through these efforts, we identified GDC-0334 as a potent, orally bioavailable crystalline inhibitor that demonstrated efficacy in both a rat target engagement model as well as in models of efficacy in multiple species. Through extensive investment in CryoEM at Genentech, we have enabled a 3.8Å structure of GDC-0334 bound to TRPA1 that rationalizes its observed activity.

61 James THOMPSON GlaxoSmithKline/University of Strathclyde , United Kingdom

ames Thompson did his undergraduate studies at the University of Cambridge, studying Natural JSciences and graduating in 2016. During his final year, he worked on the total synthesis ofa marine natural product under the supervision of Ian Paterson. He then commenced his PhD studies as a part of the GlaxoSmithKline/University of Strathclyde collaborative PhD programme in 2016, and he is now in his final year of his PhD studies.

uring his PhD he has been working on αV integrin antagonists, supervised by John DPritchard at GlaxoSmithKline and Professor Billy Kerr at the University of Strathclyde.

62 OC05 INVESTIGATING THE CHAMELEONIC PROPERTIES OF RGD INTEGRIN ANTAGONISTS FOR THE TREATMENT OF IPF

James D.F. Thompson (1,2), John M. Pritchard (1), William J. Kerr (2)

1) GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts, SG1 2NY, England 2) Dept. of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow, G1 1XL, Scotland

This work describes an investigation into the unusual permeability of a candidate-quality RGD integrin antagonist (1) for the treatment of Idiopathic Pulmonary Fibrosis, in particular its ability to show chameleonic behaviour depending on the polarity of its environment, as shown in the figure above. The importance of molecular chameleons is gaining appreciation, as new, more difficult-to-drug targets require molecules that fall beyond the ‘rule of 5’, but still possess oral bioavailability. In this case, this behaviour allows for the compound to transiently appear more lipophilic during permeation, then to reveal its polar functionality upon binding. The zwitterionic nature of RGD integrin inhibitors means that obtaining passive permeability is a challenge. During development of 1, it was found to have enhanced permeability over its diastereomer. This enhanced permeability was not predicted, and it was hypothesised that this enhancement may be a conformational effect, since the compounds have identical measured lipophilicities and pKas. Several analogues have been synthesised to investigate how changing the flexibility of the core of the compound affects the permeability. Additionally, the largely untapped resource of 15N NMR has been used in a unique fashion to show the presence of a greater extent of intramolecular hydrogen bonding in 1 than its diastereomer, which is supported by computational investigations and physicochemical experiments. These methods have subsequently been used to rationalise the permeability of other more recent series of RGD integrin antagonists. Based on these findings, work is ongoing to show the use of this method predictively, to allow ranking of possible future targets based on predicted permeability. Initial results of these predictions are very positive. This will aid future medicinal chemistry work, especially for pharmacophores where designing passively permeable compounds is a challenge, such as those beyond the ‘rule of 5’.

63 Nils PEMBERTON AstraZeneca, Sweden

ils Pemberton is Associate Principal Scientist in medicinal chemistry in the Biopharmaceutical Nunit of AstraZeneca R&D in Gothenburg Sweden. Nils carried out his PhD research at Umeå University working with method development in heterocyclic chemistry and design of small molecules targeting virulence factors. This was followed by a postdoctoral position at Gothenburg University working with design and synthesis of chromone based peptidomimetics.

e joined AstraZeneca in 2009 and has more than ten years’ experience of optimizing Hdrugs against a wide range of respiratory and inflammation targets, with particular interest in the field of kinase inhibitor research and lead generation strategies.

64 OC06 DISCOVERY OF AZD3458 A HIGHLY SELECTIVE PI3Kγ INHIBITOR: COMBINING STRUCTURE, HDX-MS AND BINDING KINETICS TO UNDERSTAND THE MODE OF ACTION

Nils Pemberton

Medicinal Chemistry, Respiratory, Inflammation and Autoimmune (RIA), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden

PI3Kγ is a lipid kinase that regulates key immune cell functions and has for several years been an interesting target for inflammatory diseases and more recently also in the immuno-oncology field. It has proven challenging to identify truly selective PI3Kγ inhibitors due to the high sequence homology between the PI3K isoforms (α, β, γ, and δ). In this presentation, the discovery of a new chemotype of PI3Kγ inhibitors exhibiting over 1,000-fold selectivity over PI3Kα and PI3Kβ will be described. HDX-MS in combination with X-ray structures and binding kinetics was used to study the mode of action and show that this highly selective chemical series bind to an active state of PI3Kγ. This is the first examples of PI3K inhibitors with a binding mode that resembles type II protein kinase inhibitors. Optimisation of the series culminated in the discovery of the orally bioavailable clinical candidate AZD3458 a sub-nanomolar PI3Kγ inhibitor which is highly efficacious in an LPS induced acute inflammation in vivo model.

65 Vicky STEADMAN Eurofins Discovery, United Kingdom

icky carried out a PhD and post-doc in total synthesis of macrocyclic natural products at VCambridge University with Prof Ian Paterson and at U Penn with Prof Amos B. Smith, III. Her industrial career initiated at Merck (Terling’s Park) working on neuroscience targets. She then moved to GlaxoSmithKline (Harlow) focussing on anti-infectives and anti-inflammatories. Upon joining Selcia in 2008, she rose from Senior Scientist to Director of Discovery. Upon Selcia’s acquisition by Eurofins in 2017, she became General Manager of Eurofins Integrated Discovery, part of Eurofins Discovery.

icky has a strong track record in innovative medicinal chemistry, and has delivered multiple Vpre-clinical candidates for customers. he is named on around 30 papers and patents Sand is a Fellow of the Royal Society of Chemistry.

66 OC07 THE DISCOVERY OF A POTENT AND ORALLY BIOAVAILABLE MACROCYCLIC CYCLOPHILIN INHIBITOR BASED ON THE STRUCTURAL SIMPLIFICATION OF SANGLIFEHRIN A

Vicky Steadman (1), Richard Mackman (2), David Dean (1), Petr Jansa (2), Karine Poullennec (1), Todd Appleby (2), Carol Austin (1), Caroline Blakemore (2), Ruby Cai (2), Carina Cannizzaro (2), Gregory Chin (2), Jean-Yves Chiva (1), Neil Dunbar (1), Hans Fliri (3), Adrian Highton (1), Hon Hui (2), Mingzhe Ji (2), Haolun Jin (2), Kapil Karki (2), Andrew Keats (1), Linos Lazarides (1), Yu-Jen Lee (2), Albert Liclican (2), Michael Mish (2), Bernard Murray (2), Simon Pettit (2), Peter Pyun (2), Michael Sangi (2), Rex Santos (2), Jonathan Sanvoisin (1), Uli Schmitz (2), Adam Schrier (2), Dustin Siegel (2), David Sperandio (2), George Stepan (2), Yang Tian (2), Gregory Watt (1), Hai Yang (2), Brian Schultz (2)

1) Eurofins Discovery, Fyfield Business and Research Park, Fyfield Road, Essex, CM5 0GS, UK 2) Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA 94404, US 3) Cypralis Ltd., Babraham Research Campus, Cambridge, CB22 3AT, UK

Cyclophilins (Cyp) are a family of peptidyl-prolyl isomerases involved in a range of biological processes implicated in a variety of diseases. Our endeavour was to identify a synthetic, orally bioavailable, non-immunosuppressive small molecule Cyp inhibitor with potent anti-Hepatitis C virus (HCV) activity that could serve as part of an all oral antiviral combination therapy. Our drug discovery approach1 was focussed on the structural simplification of the known Cyp inhibitor natural product Sanglifehrin A. Our efforts resulted in an initial simplified lead 2 which was further optimized using structure based drug design to a potent and orally bioavailable inhibitor 3. The macrocyle ring size was reduced by one atom, and an internal hydrogen bong drove improved permeability and drug-like properties. Macrocycle 3 demonstrates potent Cyp inhibition, potent anti-HCV 2a activity, and high oral bioavailability. The synthetic accesibility and properties of 3 support its potential as an anti-HCV agent and for interrogating the role of Cyp inhibition in a variety of diseases.

References J. Med. Chem, 2018, 61(21), 9473-9499 (1

67 Julian LEVELL Constellation Pharmaceuticals, United States

r Julian Levell is VP of Drug Discovery at Constellation Pharmaceuticals in Boston USA, Dwith responsibility for small molecule research efforts in medicinal chemistry, molecular modelling, structural biology, protein production, DMPK, automation, compound management, biochemistry and biophysics.

ulian carried out his PhD research at Cardiff University on organic photochromic molecules, Jwhich included co-invention of a series of compounds which were incorporated into Transitions™ lenses. He went on to do postdoctoral research at the University of Florida with Prof Alan Katritzky on the development of novel heterocyclic chemistry methodology. Since then, Julian has worked in biotech and pharma research for over 20 years, spending time in California at Centaur Pharmaceuticals, Pennsylvania and New Jersey at Rhone-Poulenc Rorer / Aventis / Sanofi, and in Boston at the Novartis Institutes for Biomedical Research.

uring his career, Julian has led teams and projects across multiple disease areas including Dcardiovascular, diabetes, asthma, neuroscience, and oncology; with 9 programs transitioning through IND. He has also spent time in South Africa to help build drug discovery capabilities at the H3D research center in Cape Town with Prof Kelly Chibale.

ulian has over 40 patents and publications, is a member of American Chemical Society, a Fellow Jof the Royal Society of Chemistry, and is a core member of the NIH National Cancer Institutes (NCI) Experimental Therapeutics (NExT) review committee and Special Emphasis Panel (SEP).

68 OC08 THE BIG IMPACT OF SMALL CHANGES : TOWARDS BEST-IN-CLASS EZH2 AND LSD1 INHIBITORS

Julian Levell

Constellation Pharmaceuticals, Inc., Cambridge MA 02142, USA

We have identified small, but kinetically significant modifications of our proprietary EZH2 and LSD1 scaffolds. Heteroatom and halogen modifications to the ubiquitous EZH2-binding pyridone moiety impart non-obvious changes to the binding kinetics and permeability properties of the parent compounds. Extended conjugation of the aminocyclopropane warhead, which specifically targets the FAD cofactor in the ternary LSD1 complex, modifies the kinetic binding profile and yields adducts which have the potential to expand the therapeutic window. Application of these changes during lead optimization necessitated the development of new assays and new tools to fully appreciate the potential benefits of these changes. Incorporation ultimately led to the identification of clinical candidates for both EZH2 and LSD1.

69 Dirk TRAUNER New York University, United States

irk Trauner was born and raised in Linz, Austria, studied biology and chemistry at the University Dof Vienna, and received his undergraduate degree in chemistry from the Free University, Berlin. He then pursued graduate studies in chemistry under the direction of Prof. Johann Mulzer, with whom he moved to the University of Frankfurt and then back to Vienna where he obtained his Ph.D. Following a stint in the Austrian Army, he became a postdoctoral fellow with Prof. Samuel J. Danishefsky at the Memorial Sloan-Kettering Cancer Center. After two great years in New York City, Dr Trauner joined the Department of Chemistry at the University of California, Berkeley, where he rose through the ranks to become an Associate Professor of chemistry (with tenure) and a member of the Lawrence Berkeley National Laboratory. In 2008, he moved to the University of Munich as a Professor of Chemistry and Chemical Genetics. In the Spring of 2017 he returned to the United States as the Janice Cutler Chair in Chemistry at New York University (Department of Chemistry).

e also holds and appointment at the NYU Langone School of Medicine and is a member Hof the NYU Neuroscience Institute and of the Perlmutter Cancer Center.

70 KL03 CONTROLLING THE FATE AND FUNCTION OF PROTEINS WITH PHOTOPHARMACOLOGY

Dirk H. Trauner

New York University, Department of Chemistry, Silver Center for Arts and Science - 10th Floor, 100 Washington Square East, NY 10003 New York, United States

Photopharmacology endeavors to control biological function with synthetic photoswitches that interact in various ways with their biological targets. These include ion channels, transporters, GPCRs, enzymes, molecular motors, scaffolding proteins, and elements of the cytoskeleton. I will discuss the advantages and disadvantages of photopharmacology and its potential applications in biology and medicine, in particular with respect to controlling cell proliferation, cell migration, and targeted protein degradation. As a self-respecting synthetic chemist, I will be try to sneak in a natural product total synthesis.

References 1) ChemRxiv (preprint) 2019, DOI: 10.26434/chemrxiv.8206688.

71 72 POSTERS

Frontiers of Synthetic Chemistry

73 P001 SYNTHESIS OF N-(2-HALOPYRAZOLYL-2-HYDROXYETHYL)IMIDAZOLES AS POTENTIAL ANTIFUNGAL AGENTS

Aranzazu-Giraldo Sandra Lorena, Portilla Jaime

Universidad de los Andes, Carrera 1 N° 18A- 12, Bogotá, Colombia

Fungal infections have seen increase during the past several decades, becoming a major risk for public health. As a result, around 1.6 million people die annually because of fungal diseases.1 Fluconazole and Voriconazole are the most common medicines for treating diseases cause by fungi.2 However, several factors have limited their antifungal activity, such as drug resistance, narrow antifungal spectrum, low bioavailability and the similarity between mammals and fungi cells.3 For the previous reasons, the discovery of new antifungals is challenging and essential. Herein, we have obtained novel N-(2-halopyrazolyl-2-hydroxyethyl)imidazoles 6 via a four-step sequence starting from ethyl 4,4,4-trifluoroacetoacetate 1 and haloarylhydrazines 2a-g (Scheme 1). Alcohols 6 have the privileged 2-haloaryl-2-hydroxyethyl moiety at position 1 of the imidazolic ring, and thus, have resemblance to some azole drugs.4 This moiety can improve the biological properties by increased flexibility, solubility, absorption and transport of drugs.5

References 1) Cortes, J. C. G.; Curto, M. A.; Carvalho, V. S. D.; Perez, P.; Ribas, J. C. Biotechnol. Adv. 2019, 37, 1-23. 2) Zhao, S.; Zhang, X.; Wei, P.; Su, X.; Zhao, L.; Wu, M.; Hao, C.; Liu, C.; Zhao, D.; Cheng, M. Eur. J. Med. Chem. 2017, 137, 96-107. 3) Emami, S.; Ghobadi, E.; Saednia, S.; Hashemi, S. M. Eur. J. Med. Chem. 2019, 170, 173-194. 4) Kathiravan, M. K.; Salakeb, A. B.; Chotheb, A. S.; Dudhe, P. B.; Watode, R. P.; Mukta, M. S.; Gadhwe, S. Bioorg. Med. Chem. 2012, 20, 5678-5698. 5) Türkmen, H.; Ceyhan, N.; Ülkü Karabay Yavaşoğlu, N.; Özdemir, G.; Çetinkaya, B. Eur. J. Med. Chem. 2011, 46, 2895-2900.

74 P002 A CHEMOSELECTIVE, REGIOSPECIFIC, METAL-, AZIDE- AND HALOGEN-FREE SYNTHESIS OF 1,2,3-TRIAZOLES

Peter. R. Clark (1,2), Glynn. D. Williams (1), Nicholas. C. O. Tomkinson (2)

1) Chemical Development, GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, United Kingdom 2) Department of Pure and Applied Chemistry, University of Strathclyde 295 Cathedral Street, Glasgow, G1 1XL, United Kingdom

The copper catalysed azide-alkyne cycloaddition (CuAAC) pioneered by Sharpless[1] and Meldal[2] has made access to 1,2,3‑triazoles simple and efficient, with applications in diverse areas such as chemical biology, medicinal chemistry, materials and sensors. Using the CuAAC chemistry to synthesise 1,2,3-triazoles on a large scale represents a major industrial challenge. [3] Alkyl azides are highly energetic species which are often produced in‑situ from sodium azide,[4] presenting a fundamental risk of producing copper azide, a powerful friction and shock-sensitive detonator. Whilst there are azide-free methods to synthesise 1,2,3‑triazoles, most involve a multi-step synthesis and use halogens and/or metals with stoichiometric oxidants.[5] Within this discussion we will present the development of a novel, redox-neutral 3-component coupling of α -ketoacetals, tosyl hydrazide and primary amines to form 1,2,3-triazoles in less than 10 minutes.[6] This project addresses key safety issues with CuAAC’s and we show scalability, application and process safety. Further, the method presents a significant advancement in the redox-neutral, azide- and halogen-free synthesis of these heterocycles by providing access to 1,4-, 1,5- and 1,4,5- substituted triazoles regiospecifically in excellent yields. Fundamental aspects of stereochemistry, chemoselectivity and functional group tolerance are also addressed. This one‑pot procedure has potential applications within the fields of chemical biology, medicinal chemistry and the scale-up of important pharmaceutical compounds.

References 1) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew. Chem. Int. Ed. 2002, 41, 2596-2599. 2) C. W. Tornøe, C. Christensen, M. Meldal, J. Org. Chem. 2002, 67, 3057-3064. 3) R. Hanselmann, G. E. Job, G. Johnson, R. Lou, J. G. Martynow, M. M. Reeve, Org. Process. Res. Dev. 2010, 14, 152-158. 4) S. Karlsson, C. Cook, H. Emtenäs, K. Fan, P. Gillespie, M. Mohamed, Org. Process. Res. Dev. 2017, 21, 1668-1674. 5) a) S. S. van Berkel, S. Brauch, L. Gabriel, M. Henze, S. Stark, D. Vasilev, L. A. Wessjohann, M. Abbas, B. Westermann, Angew. Chem. Int. Ed. 2012, 51, 5343-5346; b) H.-W. Bai, Z.-J. Cai, S.-Y. Wang, S.-J. Ji, Org. Lett. 2015, 17, 2898-2901 6) Submitted for publication

75 P003 ENANTIOSELECTIVE C-H BORYLATION CONTROLLED BY A CHIRAL COUNTER-CATION

James L. Douthwaite, Georgi R. Genov, Antti S. K. Lahdenperä, David C. Gibson, Robert J. Phipps

Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK

Ion-Pairing has found widespread use in asymmetric catalysis, with chiral anions being used to control enantioselectivity in a number of organocatalytic and transition metal catalysed processes.1 On the other hand, chiral cations have generally been limited to use in organo- and phase-transfer catalysis,2 as reactions involving transition metals rarely involve anionic intermediates.3 The Phipps group has recently developed a novel bipyridine ligand L, which contains an anionic sulfonate group. Originally designed to control the regioselectivity of iridium catalysed aromatic C–H borylation through hydrogen bonding,4 we have now investigated the effects of changing the associated counter-cation of the ligand from achiral tetrabutylammonium to a chiral quaternary ammonium salt derived from the privileged class of cinchonium cations (cat. 1) to give L* (Figure 1). Using this alternate approach for asymmetric transition metal catalysis, we have been able to realise an enantioselective, desymmetrising C–H borylation reaction, with the sole source of chirality being the counter-cation of the ligand.

We have successfully desymmetrised pro-chiral benzhydrylamide substrates 1 to give chiral borylated products 2 (Figure 2a) with up to excellent levels of enantioselectivity (97% ee) and regioselectivity (16.2:1 rr). These results represent a rare case of an enantioselective desymmetrising reaction at a remote aryl C–H bond.5 Elaboration of the reaction products into complex scaffolds has then been performed site-selectively (>20:1 rr, Figure 2b), giving access to compounds 3 and 4 which contain a range of functional handles, for further transformations, around a single stereocenter.

References 1) K. Brak and E. N. Jacobsen, Angew. Chem. Int. Ed., 2013, 52, 534-561 2) a) T. Hashimoto and K. Maruoka, Chem. Rev., 2007, 12, 5656-5682; b) T. Ooi and K. Maruoka, Angew. Chem. Int. Ed., 2007, 46, 4222-4266; c) S. Shirakawa and K. Maruoka, Angew. Chem. Int. Ed., 2013, 52, 4312-4348 3) a) K. Ohmatsu, N. Imagawa and T. Ooi, Nat. Chem., 2014, 6, 47-51; b) L. Zong, C. Wang, A.M.P Moelijadi, X. Ye, R. Ganguly, Y. Li, H. Hirao and C-H. Tan, Nat. Commun., 2016, 7, 13455 4) H. J. Davis, G. R. Genov and R. J. Phipps, Angew. Chem. Int. Ed., 2017, 56, 13351-13355 5) H. Shi, A. N. Herron, Y. Shao, Q. Shao and J-Q. Yu., Nature, 2018, 558, 581-585 76 P004 ENANTIO- AND DIASTEREOSELECTIVE SUZUKI-MIYAURA COUPLING WITH RACEMIC BICYCLES

F. Wieland Goetzke (1), Roman Kuçera (1), Mike Mortimore (2), Stephen P. Fletcher (1)

1) Department of Chemistry, Chemistry Research Laboratory University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK 2) Vertex Pharmaceuticals (Europe) Ltd, 86-88 Jubilee Avenue, Milton Park, Abingdon OX14 4RW, UK

Asymmetric carbon-carbon bond forming reactions with high functional group tolerance still belong to the biggest challenges for drug design.[1] Especially, enantioselective cross-couplings with non-stabilized nucleophiles remain difficult.[2] Recently our group has reported on a rhodium-catalyzed asymmetric allylic arylation of cyclic racemic halides with (hetero)arylboronic acids.[3,4]

Herein we describe a rhodium catalyzed enantio- and diastereoselective cross-coupling between racemic fused bicyclic allylic chlorides and boronic acids.[5] The highly stereoselective transformation allows for the coupling of aryl-, hetereoaryl- and vinyl boronic acids and gives access to functionalized bicyclic cyclopentenes. This dynamic kinetic transformation (DYKAT) takes advantage of the pseudo-symmetry of the disubstituted starting materials whereas a bicyclic allylic chloride starting material without pseudo-symmetry undergoes a highly enantioselective regiodivergent reaction. We discuss mechanistic aspects of this reaction and show its application in the catalytic asymmetric synthesis of the prostaglandin analogue Tafluprost.[6]

References 1) D. C. Blakemore, L. Castro, I. Churcher, D. C. Rees, A. W. Thomas, D. M. Wilson, A. Wood, Nat. Chem. 2018, 10, 383–394. 2) V. Bhat, E. R. Welin, X. Guo, B. M. Stoltz, Chem. Rev. 2017, 117, 4528–4561. 3) M. Sidera, S. P. Fletcher, Nat. Chem. 2015, 7, 935–939. 4) P. Schafer, T. Palacin, M. Sidera, S. P. Fletcher, Nat. Commun. 2017, 8, 15762. 5) F. W. Goetzke, M. Mortimore, S. P. Fletcher, Angew. Chem. Int. Ed. 2019, 58, 12128–12132. 6) R. Kuçera, F. W. Goetzke, S. P. Fletcher, manuscript in preparation.

77 P005 ECOCATALYZED SYNTHESIS OF VALUABLE THERAPEUTIC MOLECULES

Théo Guerin (1,2), Christophe Waterlot (1), Alina Ghinet (2)

1) Laboratoire Génie Civil et géoEnvironnement (LGCgE), Yncréa Hauts-de-France, 48 boulevard Vauban 59046 Lille Cedex, France 2) Laboratoire de chimie durable et santé, Yncréa Hauts-de-France, 13 rue de Toul 59046 Lille Cedex, France

The Hauts-de-France region has areas whose soils are deeply contaminated with heavy metals (e.g. lead, cadmium and zinc) due to the past industrial activities. Since these contaminants are not biodegradable, they have accumulated over time and are now a source of environmental and health hazards. Several ways were deployed to rehabilitate these soils. Among them, phytotechnologies (e.g. phytoremediation and aided-phytoremediation) appeared to be the most appropriate to these large contaminated areas because the least expensive. This involves producing biomasses on these contaminated soils which are able to accumulate metals and/or metalloids in the roots or aerial parts. Biomasses are then recovered and transformed into plant-based catalysts, also called ecocatalysts or biosourced catalysts. Ecocatalysis concept has been discovered by the team of Pr. Grison a decade ago[1] and led to the filing of numerous patents and publications. Indeed, this technology has proved effective in many different chemical reactions such as Friedel-Crafts alkylation and acylation, Biginelli reaction or Suzuki–Miyaura coupling, using different hyperaccumulating plant species[2] to replace conventional catalysts. In this work, the conception of our heterogeneous ecocatalysts from non-hyperaccumulative biomasses[3] as well as their application in the synthesis of several therapeutic compounds through aza-Michael and amidification reactions are presented. In particular, the synthesis of moclobemide (Scheme 1), a molecule used to treat depression, using several catalysts and ecocatalysts in order to compare their efficiency will be discussed in details. The use of ecocatalysts led to a very simple sustainable synthetic procedure, which generates interesting results in terms of green chemistry metrics.

Scheme 1. Synthesis of marketed moclobemide

References 1) Grison, C., Escande, V., Biton, J. Ecocatalysis: A New Integrated Approach to Scientific Ecology. Elsevier, ISTE Press 2015, 100 pp. 2) Hechelski, M., Ghinet, A., Louvel, B., Dufrénoy, P., Rigo, B., Daïch, A., Waterlot, C. From Conventional Lewis Acids to Heterogeneous Montmorillonite K10: Eco-Friendly Plant-Based Catalysts Used as Green Lewis Acids. ChemSusChem 2018, 11, 1249–1277. 3) Hechelski, M., Waterlot, C., Dufrénoy, P., Louvel, B., Daïch, A., Ghinet, A. Biomass of ryegrass from field experiments: Toward a cost-effective and efficient biosourced catalyst for the synthesis of Moclobemide. Submitted to Green Chemistry Letters & Reviews

78 P006 USING ION-PAIRING TO CONTROL REGIOSELECTIVITY IN IRIDIUM-CATALYSED C-H BORYLATION OF ARENES

Benjamin D. Williams, Madalina T. Mihai, Robert J. Phipps

Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK

Iridium-catalysed C–H borylation has become a powerful synthetic tool for the elaboration of aromatic rings.1 Under standard conditions, the regioselectivity of this functionalisation is almost entirely governed by steric factors with very little influence from electronic effects. Whilst a single borylated product can be obtained from 1,3-disubstituted arenes, mono- and 1,2-disubstituted substrates often lead to an inseparable mixture of regioisomers. Employing non-covalent interactions has proven a successful strategy to control the regioselectivity of this transformation.2 In particular, the Phipps group has utilised an ion-pairing interaction between an anionic sulfonate group on bipyridine ligand L1 and a cationic quaternary ammonium group on the substrate to achieve higher levels of meta C–H borylation (Figure 1a).3 We herein report the studies towards achieving meta-selective borylation of anionic aromatic sulfonates through ion-pairing with cationic ligand L2 (Figure 1b) and how para-selective borylation of these substrates was realised through the use of a bulky counter cation (Figure 1c).

We have successfully expanded the scope of the para-selective borylation through temporary sulfonation of a range of common aromatic building blocks (see selected examples in Figure 2).4 Simple synthesis of substrates, use of commercially available ligands and facile sulfonate removal all result in an attractive method for the construction of highly functionalised aromatics with good to excellent selectivities. Ongoing efforts are being made to pursue the complementary meta-directed borylation of these substrates.

References 1) Hartwig, J. F. Acc. Chem. Res. 2012, 45, 864–873. 2) Davis, H. J.; Phipps, R. J. Chem. Sci. 2017, 8, 864–877. 3) Davis, H. J.; Mihai, M. T.; Phipps, R. J. J. Am. Chem. Soc. 2016, 138, 12759–12762. 4) Mihai, M. T.; Williams, B. D.; Phipps, R. J. J. Am. Chem. Soc. 2019, 141, 15477–15482. 79 P007 THE HIGH-PRESSURE MEDIATED CYCLOADDITION OF THIOCARBONYL YLIDES: APPLICATIONS AND LIMITATIONS

Franz-Lucas Haut, Christoph Habiger, Thomas Magauer

Institute of Organic Chemistry and Center for Molecular Biosciences, Leopold-Franzens-University Innsbruck, Innrain 80−82, 6020 Innsbruck, Austria

Here we present a comprehensive study on the [3+2]-cycloaddition of thiocarbonyl ylides with a wide variety of alkenes and alkynes. The obtained dihydro- and tetrahydrothiophene products serve as exceptionally versatile intermediates providing access to thiophenes, dienes, dendralenes, and vic-quarternary carbon centers. The use of high-pressure conditions enables thermally unstable, sterically encumbered or moderately reactive substrates to undergo the cycloaddition under mild conditions, thereby increasing the yield by up to 58%. In addition, we showcase its utility by the formal syntheses of the pharmaceuticals NGB 4420 and tenilapine.

References 1) F.-L. Haut, C. Habiger, K. Speck, K. Wurst, P. Mayer, J. N. Korber, T. Müller, T. Magauer J. Am. Chem. Soc. 2019, 141, 13352–13357. 2) K. Speck, T. Magauer Chem. Eur. J. 2017, 23, 1157−1165. 3) N. Winter, D. Trauner J. Am. Chem. Soc. 2017, 139, 11706−11709. 4) M. Aono, Y. Terao, K. Achiwa Heterocycles 1995, 40, 249−260.

80 P008 TOWARD A SELECTIVE SYN-BIMANE FLUORESCENT PROBE FOR ALDOLASE CLASS-1

Joy Karmakar, Flavio Grynszpan

Department of Chemical Sciences, Ariel University, Ariel, 40700, ISRAEL, Email: [email protected]

Bimanes are low molecular weight heterocyclic molecules discovered by Kosower and coworkers four decades ago.1 Recently, the original synthesis has been modified by our group using a user-friendly green chemistry approach.2 Some syn-bimanes (e.g., 1) are of special interest due to their striking luminescence properties. Numerous bimane derivatives have been reported over the years. Among them, monobromobimane (2), which has been extensively used as a fluorescent tag for biologically occurring thiols.3 The α- position Iodo-derivative (3) of bimane 1 has also been reported previously and used for C-C couplings with acetylenes.4 We have recently modified the synthesis of 3, reducing the number of steps and allowing the multigram scale preparation of this useful intermediate. For instance, the novel aldehyde substituted fluorescent probe (4) was prepared following this approach. In principle, this probe will selectively react with nucleophilic amines leading to a fluorescent modification. As an example, Aldolase A presents a nucleophilic amine group in its active site which will be targeted by 4. The formation of a protonated Schiff base of 4 with the enzyme (5) is expected to result in a distinct fluorescent beacon. Synthesis and characterization of 4, as well as preliminary results regarding the corresponding imine formation, will be presented.

References 1) Kosower, E. M.; Pazhenchevsky, B. Bimanes. 5. Synthesis and Properties of syn- and anti-1,5-Diazabicyclo[3.3.0]Octadienediones (9,10-Dioxabimanes). J. Am. Chem. Soc. 1980, 102 (15), 4983–4993. 2) Neogi, I.; Das, P. J.; Grynszpan, F. Dihalogen and Solvent-Free Preparation of syn- Bimane. Synlett 2018, 29 (8), 1043–1046. 3) Kosower, N. S.; Kosower, E. M.; Newton, G. L.; Ranney, H. M. Bimane Fluorescent Labels: Labeling of Normal Human Red Cells under Physiological Conditions. Proc. Natl. Acad. Sci. 1979, 76 (7), 3382–3386. 4) Kosower, E. M.; Ben-Shoshan, M. Bimane Acetylenes and Diacetylenes. Bimanes. 33. J. Org. Chem. 1996, 61 (17), 5871–5884.

81 P009 SYNTHESIS, PHARMACOLOGICAL AND STRUCTURAL STUDIES OF MULTI-TARGET INDOLE DERIVATIVES

Magda Kondej (1), Tomasz M. Wróbel (1,2), Andrea G. Silva (3), Piotr Stępnicki (1), Oliwia Koszła (1), Ewa Kędzierska (4), Agata Bartyzel (5), Grażyna Biała (4), Dariusz Matosiuk (1), Maria I. Loza (3), Marián Castro (3), Agnieszka A. Kaczor (1,6)

1) Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodźki St., PL-20093, Lublin, Poland 2) Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark 3) Department of Pharmacology, Universidade de Santiago de Compostela, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Avda de Barcelona, Santiago de Compostela, E-15782, Spain 4) Department of Pharmacology and Pharmacodynamics, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodźki St., PL-20093, Lublin, Poland 5) Department of General and Coordination Chemistry, Maria Curie-Skłodowska University, M. Curie-Skłodowskiej Sq. 2, PL-20031, Lublin, Poland 6) School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, FI-70211, Kuopio, Finland

Schizophrenia is a chronic and severe mental disorder that affects how a person thinks, feels, and behaves. The pathomechanism is not fully understood but involves many neurotransmitters and their receptors [1]. Here we present synthesis, structural,thermal and pharmacological studies of 3-(1,2,3,6-tetrahydropyridin-4-yl)-1 H-indoles. These compounds were designed as modifications of the experimentally confirmed virtual hit, D2AAK1, and synthesized from indole or 5-alkoxyindoles and N-substituted piperidin-4-ones in methanol in the presence of potassium hydroxide (Fig. 1).

Figure 1. Reaction scheme.

The docking poses of new compounds in the orthosteric pockets of dopamine D2 and serotonin 5-HT1A and 5-HT2A receptors are comparable and correspond to the previously reported bonding mode of the virtual hit D2AAK1 [2]. One of the synthesized compound was selected for X-ray studies to get knowledge about its energetically stable conformation in the solid state. The interatomic distances and angles for this compound are in agreement with those described in the literature and are similar to those observed for the other closely related indole derivatives. The analysis of SAR indicated the bulkiness of 5-alkoxy substituent is not favorable for activity while the effect of N-methyl aryl substituent is less important. The compound with the most favorable multi-receptor profile was subjected to in vivo investigations [3]. In summary, the new multi-target compounds have a good multi-receptor properties and can contribute to the development of better and more effective treatment of schizophrenia. The above research is part of the project implemented by OPUS 2017/27/B/NZ7/01767.

References 1) M. Kondej, et al., Multi-target approach for drug discovery against schizophrenia, Int. J. Mol. Sci. 19 (2018) 3105. 2) A.A. Kaczor, et al., Structure-based virtual screening for dopamine D2 receptor ligands as potential antipsychotics, ChemMedChem 11 (2016) 718–729. 3) M. Kondej, et al., Synthesis, pharmacological and structural studies of 5-substituted-3-(1-arylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles as multi-target ligands of aminergic GPCRs, Eur.J.Med.Chem. 180 (2019) 673–689.

82 P010 DISCOVERY AND RATIONALIZATION OF ENERGY-TRANSFER-ENABLED CYCLIZATION REACTIONS USING A COMBINED SCREENING APPROACH

Felix Strieth-Kalthoff (1), Christian Henkel (2), Michael Teders (1), Axel Kahnt (3), Wolfgang Knolle (3), Adrián Gómez-Suárez (1), Konstantin Dirian (2), Wiebke Alex (2), Klaus Bergander (1), Constantin G. Daniliuc (1), Bernd Abel (3), Dirk M. Guldi (2), Frank Glorius (1)

1) Westfälische Wilhelms-Universität Münster, Organisch-Chemisches Institut, Corrensstr. 40, 48149 Münster, Germany 2) Friedrich-Alexander-Universität Erlangen-Nürnberg, Department Chemie und Pharmazie, Lehrstuhl für Physikalische Chemie I, Egerlandstr. 3, 91058 Erlangen, Germany 3) Leibniz-Institut für Oberflächenmodifizierung e.V., Permoserstr. 15, 04318 Leipzig, Germany

The discovery of novel reactivity patterns, along with their synthetic applications, is a key challenge for organic chemists. While knowledge-guided reaction design is widely established, many ground-breaking discoveries, however, were the result of experimental serendipity. For this reason, serendipity-based screening protocols have emerged as a powerful, complementary apporach towards the discovery of novel reactivity during the last 20 yeras.[1] Herein, a two-dimensional synergistic screening approach is reported. The combination of mechanism-based[2] and reaction-based[3] screening allows for rapid access to a number of unprecedented photocatalytic transformations.

By this strategy,[4] two unforeseen visible-light-mediated cyclization reactions, yielding fused cyclobutane or cyclobutene scaffolds, could be discovered: The energy transfer activation of benzothiophenes, giving access to dearomatized scaffolds, was investigated in detail using advanced spectroscopic techniques (transient absorption spectroscopy and pulse radiolysis), substantiating an endergonic "uphill" energy transfer event. Using enones as quenchers, an unforeseen cycloaddition–rearrangement cascade was discovered and elaborated.

The presented two-dimensional screening approach cann offer the potential to serve as a versatile, efficient statregy for the discovery of unpredicted reactivity modes – eventually generating the framework for rational reaction design.

References 1) K. D. Collins, T. Gensch, F. Glorius, Nat. Chem. 2014, 6, 859–871. 2) M. N. Hopkinson, A. Gómez-Suárez, M. Teders, B. Sahoo, F. Glorius, Angew. Chem. Int. Ed. 2016, 55, 4361–4366. 3) A. McNally, C. K. Prier, D. W. C. MacMillan, Science 2011, 334, 1114–1117. 4) F. Strieth-Kalthoff, C. Henkel, M. Teders, A. Kahnt, W. Knolle, A. Gómez-Suárez, K. Dirían, W. Alex, K. Bergander, C. G. Daniliuc, B. Abel, D. M. Guldi, F. Glorius, Chem 2019, 5, 2183–2194.

83 P011 NEW COVALENT pROBES: FRAGMENT-BASED DISCOVERY OF POTENT BRD-4 INHIBITORS

Tatiana Matviyuk, Anton Zhemera, Timur Savchenko, Sergey Zozulya

Enamine Ltd, 78 Chervonotkatska Str., 02094 Kyiv, Ukraine

Covalent fragment-based approach followed by “SAR by catalog” was used for the discovery of bromodomain-containing protein 4 (BRD4) inhibitors. Initial screening against bromodomain 1 of BRD4 based on the thermal shift assay (TSA) commenced from the library of 3695 fragment library. After verification of initial data, 73 fragments were identified as hits. A follow-up library was constructed by selection of analogs available by parallel synthesis and in-stock screening collection. Herein, we describe our approaches and optimization process to parallel synthesis of sulfonyl fluorides that resulted in enumeration of hit follow-up libraries. Screening of the synthesized sets using TSA, followed by re-testing at several concentrations, counter-screen, and TR-FRET assay resulted in 18 hits. Compounds derived from the initial fragment hits showed at least 3–5-fold better hit rate. Finally three compounds with IC50 = 1.9–7.4 μM were identified, and docking poses in the BRD4 binding site were predicted.

84 P012 DISCOVERY AND DEVELOPMENT OF A NOVEL ESTERIFICATION REACTION ENABLED BY HIGH-THROUGHPUT EXPERIMENTATION

Andrew McGrath (1), Khadija Shafiq (1,2), Tim Cernak (1)

1) Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA 2) Department of Biological Sciences, College of Science, California Polytechnic University, Pomona, CA, 91678, USA

Coupling reactions are important tools in the arsenal of the medicinal chemist. A wide diversity of commercially available building blocks provide the ability to sample diverse pockets of chemical space using coupling reactions. Current practice favors the use of a narrow subset of coupling reactions with a broad diversity of building blocks. We endeavor to explore an approach that uses a narrow subset of building blocks, and a broad diversity of coupling reactions. Towards this objective, we will report in this poster the development of a novel esterification reaction, which operates through C–N bond activation. This unorthodox reaction was discovered and optimized using high-throughput experimentation. High-throughput synthesis revealed an interplay of substrate and reaction conditions. This poster will detail our discovery and development of this new esterification reaction using high-throughput and automated synthesis.

85 P013 A BIOMIMETIC SYNTHESIS ELUCIDATES THE ORIGIN OF PREUISOLACTONE A

Alexander Novak, Claire Grigglestone, Dirk Trauner

Department of Chemistry, New York University, Silver Center, 100 Washington Square East, Room 712, New York, New York, 10002, United States

Preuisolactone A is a recently isolated, racemic natural product from the endophytic fungus Preussia isomera. It is marked by a caged structure that contains seven adjacent stereocenters, two of which are quarternary. Biosynthetically, preuisolactone A was proposed to be formed via the terpene pathway featuring several oxidative editing steps. We propose an alternative biosynthetic hypothesis and have completed a short, biomimetic synthesis that follows our proposal. Its features are a purpurogallin-type [5+2]-cycloaddition, followed by a retro-Dieckmann reaction, vinylogous aldol addition, oxidative lactonization and a final, unprecedented benzilic acid rearrangement. The synthesis furnished preuisolactone A in essentially three steps in high overall yield. Our work explains why preuisolactone A has been isolated as a racemate and suggests that it is not a terpenoid but a phenolic polyketide.

References 1) J. Am. Chem. Soc. 2019, 141, 15515−15518.

86 P014 SYNTHESIS AND APPLICATIONS OF 4,5-DISUBSTITUTED CARBAZOLES

Ian A. Pocock, Alya Alotaibi, Kesar Jagdev, Connor Prior, Richard S. Grainger

School of Chemistry, University of Birmingham, Birmingham, B15 2TT, UK

First isolated in 1872,1 9H-carbazole and its derivatives represent a privileged scaffold, found widely in the fields of natural products and medicinal chemistry,2 optoelectronics,3 and organic light-emitting materials.4 Despite the importance of these structures, synthetic methods towards direct C4 functionalisation of carbazole are limited to just one,5 with difunctionalisation at C4 and C5 unreported. Existing methods for the preparation of 4,5-disubstituted carbazoles requires construction of the core heterocycle as the key bond-forming step, often leading to lengthy syntheses.6 We have developed an efficient strategy for the synthesis of 4,5-disubstituted carbazoles via regioselective dilithiation and electrophilic trapping. In this presentation, we report on the scope of this transformation as well as investigate the synthetic applications of the products.

References 1) Graebe, C.; Glaser, C. Ber. Dtsch. Chem. Ges. 1872, 5, 12. 2) a) Yaqub, G.; Hussain, E. A.; Rehman, M. A.; Mateen, B. Asian J. Chem. 2009, 21, 2485–2520; b) Schmidt, A. W.; Reddy, K. R.; Knölker, H-.J. Chem. Rev. 2012, 112, 3193–3328; c) Głuszyńska, A. Eur. J. Med. Chem. 2015, 94, 405–426; d) Issa, S.; Prandina, A.; Bedel, N.; Rongved, P.; Yous, S.; Borgne, M. L.; Bouaziz, Z. J. Enzyme Inhib. Med. Chem. 2019, 34, 1321–1346. 3) a) Li, J.; Grimsdale, A. C. Chem. Soc. Rev. 2010, 39, 2399–2410; b) Sathiyan, G.; Sivakumar, E. K. T.; Ganesamoorthy, R.; Thangamuthu, R.; Sakthivel, P. Tetrahedron Lett. 2016, 57, 243–252. 4) a) Jiang, H.; Sun, J.; Zhang, J. Curr. Org. Chem. 2012, 16, 2014–2025; b) Yumiao, S.; Haijuan, L.; Wenmu, L. Prog. Chem. 2015, 27, 1384–1384; c) Wex, B.; Kaafarani, B. R. J. Mater. Chem. C 2017, 5, 8622. 5) Leitch, J. A.; Heron, C. J.; McKnight, J.;Kociok-Köhn, G.; Bhonoah, Y.; Frost, C. G. Chem. Commun. 2017, 53, 13039. 6) Knölker, H.-J. Chem. Letts. 2009, 38, 8–13; Roy, J.; Jana, A. K.; Mal, D. Tetrahedron 2012, 68, 6099–6121. 87 P015 DEAMINATIVE STRATEGY FOR VISIBLE-LIGHT-MEDIATED C–B AND C–C BOND FORMATION VIA ELECTRON-DONOR-ACCEPTOR COMPLEXES

Frederik Sandfort, Felix Strieth-Kalthoff, Michael J. James, Felix J. R. Klauck, Frank Glorius

Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstr. 40, 48149 Münster, Germany

The activation of aliphatic amines for nucleophilic substitution reactions via the formation of pyridinium salts was introduced by Katritzky 30 years ago.[1] Recently, chemists have become interested in the use of these redox-active Katritzky salts as single electron acceptors in Nickel and photoredox catalysis to generate alkyl radicals from the corresponding amines in a deaminative manifold.[2,3] Herein, we present the use of these pyridinium salts in electron-donor-acceptor complexes for C–B and C–C bond formation.[4,5] The transformations do not require any (photo)catalyst and proceed under mild, visible-light-mediated conditions. The key electron-donor-acceptor complexes were characterized in detail by both experimental and computational investigations.

References 1) A. R. Katritzky, U. Gruntz, D. H. Kenny, M. C. Rezende, H. Sheikh, J. Chem. Soc. Perkin Trans. 1 1979, 430. 2) C. H. Basch, J. Liao, J. Xu, J. J. Piane, M. P. Watson, J. Am. Chem. Soc. 2017, 139, 5313. 3) F. J. R. Klauck, M. J. James, F. Glorius, Angew. Chem. Int. Ed. 2017, 56, 12336. 4) F. Sandfort, F. Strieth-Kalthoff, F. J. R. Klauck, M. J. James, F. Glorius, Chem. Eur. J. 2018, 24, 17210. 5) M. J. James, F. Strieth‐Kalthoff, F. Sandfort, F. J. R. Klauck, F. Wagener, F. Glorius, Chem. Eur. J. 2019, 25, 8240.

88 POSTERS

Structure and Biophysics - Companions for Medicinal Chemistry

89 P021 EFFECT OF 2ND AND 3RD GENERATION PAMAM DENDRIMERS ON PRO-INFLAMMATORY CYTOKINES IN HUMAN KERATINOCYTES AND FIBROBLASTS

Anna Bielawska (1), Robert Czarnomysy (2), Krzysztof Bielawski (2)

1) Medical University of Bialystok, Department of Biotechnology, Kilinskiego 1, 15-089 Bialystok, Poland 2) Medical University of Bialystok, Department of Synthesis and Technology of Drugs, Kilinskiego 1, 15-089 Bialystok, Poland

PAMAM dendrimers are able to improve dermal therapy efficiency due to their capability to enhance drug molecule permeability through the membranes, to improve drug solubility and pharmacological activity. In addition, thanks to the hydrophilic outer shells and the hydrophobic interiors, they can act as effective penetration enhancers. For example, a study using ketoprofen and dilfunisal (in vitro permeation studies on excised rat skins) showed that PAMAM dendrimers significantly enhanced the steady-state flux of both drugs compared with the drug suspensions without PAMAM dendrimers. Poly(amidoamine) (PAMAM) dendrimers are of considerable interest when used as a carrier for topical drugs for the skin, although little is known about their possible side effects. A good in vitro model for testing skin diseases are keratinocytes and fibroblasts. Keratinocytes occupy an important place in the immune response of the skin by the release of pro-inflammatory chemokines, cytokines, proteases, growth factors, and matrix metalloproteinases. These cells also recruit, stimulate and coordinate the activities of many types of cells involved in healing and recapitulate the epidermal barrier layer of the skin. Fibroblasts are cells necessary for tissue repair. They are one of the first cells that appear in damaged places. Inflammatory response induced by nanoparticles may have a toxic mechanism, and in this study we highlighted the inflammatory mediators (IL-6, IL-8 IL-1β) induced by PAMAM dendrimers. We noticed that the secretion level of all three inflammatory mediators, following the exposure of fibroblasts and keratinocytes to PAMAM dendrimers, is dependent on dendrimer concentration and generation. An increase in IL-1β secretion occurred from the lowest concentration of PAMAM dendrimers used in the study (0.3 mg/ml). In turn, in the case of IL-6 and IL-8, this increase began at a concentration of 1.5 mg/ml. Interestingly, in the case of both of these cytokines at 0.3 mg/ml, we observed a decrease in the interleukin concentration below the control. In addition, the inflammatory path induced by the tested compounds was caused by damage in the mitochondria, which we observed as a significant decrease in the mitochondrial membrane potential. The results of our study showed that PAMAM dendrimers can cause disorders of cell proliferation and differentiation and may be the cause of cell cycle deregulation and chronic adverse inflammation. It is well known that in the inflammatory process the primary inflammatory cytokine interleukin-1β (IL-1β) induces IL-6 expression. We also observed this trend in our work. In response to epidermal injuries or certain pathologic conditions, epidermal keratinocytes not only produce pro-inflammatory cytokines, but also migrate to sites of injury and enable weakening of intercellular adhesions such as desmosomes. Some preparations cause a disruptor in the metabolism of keratinocytes and their abnormal keratosis, consisting of the separation of individual cells in the spinous layer, with formation of horn seeds and the formation of so-called round cells that we also observed in our study. Our research has shown that PAMAM dendrimers of the second and third generation may be the cause of chronic inflammation in skin-derived human keratinocytes and fibroblasts. Cell proliferation inhibition was dose-dependent and the most significant decrease in survival was observed with the 3rd generation PAMAM dendrimers. Therefore, at the stage of designing nanocarriers based on dendrimers to deliver the drug into the skin, low carrier concentration should be preferred and the use of the 2nd PAMAM should be considered.

90 P022 CYTOTOXICITY OF 2ND AND 3RD GENERATION PAMAM DENDRIMERS IN HUMAN KERATINOCYTES AND FIBROBLASTS

Krzysztof Bielawski, Robert Czarnomysy

Department of Synthesis and Technology of Drugs, Medical University of Bialystok, Kilinskiego 1, 15-089 Bialystok, Poland

In medicine, one of the most commonly used groups of nanoparticles as drug carriers are dendrimers. Dendrimers are created by gradually adding polymer layers around the central core, thus creating subsequent generations. A unique feature of these structures is their polyvalence, which is directly related to the occurrence of many different functional groups on their surface. Dendrimers also enable precise control of the size, shape, and distribution of functional groups on the surface of the carrier, which is desirable in drug design. Dosing the drug to the skin with microparticles and nanocarriers could significantly improve the treatment of many skin diseases. In any case, toxicological and environmental safety of micro- and nanoparticles should be considered with great caution. For this reason, it is important to determine their toxicity on skin-derived keratinocytes and fibroblasts. They are two of the main cell types that react to the inflammatory phase in the skin repair/regeneration process. The aim of the study was to investigate the influence of 2nd and 3rd generation PAMAM dendrimers on keratinocyte and fibroblast skin cells. The effect of the tested compounds on collagen biosynthesis was determined using 5[3H]-proline incorporation bioassay. Morphological changes accompanying cell growth inhibition were observed using a confocal microscope. To evaluate the percentage of apoptotic/necrotic cells and the cell growth dynamic of apoptotic features, we performed Annexin V/PI double staining assay, assessed caspase activity, and performed cell cycle analysis by flow cytometry. The observed decrease of collagen biosynthesis is directly proportional to dendrimer concentration and generation. The higher the concentration and the higher the nanoparticle generation, the greater the decrease. Disturbed biosynthesis of this protein, which increases with the diameter of the nanoparticles, although it may appear to contradict commonly accepted views of increased toxicity with a reduced size of nanoparticles, but can be explained in terms of linear correlation with the number of surface amino groups of PAMAM dendrimers. The process of apoptosis is closely related to proteins called caspases. In our study, we observed an increase in the active forms of caspase-3 and -8. Differences in caspase-3 activity are consistent with a trend similar to caspase-8. In both cases, the activity profile and percentage activity compared to the control depend on the generation and concentrations of the dendrimer. Our results suggest that apoptosis of fibroblasts and keratinocytes in the presence of PAMAM dendrimers follows the mitochondrial pathway, with a decrease in mitochondrial membrane potential, as well as the extrinsic pathway with a significant increase in expression and caspase-8. As assessed by means of a flow cytometer, there was an increase in the number of apoptotic cells in each of the tested concentrations of PAMAM dendrimers. With increasing concentrations, not only was there an increase in the number of apoptotic cells, but at the highest concentration of 3.0 mg/ml of third generation dendrimers a significant increase in the number of necrotic cells was observed. This was particularly noticeable in the case of fibroblasts. Significantly higher cell death as a result of necrosis after treatment with higher concentrations of third generation dendrimers may suggest a disorganization of cell proliferation. In addition, along with the increase in apoptosis/necrosis of fibroblasts and keratinocytes, we noticed cell cycle abnormalities. The cell cycle was stopped mainly in phase S. The observed phenomenon of S-phase arrest can lead to numerous mutations, and ultimately cell death. Furthermore, abnormal cell proliferation, which results from cell cycle deregulation, might even lead to neoplastic changes.

91 P023 CRYO-EM AND X-RAY FREE ELECTRON LASER ENABLED STRUCTURE BASED DRUG DISCOVERY ON CHALLENGING MEMBRANE PROTEIN TARGETS

Michael Hennig

leadXpro AG, PARK INNOVAARE, CH-5234 Villigen, Switzerland

Due to their central importance in many physiological processes, membrane proteins are drug targets for around 60% of all approved drugs. Structure based drug discovery on soluble proteins is managed well within the project timelines and portfolio changes in pharmaceutical industry, but transmembrane proteins remain a significant challenge because of their difficulty to be expressed, purified and made them work for biophysical methods and structural investigation. Consequently, membrane proteins needyet to be fully exploited for structure based drug design and high resolution three dimensional structure of complexes with potential drug molecules will significantly facilitate the drug discovery process. Based on the preferred access to the SLS/SwissFEL at the Paul Scherrer Institute and the cryo-EM facility of the University of Basel (C-CINA), leadXpro is able to screen, optimize and structurally characterize small molecule and biotherapeutics in complex with protein drug targets timely to impact the drug discovery of novel therapeutics. Showcase examples will include the structure determination of the chemokine receptor CCR2, an emerging target for inflammation, arthritis and oncology by serial crystallography. Here we explore structural details of ligand binding at the orthosteric and allosteric binding sites to address challenges on drug efficacy and specificity. Furthermore, examples of high resolution cryo-EM structures of a human TRPV with bound small molecule agonist as well as an antibiotics transporter target. In August 2018, the SwissFEL facility was used for the very first biostructure experiments. This new facility enables more physiologically relevant room temperature structures giving essential data on protein flexibility at the ligand binding site and new insights for computational chemistry. Furthermore, femtosecond X-ray pulses enable monitoring and capturing of dynamic processes of ligand binding and associated conformational changes with great impact to the design of candidate drug compounds.

References 1) Renaud, J-P., Chung, C-W., Danielson, U.H., Egner, U., Hennig, M., Hubbard, R.E., Nar, H. Biophysics in drug discovery : impact, challenges and opportunities. Nature Reviews Drug Discovery 15, 679-698 (2016). 2) Weinert, T., et al. Serial millisecond crystallography for routine room-temperature structure determination at synchrotrons. Nature Communication, 8, 542 (2017). 3) Cheng, R.K.Y., Abela, R. & Hennig, M., X-ray free electron laser: opportunities for drug discovery, Essays in Biochemistry 61, 1-14 (2017). 4) Apel, A-K., et al. Crystal structure of CC chemokine receptor 2A in complex with an orthosteric antagonist provides insights for the design of selective antagonists. Structure 27, 1-12 (2019), https://doi.org/10.1016/j.str.2018.10.027

92 POSTERS

Protein Degradation: New Rules for Drug Discovery

93 P031 DEVELOPMENT OF OSMI-4-BASED BIOCHEMICAL PROBES FOR OGT

Aleša Bricelj (1), Elena Maria Loi (1), Martina Gobec (1), Christian Steinebach (2), Michael Gütschow (2), Roland J. Pieters (3), Izidor Sosič (1), Marko Anderluh (1)

1) University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia 2) University of Bonn, Pharmaceutical Institute, An der Immenburg 4, 53121 Bonn, Germany 3) Department of Chemical Biology & Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

Enzyme O-GlcNAc transferase (OGT) can be found in metazoan cells and is responsible for posttranslational protein modification of serine and threonine residues by the addition of N-acetyl-d-glucosamine. By altering the stability, localisation, activity and biological interactions of the modified proteins, O-GlcNAcylation is involved in regulating gene expression, metabolism, cellular stress responses, insulin signalling and proteostasis in response to nutrient availability.1 Elevation of OGT levels has been observed in insulin resistance, diabetic complications and numerous cancer types,2,3 which has prompted the development of OGT inhibitors, such as the low nanomolar inhibitor OSMI-4.4 Interestingly, the compound and its analogue OSMI-2 failed to produce an effective OGT inhibition due to rebound enzyme expression followed after the prolonged cell treatment.4 It is therefore questionable whether a sustainable therapeutic effect can be achieved, even if using a potent enzyme inhibitor. To deepen our understanding of OGT biology, reliable probes are needed, e.g. fluorescent probes or proteolysis-targeting chimeras (PROTACs). The latter are chimeric molecules that utilise the ubiquitin-proteasome system to induce proteolytic degradation of targeted proteins. They are composed of three parts: a ligand for the E3 ligase, a ligand binding to the protein of interest (POI), and a linker connecting the two. The mechanism of action allows PROTACs to induce the degradation of the targeted protein in low concentrations and with high selectivity.5 Building on OSMI-4 as the ligand binding to the POI, we modified its structure by derivatisation of the carboxylic acid which subsequently allowed us to attach various linker-pomalidomide conjugates from our PROTAC toolbox6 using click chemistry. All molecules were evaluated for their binding affinity to OGT and their ability to induce the degradation of the targeted protein in several cell lines. Our approach could result in a sustainable therapeutic response by defeating the enzyme overexpression.

References 1) Walker, S. et al. Annu. Rev. Biochem. 85:1, 631-657 (2016) 2) Ferrer CM. et al. J Mol Biol. 428,16, 3282-3294 (2016) 3) Ma, J. and Hart, GW. Expert Rev Proteomic.10(4), 365–380 (2013) 4) Martin S. et al. JACS. 140(42), 13542–13545 (2018) 5) Lai, AC. and Crews, CM. Nat. Rev. Drug Discov. 16(2), 101–114 (2017) 6) Steinebach, C. et al. Med. Chem. Commun. 10, 1037-1041(2019) 94 POSTERS

Innovation and Inspiration from Natural Products

95 P041 MACROLIDE INSPIRED MACROCYCLES AS A PROMISING TEMPLATES FOR CHALLENGING TARGETS

Sulejman Alihodzic

Fidelta Ltd, Prilaz baruna Filipovica 29, 10000 Zagreb, Croatia

Many of the recently identified targets in the last decade fall into the broad category of protein-protein interactions characterised with key binding interactions spread over the wide and flat protein surfaces. Such interaction sites are mainly intractable with traditional small molecule drugs. This has resulted in efforts to exploit the chemical space of natural products and macrocyclic molecules [1]. Macrocycles belong to a middle chemical space with properties between small molecules and biologicals, and although they do not follow Lipinski rule of 5, they do have druggable PhysChem properties [2]. Novel macrolide inspired macrocyclic library is prepared using FideltaMacroTM technology. It was built using our long-term experience and in-house knowledge on the chemistry and pharmacology of this class [3-5]. Macrocycles are designed to diversify and enrich chemical space with different ring sizes, a variety of 3D shapes and potential pharmacophoric features with the aim to maintain the attractive PK and ADME profile. PhysChem properties have been measured and modulated using high-throughput chromatographic determination of lipophilicity and permeability parameters. Target based approach as well as phenotypic screening in anti-inflammatory area has been performed and several promising chemical scaffolds have been identified. We will present recent results on the first generation of our macrolide inspired macrocyclic library including in vitro screening, pharmacokinetic data as well as in vivo proof of concept.

References 1) Dougherty PG et al. Macrocycles as protein-protein interaction inhibitors. Biochem J 2017; 474(7):1109-1125. 2) Alihodzic S et al. Current Trends in Macrocyclic Drug Discovery and beyond-Ro5, Prog Med Chem 2018; 57(1):113-233. 3) Stepanic V et al. Physico-chemical profile of macrolides and their comparison with small molecules, Eur J Med Chem 2012; 47(1):462-472. 4) Fajdetic A et al. Seco Macrolide Compounds, WO2017194452A1. 5) Arsic B et al. Macrolides: Properties, Synthesis and Applications. Berlin: De Gruyter; 2018.

96 P042 BIO-SOURCED ANTIFUNGAL AGENTS FOR CROP PROTECTION WITH NO IMPACT ON ENVIRONMENT AND HUMAN HEALTH

Audrey Damiens (1), Ali Siah (2), Muriel Billamboz (1)

1) Ecole des Hautes Etudes d’Ingénieur (HEI), Yncréa Hauts-de-France, Laboratoire de Chimie Durable et Santé, 13 Rue de Toul, 59000 Lille, France 2) Institut Charles Violette (EA 7394), ISA, SFR Condorcet FR CNRS 3417, Lille, France

Key words: bio-resources, green chemistry, antifungal, wheat, rape, nontoxicity, biodegradability

Agriculture must face challenging and apparently contradictory issues: becoming both competitive and sustainable. The use of agricultural inputs since previous decades can have in the medium-to-long term adverse impacts on the human health and on the environment. The residues dispersed on agricultural areas cause the appearance of resistant fungal strains, which, by crossing with the human pathogens, end up impacting the human health[1]. In that way, European political and legislative initiatives are taken in order to develop efficient eco-friendly methods in plant protection. For example, in France, Ecophyto II plan felt into place in 2008 with the aim of halving by 2025 the use of crop protection products.[2] In that respect, our objectives are to develop new potential bio-sourced antifungal agents for plant protection by using bio-sourced platform molecules (as described in the IAR report[3]) modified by green chemical technologies. We target plant diseases which affect the most widespread european cereal crops (wheat) and also oleaginous cultures (rape). Therefore, all candidates will be tested against plant pathogens as Zymoseptoria tritici, Fusarium solani, Sclerotinia sclerotiorum, Phoma lingam and so on. These pathogens have been selected due to their harmfulness on cultures coupled with the appearance of resistance to several classes of pesticides. Researches are done by taking into account the global toxicity of the compounds in an early stage, in order to design accurate antifungal agents without human health impacts and good biodegradation properties in soils. Indeed, compounds are evaluated on various human cell lines (representative of several organs and skin), mouse models, human pathogen yeast (C. albicans) and nematodes (C. elegans). The first stage of the study is focused on the wheat septoria disease; among about one hundred of compounds were tested in vitro[4] for their potential antifungal activity on the pathogen Zymoseptoria tritici. Among them forty molecules lead to an inhibition rate of 100% at a concentration of 100 mg/L and five molecules showed a higher antifungal activity with IC50 between 6 and 17 mg/L. Moreover, these five candidates were also evaluated in vitro on ten different resistant and non-resistant strains of Zymospetoria tritici and some very encouraging results have been obtained. Furthermore, first results of cytotoxicity evaluation of our potential antifungal agents on kidney cells prove that they seem to be not hazardous. More active compounds are currently assessed for their antifungal activity on wheat in a greenhouse and new candidates will be designed for in vitro screening before studying antifungal potential of all these candidates on other pathogens.

References 1) Vaezi, A., Fakhim, H., Javidnia, J., Khodavaisy, S., Abtahian, Z., Vojoodi, M., Nourbakhsh, F., Badali, H., J. Mycol. Méd., 2018, 28, 59-64. 2) https://chambres-agriculture.fr/agriculteur-et-politiques/ecophyto/plan-ecophyto-2/ 3) Le panorama international des intermédiaires chimiques biosourcés, dix ans d’évolution décryptés, Rapport du pôle IAR, 2015. 4) Siah, A., Deweer, C., Morand, E., Reignault, P., Halama, P., Crop Prot., 2010, 29, 737-743. 97 P043 SELECTIVE FKBP51 LIGANDS BY CONFORMATION-SPECIFIC BINDING

Felix Hausch

Technische Universität Darmstadt, Alarich-Weiss-Str. 4, 64287 Darmstadt, Germany

The FK506-binding protein 51 (FKBP51) plays a key role in human stress biology and contributes to major depression, obesity and chronic pain. Drug discovery for FKBP51 has been hampered by lack of selectivity against the highly homologous functional counter-player FKBP52. Here, we present the discovery of SAFit2, the first potent and highly selective inhibitor of FKBP51[1]. SAFit2 achieves selectivity for FKBP51 by stabilizing a transient conformation that much less favorable for FKBP52. This otherwise invisible transient binding pocket can be detected by NMR studies to preexist as a very low populated minor conformation in the apo state[2]. By using SAFit ligands, we demonstrate that selective inhibition of FKBP51 enhances neurite elongation in neuronal cultures and improves neuroendocrine feedback and stress-coping behavior in mice[1,3,6]. Furthermore, SAFit2 ameliorated inflammatory pain-induced disabilities[4], diet-induced obesity[5], and alcohol-seeking behavior[7]. Our findings show how high selectivity can be achieved in the conserved class of FKBP proteins by exploiting differences in conformational dynamics. The resulting ligands allowed to validate FKBP51 inhibition as a novel pharmacological treatment option for depression, obesity and chronic pain.

References 1 ) Gaali, Kirschner et al. Selective inhibitors of the FK506-binding protein 51 by induced fit. Nat Chem Biol 2015, 11, 33-7 2) Jagtap, et al. Selective inhibitors of FKBP51 employ conformational selection of dynamic invisible states. Angew Chem 2019, in press. 3) Hartmann et al. Pharmacological Inhibition of the Psychiatric Risk Factor FKBP51 Has Anxiolytic Properties. J Neurosci 2015, 35, 9007-16. 4) Maiaru et al. The stress regulator FKBP51 drives chronic pain by modulating spinal glucocorticoid signaling. Sci Transl Med 2016, 8, 325ra19. 5) Balsevich et al. Stress-responsive FKBP51 regulates AKT2-AS160 signaling and metabolic function. Nat Commun 2017, 8, 1725. 6) Zannas et al. Epigenetic upregulation of FKBP5 by a aging and stress contributes to NF-κB-driven inflammation and cardiovascular risk. Proc Natl Acad Sci USA 2019, in press. 7) König et al., The selective FKBP51 inhibitor SAFit2 reduces alcohol consumption and reinstatement of conditioned alcohol effects in mice. Addict Biol (2019):in press.

98 P044 COMBATING THE "POST-ANTIBIOTIC ERA" : ARE THERE NOVEL STRUCTURES AND MODE OF ACTIONS?

Flavia Izzo, Frank Kraus, Bernd Plietker

Stuttgart University, Institüt für Organische Chemie, Pfaffenwaldring 55, 70569 Stuttgart, Germany

The overuse of antibiotics has led to antibiotic resistance becoming one of the biggest threats to global health. With once treatable common infections, such as gonorrhoea, pneumonia and tuberculosis are becoming harder to defeat using existing antibiotics, due to the emergence of antibiotic resistant strains.1 It is predicted that by 2050 antibiotic resistance will be the leading cause of deaths in Europe, if no innovative class of antibiotics have been developed.2 Most recently, it was proposed that the world will enter a “post-antibiotic era”.3 Natural products have been the inspiration for drug discovery for over 100 year and continue to provide unprecedented scaffolds for medicinal chemistry. One such class of natural products are Polycyclic p olyprenylated acylphloroglucinols (PPAPs) firstly isolated from the Clusiaceae family of trees and shrubs. Their core structure contains a bicyclo[3.3.1]nonane-2,4,9-trione that is substituted with a variety of unsaturated side chains (Figure 1A).

Figure 1. A) General type-B PPAP structure with variable residues 1-4; B) Transformation over time of S.aureus HG001 after treatment with PPAP23 Due to the diverse range of biological activities, including antifungal, antiprotozoal, antiviral, antiproliferative, antidepressant, and antimicrobial activity,4 PPAPs have become attractive lead compounds for drug discovery. The Plietker group has been working on the development of a fast and telescopic route for the synthesis of endo- type B PPAPs in only 7-10 steps starting from the inexpensive acetylacetone.4 Thanks to a wider collaboration with technical biochemistry, microbiology and clinical biology based in: Universität Stuttgart, Universität Tübingen, Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie Stuttgart, Universitätsklinikum Ulm, Technische Universität Braunschweig, Freie Universität Berlin the antimicrobial activity of a large number of natural and non natural PPAPs has been investigated showing remarkable results (Figure 1B).4-5 In this presentation the latest progress of the aforementioned collaboration will be highlighted and discussed.

References 1) WHO statement on antibiotic resistance, 2018. 2) BBC news, Fergus Walsh, 2014. 3) A. J. Alanis, Archives of Medical Research, 2005, 36, 697; J. P. Dahiya, D. C. Wilkie, A. G. Van Kessel, M. D. Drew, Animal Feed Science and Technology 2006, 129, 60. 4) X.-W Yang, R. B. Grossman, G. Xu, Chem. Rev. 2018, 118, 3508; C. Guttroff, A. Baykal, H. Wang, P. Popella, F. Kraus, N. Biber, S. Krauss, F. Götz, B. Plietker, Angew. Chem. Int. Ed. 2017, 56, 15852; F. Horeischi, N. Biber, B. Plietker, J. Am. Chem. Soc. 2014, 136, 4026; N. Biber, K. Möws, B. Plietker, Nature Chemistry 2011, 3, 938. 5) Wang, H., F. Kraus, P. Popella, A. Baykal, C. Guttroff, P. Francois, P. Sass, B. Plietker & F. Götz, Front. Microbiol., 2019, 10, 3389.

99 P045 INHIBITORY EFFECTS OF CERAMIDE FROM BRASSICA NAPUS ON THE ATOPIC FUNCTION VIA THE REGULATION OF HUMAN KALLIKREIN 5 AND 7 PROTEASE

Yu Mi Kim, Kyung Suk Bae, Hyung-In Moon

SKEDERM cosmetic R&D center, 240 Teheran-ro, Gangnam-gu, Seoul, South Korea 06221

The stratum corneum tryptic enzyme kallikrein 5 (KLK5) is a serine protease that is involved in the cell renewal and maintenance of the skin barrier functions. The excessive activation of KLK5 causes an exacerbation of dermatoses, such as rosacea and atopic dermatitis. Brassica napus play a well-known role in the treatment of canola oil through their anti-oxidative and DNA protective properties. We aimed to investigate whether the bioactive ceramide modulate the KLK5 protease. The ceramide were evaluated using an enzymatic assay to measure the anti-KLK5 activity. Our study revealed that the ceramides modulate the KLK5 and 7 protease activity. Ceramides may affect the skin barrier and atopic function via the regulation of proteases. Keywords: Brassica napus; ceramide; kallikrein 5; skin barrier; rosacea; atopic dermatitis

References 1) Pampalakis, G., Zingkou, E., Kaklamanis, L., Spella, M., Stathopoulos, G.T., Sotiropoulou, G. Elimination of KLK5 inhibits early skin tumorigenesis by reducing epidermal proteolysis and reinforcing epidermal microstructure. Biochim Biophys Acta Mol Basis Dis. 2019;2;1865(11):165520. 2) Caubet, C., Jonca, N., Brattsand, M., Guerrin, M., Bernard, D., Schmidt, R., Egelrud, T., Simon, M., Serre, G. Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family, SCTE/KLK5/hK5 and SCCE/KLK7/hK7. J Invest Dermatol.2004;122(5):1235-1244 3) Harouse, J.M., Bhat, S., Spitalnik, S.L., Laughlin, M., Stefano, K., Silberberg, D.H., Gonzalez- Scarano F. Inhibition of entry of HIV-1 in neural cell lines by antibodies against galactosyl ceramide. Science. 1991;19;253(5017:320-323. 4) Kim,,Y.M., Bae K.S. Protective Effects of C24 Ceramide From the Seeds of Brassica napus L. Against Ultraviolet B-Induced Photoaging in Normal Human Dermal Fibroblasts. NAT PROD COMMUN. 2019:June: 1-5. 5) Lim, S.W., Hong, S.P., Jeong, S.W., Kim, B., Bak, H., Ryoo, H.C., Lee, S.H., Ahn, S.K. Simultaneous effect of ursolic acid and oleanolic acid on epidermal permeability barrier function and epidermal keratinocyte differentiation via peroxisome proliferator-activated receptor-alpha. J Dermatol. 2007;34(9):625-634.

100 P046 SYNTHESIS OF NON-HYDROLYSABLE “SUPER SUBSTRATES” OF PHOSPHATIDYLINOSITOL 4-KINASES

Hubert Hřebabecký, Milan Dejmek, Martin Dračínský, Martin Klíma, Evžen Bouřa, Radim Nencka

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Gilead Sciences Research Centre at IOCB Prague, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic

Phosphatidylinositol 4-kinases (PI4Ks) are enzymes responsible for transfer of phosphate group from ATP to phosphatidylinositol, a common constituent of the plasma membranes in cells. The product of this reaction, phosphatidylinositol 4-phosphate (PI4P), plays numerous roles in cell signaling and is essentially implicated in process of membrane budding.[1] In human cells there are four different PI4Ks, divided into two classes – class II, which includes PI4KIIa and PI4KIIb, and class III containing PI4KIIIa and PI4KIIIb. Both members of the class III are well-known host factors implicated in replication of various RNA viruses. Both PI4KIIIa and PI4KIIIb play an essential role in life cycle of hepatitis C virus (HCV). These PI4Ks are necessary for reorganization of cellular membranes indispensable from formation of replication organelles sometimes called membranous web. In contrast, members of Picornaviridae family exploit only PI4KIIIb for these purposes.[2] Although us and others have reported crystal structures of PI4KIIa, PI4KIIb and also PI4KIIIb with nucleoside and non-nucleoside inhibitors [3,4,5], so far, there is no crystal structure unveiling the position of the phosphatidylinositol within the active site. Here we report the design and synthesis of novel super substrate complexes of ADP and PI4P containing non-hydrolysable bisphosphonate motive. Our goal is to use these compounds in our crystallization experiments, which should build bases for better understanding of this phosphorylation process and serve for further design of novel PI4K inhibitors.

The work was supported from European Regional Development Fund; OP RDE; Project: "Chemical biology for drugging undruggable targets (ChemBioDrug)" (No. CZ.02.1.01/0.0/0.0/16_019/0000729).

References 1) Balla, A.; Balla, T. Phosphatidylinositol 4-kinases: old enzymes with emerging functions. Trends in Cell Biology 2006, 16, 351-361. 2) Boura, E.; Nencka, R. Phosphatidylinositol 4-kinases: Function, structure, and inhibition. Experimental cell research 2015, 337, 136-45. 3) Baumlova, A.; Chalupska, D.; Róźycki, B.; Jovic, M.; Wisniewski, E.; Klima, M.; Dubankova, A.; Kloer, D. P.; Nencka, R.; Balla, T.; Boura, E. The crystal structure of the phosphatidylinositol 4‐kinase IIα. EMBO reports 2014, 15, 1085-1092. 4) Mejdrová, I.; Chalupská, D.; Kögler, M.; Šála, M.; Plačková, P.; Baumlová, A.; Hřebabecký, H.; Procházková, E.; Dejmek, M.; Guillon, R.; Strunin, D.; Weber, J.; Lee, G.; Birkus, G.; Mertlíková-Kaiserová, H.; Boura, E.; Nencka, R. Highly Selective Phosphatidylinositol 4-Kinase III beta Inhibitors and Structural Insight into Their Mode of Action. Journal of Medicinal Chemistry 2015, 58, 3767-3793. 5) Burke, J. E.; Inglis, A. J.; Perisic, O.; Masson, G. R.; McLaughlin, S. H.; Rutaganira, F.; Shokat, K. M.; Williams, R. L. Structures of PI4KIIIβ complexes show simultaneous recruitment of Rab11 and its effectors. Science 2014, 344, 1035-1038.

101 P047 NOVEL MODE OF ACTION MOLECULE OSW-1 ABOLISHES THE GRP78

Michael Schaeffler

Cfm Oskar Tropitzsch GmbH, POB 568, 95605 Marktredwitz, Germany

OSW-1, a natural product isolated from the bulbs of Ornithogalum saundersiae, exhibits extremely potent anticancer activity against a wide spectrum of cancer cells with IC50 values in the sub-nM to low picomolar range and is one of the most potent anticancer agents ever tested at NCI. Its anticancer activities are about 10-100 times more potent than many well-known anticancer agents in clinical use, such as etoposide, methotrexate, mitomycin C, camptothecin, 5-FU, and paclitaxel. The IC50 values of OSW-1 against some cancer cell lines. While OSW-1 is highly potent against many types of cancers, it is less toxic to normal or nonmalignant cells than to cancer cells in vitro, demonstrating excellent therapeutic selectivity. Unlike other anticancer agents that inhibit DNA synthesis or block cell cycle progression, OSW-1 involves a novel mechanism of action that is independent of cell cycle and can effectively kill dormant stem-like cancer cells at sub-nM concentrations. It is known that GRP78 plays very important roles in cancer growth, cancer cell survival, angiogenesis, metastasis, drug resistance and cancer immunity, and the down-regulation of GRP78 can be an effective way of inhibiting cancer cell growth. In our study we discovered that incubation of HL-60 with OSW-1 resulted in a time dependent reduction of GRP78. Our experiments showed that OSW-1 induced cytosolic calcium increase, leading to the activation of cytosolic calpains and subsequent degradation of GRP78. The extremely potent anticancer activity of OSW-1 against many drug-resistant cancers coupled with excellent therapeutic selectivity and a novel mechanism of action targeting GRP78 pathway makes OSW-1 and its analogs promising payloads of ADCs for cancer treatment.

102 P048 SMALL SCALE PURIFICATION OF CONSTITUENTS FROM COMPLEX NATURAL PRODUCT EXTRACTS USING SUB-2μm CHROMATOGRAPHY

Andrew Aubin, Eric van Beelen, Jo-Ann Jablonski, Wendy Harrop

Waters Corporation, Milford, MA, 01757 USA

Extracts from natural product samples can be complex often containing a large number of diverse compounds. Increased separation performance of sub-2-μm column technology along with low dispersion instrumentation provides a tool that produces sharp, narrow, and more concentrated peaks. When there is a need to collect narrow peaks from these complex mixtures, traditional fraction collection instrumentation designed for preparative HPLC conditions does not provide an adequate solution primarily due to peak broadening through collection valves and tubing. Here we show the use of a new Waters Fraction Manager - Analytical (WFMA) for the purification on an analyitical scale. Extracts from three natural product samples (Rosemary, Schisandra Berry, and Angelica Root) were analyzed using sub-2-μm chromatography. Potential peaks of interest were identified and isolated using a fraction collector designed to collect peaks generated from sub-2-μm chromatography. Collected fractions were then analyzed to determine purity. Using the WFMA peaks of interest were isolated from 3 complex natural product extracts. Multiple modes of collection are demonstrated (time, threshold, and mixed mode). Real time collection and collection bed information can quickly be viewed from the ACQUITY console. Analysis of collected fractions showed purities of greater than 85% up to 98% with the exception of Schisandra Berry peak 1 at 70.6% which was expected as this was known to be a co-elution.

103 P049 SYNTHESIS OF (–)-MITREPHORONE A VIA A BIOINSPIRED LATE STAGE C–H OXIDATION OF (–)-MITREPHORONE B

Lukas Anton Wein (1), Klaus Wurst (2), Peter Angyal (3), Lara Weisheit (1), Thomas Magauer (1)

1) Institute of Organic Chemistry and Center for Molecular Biosciences, Leopold-Franzens-University Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria 2) Institute of General, Inorganic and Theoretical Chemistry, Leopold-Franzens-University Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria 3) Institute of Organic Chemistry, Research Centre for Natural Sciences, Magyar tudósok körútja 2, 1117 Budapest, Hungary

The ent-trachylobane natural products mitrephorone A, B and C1,2 are structurally related to the diterpenoids ent-atiserene, ent-beyerene, and ent-kaurene, but they display a rare oxidation pattern3-5. We present a bio-inspired late stage C–H oxidation of the ent-trachylobane natural product mitrephorone B to mitrephorone A. The realization of this unprecedented transformation was accomplished by either an iron-catalyzed or electrochemical oxidation and enabled access to the densely substituted oxetane in one step. However, formation of mitrephorone C, which is lacking the central oxetane unit, was not observed.6

References 1) Li, C.; Lee, D.; Graf, T. N.; Phifer, S. S.; Nakanishi, Y.; Burgess, J. P.; Riswan, S.; Setyowati, F. M.; Saribi, A. M.; Soejarto, D. D. et al. A Hexacyclic ent-Trachylobane Diterpenoid Possessing an Oxetane Ring from Mitrephora glabra. Org. Lett. 2005, 7, 5709–5712. 2) Richter, M. J. R.; Schneider, M.; Brandstätter, M.; Krautwald, S.; Carreira, E. M. Total Synthesis of (–)-Mitrephorone A. J. Am. Chem. Soc. 2018, 140, 16704–16710. 3) Hanson, J. R. Diterpenoids. Nat. Prod. Rep. 2007, 24, 1332–1341. 4) Hanson, J. R. Diterpenoids. Nat. Prod. Rep. 2006, 23, 875–885 5) Roy, A.; Roberts, F. G.; Wilderman, P. R.; Zhou, K.; Peters, R. J.; Coates, R. M. 16-Aza-ent-beyerane and 16-Aza-ent-trachylobane: potent mechanism-based inhibitors of recombinant ent-kaurene synthase from Arabidopsis thaliana. J. Am. Chem. Soc. 2007, 129, 12453–12460. 6) Hugelshofer, C. L.; Magauer, T. A Bioinspired Cyclization Sequence Enables the Asymmetric Total Synthesis of Dictyoxetane. J. Am. Chem. Soc. 2016, 138, 6420–6423.

104 P050 THE TOTAL SYNTHESIS OF (–)-CURVULAMINE

Karl Haelsig, Xuan Juan, Thomas Maimone

UC Berkeley, 1947 Oregon Street, 94703 Berkeley, United States

Curvulamine and related polypyrrole alkaloids represent a new class of natural products with unprecedented chemical structures, intriguing biological activities, and mysterious biosynthetic origins. Herein we report the first studies towards these molecules, resulting in a 10-step total synthesis of (–)-curvulamine, a dimeric member with promising gram positive and negative antibiotic activity. A number of interesting chemical findings, including exploitation of the heteroaromatic pyrrolo[1,2-a]azepinone nucleus and an efficient stereodivergent reduction, are reported.

References 1) Han, W. B.; Lu, Y. H.; Zhang, A. H.; Zhang, G. F.; Mei, Y. N.; Jiang, N.; Lei, X.; Song, Y. C.; Ng, S. W.; Tan, R. X. Org. Lett. 2014, 16, 5366.

105 P051 BIOMIMETIC MEROTERPENOID SYNTHESES: SCOPE AND LIMITATIONS OF POLYENE CYCLIZATIONS APPLIED TO THE SYNTHESIS OF HONGOQUERCIN ANALOGUES

T. Mies, A. G. M. Barrett

Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, Wood Lane, London, W12 0BZ, UK

Rigid core structures, such as the trans, trans (or cis)-decalin-chromane systems found in meroterpenoids show a range of biological effects including antimicrobial, anti-viral and anti-tumor activities.[1] The hongoquercins A and B were found to be active against methicillin‐resistant Staphylococcus aureus and vancomycin‐resistant Enterococcus faecium.[2] Having recently completed short dual biomimetic syntheses of hongoquercin A, B and several austalides,[3] we have now developed an alternative strategy to access the core of the hongoquercins that allows for late-stage derivatization studies for SAR studies. These syntheses highlight the robustness and flexibility of biomimetic aromatization as well as bioinspired polyenyne cyclization reactions.* *Manuscript in preparation

References 1) M. T. Hamann, P. J. Scheuer Tetrahedron Lett. 1991, 32, 5671-5672. M. T. Hamann, P. J. Scheuer, M. Kelly-Borges J. Org. Chem. 1993, 58, 6565-6569. S. S. Nasu, B. K. S. Yeung, M. T. Hamann, P. J. Scheuer, M. Kelly-Borges, K. Goins J. Org. Chem. 1995, 60, 7290-7292. M.-L. Bourguet-Kondracki, F. Lacombe, M. Guyot J. Nat. Prod. 1999, 62, 1304-1305. A. Jankam, M. J. Somerville, J. N. A. Hooper, D. J. Brecknell, A. Suksamrarn, M. J. Garson Tetrahedron 2007, 63, 1577-1582. S. J. Robinson, E. K. Hoobler, M. Riener, S. T. Loveridge, K. Tenney, F. A. Valeriote, T. R. Holman, P. Crews J. Nat. Prod. 2009, 72, 1857-1863. 2) D. M. Roll, J. K. Manning. G. T. Carter J. Antibiot. 1998, 51, 635-639. D. A. Abbanat, M. P. Singh, M. Greenstein J. Antibiot. 1998, 51, 708-714. 3) T. N. Barrett, A. G. M. Barrett J. Am. Chem. Soc. 2014, 136, 17013-17015. T.-K. Ma, D. C. Elliott, S. Reid, A. J. P. White, P. J. Parsons, A. G. M. Barrett J. Org. Chem. 2018, 83, 13276-13286. T.-K. Ma, P. J. Parsons, A. G. M. Barrett J. Org. Chem. 2019, 84, 4961-4970.

106 POSTERS µAccelerating Drug Discovery by Intelligence Augmentation

107 P061 ARTIFICIAL INTELLIGENCE: WILL IT CHANGE THE WAY WE RESEARCH?

Irakusne Lopez

Mestrelab Research S.L., Feliciano Barrera 9B-Bajo, 15706 Santiago de Compostela, Spain

It’s a common psychological phenomenon: repeat any word enough times, and it eventually loses all meaning, disintegrating like soggy tissue into phonetic nothingness. For many of us, the phrase “artificial intelligence” fell apart in this way a long time ago. AI is everywhere in tech right now, said to be powering everything from your TV to your toothbrush, but never have the words themselves meant less. It shouldn’t be this way. Press coverage can exaggerate research, sticking a picture of a Terminator on any vaguely AI story. Often this comes down to confusion about what artificial intelligence even is. It can be a tricky subject for non-experts, and people often mistakenly conflate contemporary AI with the version they’re most familiar with: a sci-vision of a conscious computer many times smarter than a human. Experts refer to this specific instance of AI as artificial general intelligence, and if we do ever create something like this, it’ll likely to be a long way in the future. Until then, no one is helped by exaggerating the intelligence or capabilities of AI systems. It’s better, then, to talk about “machine learning” rather than AI. This is a subfield of artificial intelligence and one that encompasses pretty much all the methods having the biggest impact on the world right now (including what’s called deep learning). As a phrase, it doesn’t have the mystique of “AI,” but it’s more helpful in explaining what the technology does. Since the very first release of Mnova, we have been (and still are!) very fortunate to include in the software the prediction of NMR spectra provided by Modgraph Consultants. It is really a privilege to offer prediction capabilities developed by the pioneers and leaders in the field for so many years. Nowadays, when Machine and Deep Learning techniques are so popular, it is worth remembering that the predictions commercialized by Modgraph have used Neural Networks (in addition to other methods, vide infra) for more than 25 years already. In this talk, we would like to show you how we use NMR Prediction in Mnova, following the concept of “unity creates strength”. The basic idea is to combine several predictors together to get better predictive power. We have borrowed from the field of Machine Learning the term "ensemble" to define this new prediction procedure. The machine learning algorithms for prediction are basic structural brick for applications built on top of it, that enable better and more efficient research. Example of one of these applications is our verification system included in our laboratory ELN, enabling easy and quick verification of synthesised molecule as well as reaction participants and avoiding time-consuming and expensive mistakes further down the research process.

References 1) J. Chem. Inf. Model., 2012, 52 (11), pp 2864–2875

108 P062 PRACTICAL APPLICATION OF DEEP LEARNING TO DRUG DISCOVERY PROJECT DATA

Matthew Segall (1), Thomas Whitehead (2), Ben Irwin (1), Julian Levell (3), Gareth Conduit (2)

1) Optibrium Limited, Cambridge, UK 2) Intellegens Limited, Cambridge, UK 3) Constellation Pharmaceuticals, Cambridge USA

We have previously described a novel deep learning method for data imputation, Alchemite™ (Whitehead et al. J. Chem. Inf. Model. (2019) 59 pp. 1197-1204). This accepts both molecular descriptors and sparse experimental data as inputs, to exploit the correlations between experimentally measured endpoints, as well as structure-activity relationships (SAR). It has been demonstrated to outperform quantitative SAR (QSAR) models, including multi-target deep learning methods, on a challenging benchmark data set of compound bioactivities. Here we will describe the application and validation of this method on drug discovery data covering two projects and diverse endpoints, including activities in both biochemical and cellular assays and absorption, distribution, metabolism and elimination (ADME) endpoints.

109 P063 INCREASED ROBUSTNESS AND THROUGHPUT IN COMPOUND PURIFICATION USING SFC AND INTELLIGENT DECISION MAKING SOFTWARE

Mark Bayliss (1), Mark Spears (1), Eric van Beelen (2), Andrew Aubin (2)

1) Virscidian Inc., Cary, NC, 27513 USA 2) Waters Corporation, Milford, MA, 01757 USA

SFC systems utilize liquid Carbon Dioxide (CO2) as its main mobile phase in combination with one or more organic solvents resulting in faster equilibration, lower pressure drops across the column, solvent reduction and lower cost per sample. The process is reproducible and applicable to a wide range of compounds relevant in the Pharmaceutical, Life Sciences, Chemical Materials and Food & Environmental markets. The new Waters Prep SFC 150 Mgm System is the ideal choice when reduction of normal-phase solvent usage and disposal is a critically important step for purification laboratories wanting to become more environmentally friendly. Here we show how the new Waters Prep SFC 150 Mgm System is perfectly suited for laboratories seeking to adopt a greener approach to high throughput purification. Another aspect of high throughput purification is around decision making - as the combination of SFC/UV/MS, column technologies and modifiers, enables analysts to rapidly evaluate a wide range of separation potentials. Normally the mix and number of method permutation screened, leads to a natural bottleneck of data processing and data interpretation. In many example scenarios that we encounter, scientists are left making the determination of the most appropriate method based on a visual comparison of the results. This way of working normally requires a high-level chromatographic expertise, time, and a direct need to interact always with the results to move the workflow forward to the next workflow stage. We find that this aspect of the workflow is natural opportunity to consider software based automated interpretation of results. For this, the challenge of automating the data reduction, data interpretation and the selection of the best separation conditions is transferred to Virscidian’s Analytical Studio software environment. In summary, individual sample raw data are automatically captured into the Analytical Studio Express data management environment, processed individually and then evaluated as a complete batch of samples once all injections have been received. The determination of the best separation is made by translating typical chromatographic variables that we as chromatographers would expect to consider, including chromatographic peak asymmetry and tailing, response, retention time within certain time start/end times into a numerical representation. Depending on the type of samples being evaluated achiral or chiral, additional relevant selection variables are considered including but not limited to solvent, temperature and column bias. A final method score is calculated, where the highest value is determined to be the most ideal separation approach and decreases to the lowest separation result. This approach has been proven over many sample examples and complexity of crude samples, to be highly robust in selecting the most ideal separation methods. Selection of focused gradients for prep upscaling is then made based on either a single substance of interest and a narrow focused gradient window or a multi-substance elution window. Prep samples are then run using the returned look list of focused gradients.

110 P064 A HIGH-THROUGHPUT EXPERIMENTATION SOFTWARE FOR THE INVENTION OF NEW COUPLING REACTIONS

Babak Mahjour, Tim Cernak

Department of Medicinal Chemistry, College of Pharmacy, University of Michigan

Coupling reactions are important tools in the arsenal of the medicinal chemist. A wide diversity of commercially available building blocks provides the ability to sample diverse pockets of chemical space using coupling reactions. Current practice favors the use of a narrow subset of coupling reactions with a broad diversity of building blocks. We endeavor to develop new coupling reactions that will expand the utility of chemical building blocks. Towards this objective, we will report in this poster the development of a general-purpose experimental design software for the preparation and analysis of high throughput chemistry screens. Following the principles of the design-make-test cycle, our software, phactorTM, allows chemists to plan, perform, and analyze experimental screens with ease. Once the screen has been executed and characterized, phactorTM allows for the bulk analysis of the results and scale up calculations for any well. This poster will detail our development of the phactorTM software, its application in the discovery of novel coupling reactions, and its interface with robotics for automated synthesis.

111 P065 THE EFFECTS OF SFC PREPARATIVE SCALE-UP ON THROUGHPUT, PURITY AND RECOVERY OF AN IMPURITY IN AN API MIXTURE

Catharine Layton, Eric van Beelen, Andrew Aubin, Jacquelyn Runco, Shawn Helmueller

Waters Corporation, Milford, MA, 01757, USA

Scale-up of SFC analytical methods to preparative scale allows laboratories to generate purified bulk quantities of target compounds. In some laboratories, users are provided with an analytical scale method from which an isolate of a specified purity and quality must be generated within strict timelines. The success of achieving this task depends directly upon the accuracy of the scale-up procedure. In this poster we will describe the preparative scale-up of an analytical scale method for isolation of milligram (mg) to gram (g) quantities (per run) for a mixture of an API and its associated impurities. A cost and time analysis is provided after scale-up to demonstrate the relationship between column size and throughput.

References 1) “Runco, J. “Beginners Guide to Preparative Chromatography”. Library of Congress 2017933625, Waters Corporation, www.waters.com, 2017.

112 POSTERS

Drug Discovery Tales

113 P071 TARGETING TRANSCRIPTION FACTORS ALLOSTERICALLY – NOVEL, POTENT HYPOXIA-INDUCIBLE FACTOR-2a (HIF-2a) INHIBITORS

Hans-Peter Buchstaller (1), Joachim Albers (1), Nina Berges (1), Ada Sala Hojman (1), Tim Knehans (1), Mireille Krier (1), Marc Lecomte (1), Matthias Leiendecker (1), Birgitta Leuthner (1), Ralph Lindemann (1), Mateusz Nowak (2), Urszula Pakulska (2), Christina Schindler (1), Ansgar Wegener (1), Adrian Zarębski (2)

1) Merck KGaA, Global Research & Development, Frankfurter Strasse 250, 64293 Darmstadt, Germany 2) Ryvu Therapeutics S.A., ul. Bobrzynskiego 14, 30-348 Krakow, Poland

Hypoxia is a feature of many cancers and a trigger for increased expression of genes associated with cell growth and metabolism. This cellular response is mediated by hypoxia-inducible factors (HIFs). HIF-2a is a member of this HIF family of transcription factors and a key oncogenic driver in cancers such as clear cell renal cell carcinoma (ccRCC). A signature feature of these cancers is the overaccumulation of HIF-2a protein, often by inactivation of the E3 ligase VHL (von Hippel-Lindau)1. Known inhibitors like PT2385 or PT2977 bind into a closed allosteric cavity in the HIF-2a subunit, preventing HIF-2α–HIF1b dimerization, which leads in turn to decreased target-gene expression.2,3 These HIF-2a inhibitors have demonstrated promising proof-of-concept clinical activity in heavily pretreated advanced ccRCC patients. We identified novel HIF-2α inhibitors by replacement of the phenyl residue with isosteric thiophene in the central scaffold. The poster will summarize our efforts to explore the steep structure-activity relationship (SAR) which is a consequence of the small, closed binding pocket. Supported by X-ray crystallography studies, we identified distinct features of the core and substituents needed for improved binding affinity. The optimization work yielded novel, potent HIF-2a inhibitors with good activity in cellular mechanistic assays and drug-like properties.

References

1) Recent reviews: Albadari, N.; Deng, S.; Li, W. Expert Opin. Drug Dis. 2019, 14, 667-682; Yu, Y.; Yu, Q.; Zhang, X. Drug Discov. Today 2019, in press. 2) Wehn, P. M.; et al. J. Med. Chem. 2018, 61, 9691−9721. 3) Xu, R.; et al. J. Med. Chem. 2019, 62, 6876−6893.

114 P072 NEW STRATEGIES FOR NEURODEGENERATIVE DRUG DISCOVERY: BUILDING PRECISE CONJUGATES ABLE TO CROSS THE BLOOD BRAIN BARRIER

Maria J. Matos (1,2), Carlos Fernandes (1), Fernanda Rodriguez-Enriquez (3), Dolores Viña (3), Eugenio Uriarte (2), Fernanda Borges (1)

1) CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal 2) Departamento de Química Orgánica, Facultad de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain 3) Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS) Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain

The twentieth century witnessed a significant demographic change in the human population of the industrialized world that is currently followed by a similar shift of life expectancy to upper age ranges in developing countries. Therefore, neurodegenerative diseases are becoming increasingly prevalent. There is an urgent need to improve the current therapies, which main problem is related to blood brain barrier crossing and brain achievement. The effectiveness of a drug is dependent on accumulation at the site of action at therapeutic levels. However, challenges such as rapid renal clearance, degradation or non-specific accumulation requires drug delivery enabling technologies.[1,2] Targeted drug delivery is a very promising concept, which still needs improvement for better clinical outcomes.[3] Understanding some of the molecular changes associated to these ubiquitous and widespread diseases, has stimulated efforts to develop drugs that specially target key proteins and delivery systems that can achieve those targets. From nanoparticles to proteins and peptides are presented as promising carriers to improve the pharmacokinetics of several in vivo bioactive molecules. Acknowledgements: Authors would like to thank Xunta da Galicia Plan of Research, Innovation and Growth 2011–2015 (Plan I2C, ED481B 2014/086–0 and ED481B 2018/007) for the financial support.

References 1) Matos, M.J. Fut. Med. Chem. 2018, 10(9), 983. 2) Fernandes, C.; Martins, C.; Fonseca, A.; Nunes, R.; Matos, M.J.; Silva, R.; Garrido, J.; Sarmento, B.; Remião, F.; Espinar-Otero, F.; Uriarte, E.; Borges, F. ACS Appl. Mater. Interfaces 2018, 10(46), 39557. 3) Matos, M.J.; Oliveira, B.L.; Martínez-Sáez, N.; Guerreiro, A.; Cal, P.M.S.D.; Bertoldo, J.; Maneiro, M.; Perkins, E.; Howard, J.; Deery, M.J.; Chalker, J.M.; Corzana, F.; Jiménez-Osés, G.; Bernardes, G.J.L. J. Am. Chem. Soc. 2018, 140, 4004.

115 P073 ELECTROSTATICS - DRIVING FORCES IN STRUCTURE-BASED DRUG DESIGN AND SYNTHESIS

Gianni Chessari

Astex Pharmaceuticals, 436 Cambridge Science Park, Cambridge, United Kingdom

Molecular electrostatic potentials are important tools in drug discovery helping medicinal and computational chemists to elucidate structure-activity relationships, to optimise binding affinity and to rationalise molecular reactive behaviours. This paper will discuss examples from Astex projects where the modulation of electrostatic potentials has contributed to the design of potent leads which were the precursors of two clinical candidates: ASTX660 (1) and ASTX295 (2). Following the success of these methods we have invested in the development of Machine Learning-based models to generate fast and reliable electrostatic potential surfaces (ESP) both for ligands and proteins (3). These methods allow us to produce near-QM quality molecular ESP surfaces in a fraction of a second and assess electrostatics on the fly during interactive structure-based design. Finally, we will discuss how molecular electrostatic potentials have been used to rationalise and predict regioselectivity in reactions developed through our HTE platform (4).

References 1) Chessari, G. et al. J. Med. Chem. 2015, 58, 6574−6588 2) Chessari, G. et al. in preparation 3) Rathi, P. C. et al. J. Med. Chem.2019, DOI: 10.1021/acs.jmedchem.9b01129 4) Grainger, R. et al. Chem. Sci., 2019, 10, 2264-2271

116 P074 FROM NORBORNYL-BASED CARBANUCLEOSIDES TO CYCLIN-DEPENDENT KINASE 2 INHIBITORS

Milan Dejmek (1), Cemal Köprülüoğlu (1,2), Michal Šála (1), Radek Jorda (3), Martin Dračínský (1), Pavel Šácha (1), Vladimír Kryštof (3), Pavel Hobza (1,2), Martin Lepšík (1), Radim Nencka (1)

1) Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nam. 2, 166 10 Prague 6, Czech Republic 2) Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Palacký University, Olomouc, 771 46 Olomouc, Czech Republic 3) Laboratory of Growth Regulators, Faculty of Science, Palacký University & Institute of Experimental Botany of the Czech Academy of Sciences, Šlechtitelů 27, 783 71 Olomouc, Czech Republic

Cyclin-dependent kinases (CDKs) are essential for numerous cell functions, including cell cycle regulation. Malfunctioning of these enzymes may, therefore, lead to various types of cancer. CDK4/CDK6 inhibitors palbociclib, ribociclib and abemaciclib have been approved by the FDA for the treatment of breast cancer1, showing the potential of molecules targeting CDKs. Cyclin-dependent kinase 2 (CDK2) is the most studied CDK family member2. We have performed a virtual screening of IOCB proprietary compound library against CDK2 kinase using quantum-mechanics based SQM/COSMO methodology.3 Three norbornane-based pseudo-nucleosides bearing a purine nucleobase were identified as CDK2 inhibitors. Using the known SAR in the purine-isostere-based kinase inhibitors4 we have predicted 72 potentially active structures. We have refined this number using the SQM/COSMO methodology and after evaluating synthetic feasibility we decided to synthesize 8 most promising compounds. Additionally, we decided to prepare 8 more compounds with the 1-hydroxymethyl-4-norbornyl moiety substituted for a cyclohexane in order to explore the importance of the key structural feature. Synthesis of the desired compounds started with the preparation of the double-bridgehead norbornane bicycle using radical cyclization as the key step. A 2-amino-6-chloropurine nucleobase was then constructed on the present amino group. A one-step strategy developed in our group proved useful for this transformation.5 A combination of two reactions without isolating the intermediate was used for the introduction of various substituents to the C-2 and C-6 positions. Either two consecutive SNAr reactions in one-pot or a combination of SNAr and a Buchwald reaction were employed, furnishing the final molecules. Synthesized compounds were evaluated for their biological activity against CDK2/CYCE. Micromolar to submicromolar values were recorded with some inactive compounds included as controls. The role of the 9-hydroxymethylnorbornyl moiety was clearly demonstrated as all compounds with this structural feature exerted submicromolar potencies. To unveil the potency determinants we have performed molecular docking and quantum-based SQM/COSMO scoring, which allowed us to identify the individual interactions in the binding cavity and clearly show roles of structural motives.

References 1) Klein, M. E.; Kovatcheva, M.; Davis, L. E.; Tap, W. D.; Koff, A.; Cancer Cell 2018, 34, 9-20. 2) Malumbres, M.; Genome Biol 2014, 15, 122. 3) Lepšík, M.; Řezáč, J.; Kolář, M.; Pecina, A.; Hobza, P.; Fanfrlík, J.; ChemPlusChem 2013, 78, 921-931. 4) Jorda, R.; Paruch, K.; Krystof, V.; Current Pharmaceutical Design 2012, 18, 2974-2980. 5) Dejmek, M.; Kovackova, S.; Zbornikova, E.; Hrebabecky, H.; Sala, M.; Dracinsky, M.; Nencka, R.; RSC Advances 2012, 2, 6970-6980.

117 P075 DISCOVERY AND OPTIMIZATION OF NEXT GENERATION REVERSIBLE METHIONINE AMINOPEPTIDASE-2 INHIBITORS - IDENTIFICATION OF METHIONINE M8891, A CLINICAL COMPOUND FOR THE TREATMENT OF CANCER

Timo Heinrich (1), Jeyaprakashnarayanan Seenisamy (2), Frank Becker (3), Beatrix Blume (1), Jörg Bomke (1), Michel Calderine (1), Uwe Eckert (1), Manja Friese-Hamim (1), Jakub Gunera (1), Kerrin Hansen (3), Rainer Kohl (1), Martin Lehmann (1), Birgitta Leuthner (1), Djordje Musil (1), Jens Pfalzgraf (1), Felix Rohdich (1), Christian Siegl (1), Dieter Spuck (1), Ansgar Wegener (1), Frank Zenke (1)

1) Merck Healthcare, Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany 2) Syngene International Ltd., Biocon Park, Plot 2&3, Bommasandra-Jigani Link Road, Bangalore 560 099, India 3) Intana Bioscience GmbH, Lochhamer Str. 29a, D-82152 Planegg/Martinsried, Germany

MetAP-2 plays a crucial role in co- and post-translational protein processing and inhibition of its proteolytic activity has been shown to block angiogenesis and tumor growth. Accordingly, small molecule inhibitors of MetAP-2 are promising options for the treatment of cancer. This talk describes the discovery and structure-based hit optimization of a novel MetAP-2 inhibitory scaffold, which coordinates the metal ions in the active site of MetAP-2 with the cyclic a-hydroxy-malonic diamide. The racemic screening hit 1 with a submicromolar enzymatic IC50 was discovered from a HTS campaign supported by serendipity. The re-synthesized eutomer confirmed this activity and inhibited HUVEC proliferation. The structural analysis of this hit revealed a sophisticated interaction pattern of polar and lipophilic contacts. Side chains of the scaffold were designed to occupy the liphophilic methionine recognition pocket as well as the shallow cavity at the opening of the active site. Optimized core decorations improved cellular potency to a two digit nanomolar IC50. In parallel, the molecular properties were carefully considered to give the advanced compound 2 showing high oral exposure and anti-tumor efficacy in xenograft models. PK drawbacks of 2 were addressed during lead optimization with focus on H-bond donor/acceptor counts. Essential for the efficient selection of candidates with in vivo activity was the identification of molecules with a long residence time on the target protein, high permeability and low efflux ratio not only in Caco-2 but also in the MDR-MDCK cell line. Biophysical parameters could only be measured via Fluorescence Cross Correlation Spectroscopy (FCCS) as not functionally active protein could be immobilized on a Surface Plasmone Resonance (SPR) compatible surface. Orally bioavailable, potent, and reversible MetAP-2 inhibitors impede growth of primary endothelial cells and demonstrated antitumoral activity in mouse models. In combination treatment with clinically relevant TKIs, significant efficacy including regression in animal models was observed with the clinical development compound M8891, which will be disclosed. An asymmetric synthesis of M8891 was established to fulfil compound demands during development.

References 1) Heinrich, T.; Seenisamy, J.; Blume, B.; Bomke, J.; Calderini, M.; Eckert, U.; Friese-Hamim, M.; Kohl, R.; Lehmann, M.; Leuthner, B.; Musil, D.; Rohdich, F.; Zenke, F. T. J. Med. Chem. 2019, 62 (10), 5025-5039. 118 P076 RATIONAL DESIGN AND OPTIMIZATION OF A NOVEL CLASS OF MACROCYCLIC ASK1 INHIBITORS

Martin Himmelbauer (1), Zhili Xin (1), Howard Jones (1), Istvan Enyedy (1), Kristopher King (2), Douglas J. Marcotte (3), Paramasivam Murugan (4), Joseph C. Santoro (4), Thomas Hesson (4), Kerri Spilker (3), Joshua L. Johnson (2), Michael J. Luzzio (1), Rab Gilfillan (1), Felix Gonzalez Lopez de Turiso (1)

1) Medicinal Chemistry. 2) Drug Metabolism and Pharmacokinetics. 3) Physical Biochemistry and Molecular Design. 4) Bioassays. Biotherapeutic and Medicinal Science. Biogen; 225 Binney Street, Cambridge, MA 02142. United States.

Apoptosis signal-regulating kinase 1 (ASK1, MAP3K5) is one of the pathways that modulate the cellular stress response and, once activated, it leads to downstream phosphorylation of mitogen-activated protein kinases (MAPKs) p38 and c-Jun-N-terminal kinase (JNK).1 These two kinases are responsible for both the inflammatory and apoptotic stress response and it has been hypothesized that modulation of ASK1 in the CNS might be a relevant strategy for the treatment of several neurological disorders.2,3 Using the X-ray cocrystal structure of a peripherally restricted ASK1 inhibitor as inspiration, we designed a novel class of macrocyclic ASK1 inhibitors represented by the general structure 1. The optimization of these analogs was enabled by a modular synthetic approach and led to the discovery of compounds with good potency, PK profile and excellent CNS-exposure.4

References 1) Matsukawa, J.; Matsuzawa, A.; Takeda, K.; Ichijo, H. The ASK1-MAP Kinase Cascades in Mammalian Stress Response. J. Biochem. 2004, 136, 261-265. 2) Kawarazaki, Y.; Ichijo, H.; Naguro, I. Apoptosis signal-regulating kinase 1 as a therapeutic target. Expert Opin. Ther. Targets. 2014, 18, 651-664. 3) Nishitoh, H.; Kadowaki, H.; Nagai, A.; Maruyama, T.; Yokota, T.; Fukutomi, H.; Noguchi, T.; Matsuzawa, A.; Takeda, K.; Ichijo, H. ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1. Genes Dev. 2008, 22, 1451-1464. 4) Himmelbauer, M. K.; Xin, Z.; Jones, H.; Enyedy, I.; King, K.; Marcotte, D. J.; Murugan, P.; Santoro, J. C.; Hesson, T.; Spilker, K.; Johnson, J. L.; Luzzio, M. J.; Gilfillan, R.; Gonzalez Lopez de Turiso, F. Rational Design and Optimization of a Novel Class of Macrocyclic ASK1-inhibitors. J. Med. Chem. DOI: 10.1021/acs.jmedchem.9b01206, Publication Date (Web) 11 Nov 2019.

119 P077 HITS FOR THE CREATING OF ANTI-TUBERCULOSIS AND ANTI-DIABETIC LEAD-COMPOUNDS AMONG β-AMINOPROPIOAMIDOXIMES DERIVATIVES

Lyudmila Kayukova (1), Kaldybay Praliyev (1), Asem Uzakova (1), Gulnur Baitursynova (1), Malik Adenov (2), Lyazzat Yeraliyeva (2), Bekzat Toksanbaeva (2), Venera Bismilda (2), Lyailya Chingissova (2), Alexander Gulyayev (3), Zarina Shulgau (3), Shynggys Sergazy (3)

1) JSC «A.B. Bekturov Institute of Chemical Sciences», 106 Sh. Ualikhanov Str., Almaty, 050010, Kazakhstan 2) RSE «National Scientific Center for Phthisiopulmonology of the Republic of Kazakhstan» MH RK, 5 Bekhozhin Str., Almaty, 050010, Kazakhstan 3) RSE «National Center for Biotechnology» SC of MES RK, Kurgalzhynskoye road, building 13/5, Nur-Sultan, 010000, Kazakhstan

Tuberculosis and diabetes mellitus have recently been acute public health problems. Tuberculosis and diabetes are seen as the convergence of two epidemics. In May 2014, the World Health Assembly endorsed WHO’s new, post-2015, global TB strategy (WHA resolution A67/11), which incorporates all essential elements of TB and diabetes collaborative activities [1, 2]. There is an urgent need for an innovative approach to the search for new synthetic drugs that simultaneously possess by anti-tuberculosis and anti-diabetic activity. The authors revealed new salts and bases of O-aroyl-β-(morpholin-1-yl)propioamidoximes and 3,5-disubstituted 1,2,4-oxadiazoles (I–V) which are competitively low-toxic, highly in vitro active on drug sensitive (DS) and multidrug resistant (MDR) strains of M. tuberculosis (MTB) and at the same time significantly reduce the glucose level in comparison with control and standards: α-amylase (α-AMLS) and α-glucosidase (α-GLCS) [3].

The most active bifunctional compounds are: Ia, IIIa–c, IVa–c, V. Their minimum inhibitory concentrations (MICs) on Shkolnikova's liquid medium on DS strains of MTB are within 0,01–2,0 μg/ml; on MDR strains of MTB within 0,01–5,0 μg/ml. At the same time, they exhibit inhibition of α-AMLS in the range 26–51%; α-GLCS in the range 23–79%. These compounds have subcutaneous LD50 values in the range 325–1385 mg/kg. Compounds IIId, e show only an interesting anti-tuberculosis activity in 0,1 μg/ml on DS and MDR strains of MTB with subcutaneous LD50 values equal 750 and 1530 mg/kg. Also a compound IIIf revealing a high inhibition of α-GLCS in 78% and an average MIC value on DS strain of MTB in 50 μg/ml is present. Compounds Ib and II show mean values of anti-TB and anti-D activity.

Rifampicin with MICs on DS and MDR strains in 1,0 and 2,0 μg/ml and subcutaneous LD50 value in 267 mg/kg was used as a reference at the definition of anti-TB activity. Acarbose with inhibition of α-AMLS in 71% and α-GLCS in 76% was adopted as a standard at the determining of anti-D activity; acarbose is practically non-toxic with oral LD50 value in 24000 mg/kg. Further development of the lead-compounds in their preclinical studies is required. Therapy with the most active and least toxic bifunctional compounds should reduce the drug burden at the treating of patients with diabetes and tuberculosis, increase the safety of the therapy and reduce the time and cost of these diseases treating. The trip to the conference was funded by the International Science and Technology Center (ISTC).

References 1) Dooley K.E., Chaisson R.E. Tuberculosis and diabetes mellitus: convergence of two Epidemics // Lancet Infect Dis. ‒ 2009. ‒ Vol. 9, № 12. ‒ Р. 737–746. Doi:10.1016/S1473-3099(09)70282-8. 2) THE LOOMING CO-EPIDEMIC OF TB-DIABETES: A CALL TO ACTION; Knut Lönnroth, WHO FORWARD. https://www.theunion.org/what-we-do/publications/technical/english/ EMBARGOED-DMTB-REPORT-Oct-22.pdf 3) Award No. 1308/ГФ4 of the Science Committee of the Ministry of Education&Science of the Republic of Kazakhstan (2015–2017). Project topic: «Development of anti-tuberculosis and antidiabetic drugs based on the new β-aminopropioamidoxime derivatives». 120 P078 DISCOVERY AND OPTIMIZATION OF PYRIDYL-CYCLOALKYL-CARBOXYLIC ACIDS AS INHIBITORS OF MICROSOMAL PROSTAGLANDIN E SYNTHASE-1 FOR THE TREATMENT OF ENDOMETRIOSIS

Marcus Koppitz

Bayer AG, Medicinal Chemistry, Muellerstrasse 178, 13353 Berlin, Germany

Here we report on novel and potent pyridyl-cycloalkyl-carboxylic acid inhibitors of microsomal prostaglandin E synthase-1 (PTGES). PTGES produces, as part of the prostaglandin pathway, prostaglandin E2 which is a well-known driver for pain and inflammation. This fact together with the observed upregulation of PTGES during inflammation suggests that blockade of the enzyme might provide a beneficial treatment option for inflammation related conditions such as endometriosis. Compound 5a, a close analogue of the screening hit, potently inhibited PTGES in vitro, displayed excellent PK properties in vitro and in vivo and demonstrated efficacy in a CFA-induced pain model in mice and in a rat dyspareunia endometriosis model and was therefore selected for further studies.

121 P079 NUCLEOSIDES MODIFIED ON SUGAR AND BASE: SYNTHESIS AND BIOLOGICAL PROFILING

Matouš Krömer (1,2,5), Iryna Listakhava (1,2,5), Marián Hajdúch (3,4), Michal Hocek (1,2)

1) Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo náměstí 2, CZ-16610 Prague 6, Czech Republic; [email protected] 2) Department of Organic Chemistry, Faculty of Science, Charles University in Prague, Hlavova 8, CZ-12843, Prague 2, Czech Republic 3) Faculty of Medicine and Dentistry, Institute of Molecular and Translational Medicine, Palacky University, Hněvotínská 5, CZ-775 15 Olomouc, Czech Republic; [email protected] 4) University Hospital in Olomouc, Hněvotínská 5, CZ-775 15 Olomouc, Czech Republic 5) These authors contributed equally

Modified nucleosides have been extensively studied for their broad biological activity spectrum. Among them, 7-deazapurine derivatives represent a prominent group showing anticancer, antiviral and antimicrobial activity[1]. Previously, we have synthesized different base-modified nucleosides modified in positions C6 or C7 by (het)aryl groups. Derivatives bearing small hetaryl rings showed remarkable cytostatic activities[2], while substitution by bulky (het)aryl group led to significant inhibition of either human or mycobacterial adenosine kinases (ADK) and, as a result in the latter case, strong antibacterial effect[3]. Since C5’ position is the catalytic site of the ADK, we envisaged that removing the hydroxyl group from this site would increase ADK inhibition and enhance biological effects[4,5]. In this study we will present desing, synthesis and biological profiling of double modified 7-deazapurine nucleosides with C5’ hydroxyl group removed and simultaneously either C6 or C7 position substituted with groups of various bulkiness.

References 1) P. Perlíková, M. Hocek, Med. Res. Rev. 2017, 37, 1429–1460. 2) P. Nauš, R. Pohl, I. Votruba, P. Džubák, M. Hajdúch, R. Ameral, G. Birkus, T. Wang, A. S. Ray, R. Mackman, et al., J. Med. Chem. 2010, 53, 460–70. 3) J. Snášel, P. Nauš, J. Dostál, A. Hnízda, J. Fanfrlík, J. Brynda, A. Bourderioux, M. Dušek, H. Dvořáková, J. Stolaříková, et al., J. Med. Chem. 2014, 57, 8268–79. 4) M. C. Long, W. B. Parker, Biochem. Pharmacol. 2006, 71, 1671–82. 5) M. C. Long, S. C. Shaddix, O. Moukha-Chafiq, J. A. Maddry, L. Nagy, W. B. Parker, Biochem. Pharmacol. 2008, 75, 1588–600.

122 P080 EARLY DRUG DISCOVERY EFFORTS TOWARDS THE IDENTIFICATION OF NOVEL EP300/CBP HAT INHIBITORS

Julian Levell, Jonathan Wilson, Archana Bommi-Reddy, Annissa Huhn, Florence Poy, Anna Gardberg, Francois Brucelle, Richard Cummings, Robert Sims

Constellation Pharmaceuticals, Inc., Cambridge MA 02142, USA

p300 and CREB-binding protein (CBP) play important roles in the epigenetic regulation of gene transcription and their disfunction has been implicated in multiple disease states. The histone acetyl transferase domain of p300 and CBP is responsible for the acetylation of lysine residues on histones, such as lysines 18 and 27 of histone 3, and acetylation of other proteins including transcription factors and hormone receptors. Through these mechanisms, p300 and CBP are responsible for regulating the transcription of multiple genes directly by modification of chromatin or indirectly by modulating the activity of transcription factors. Herein, we present Constellation’s early drug-discovery efforts toward the identification of small molecule inhibitors of the histone acetyltransferase activity of p300 and CBP. Topics will include our screening strategy, biochemical and biophysical mechanism of action studies, SAR evolution, and X-ray crystal structures of multiple lead classes.

123 P081 DEVELOPMENT OF NPP1 INHIBITORS AS POTENTIAL DRUGS FOR THE TREATMENT OF OSTEOARTHRITIS/CPPD DISEASE

Molhm Nassir (1), Uri Arad (2), Christa E. Müller (3), Bilha Fischer (1)

1) Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900 Israel 2) Department of Rheumatology, Tel Aviv Medical Center and the Faculty of Medicine, Tel Aviv University, Tel Aviv, 6997801, Israel 3) c PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany

Nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) inhibitors have been suggested as a potential treatment for calcium pyrophosphate dihydrate (CPPD) deposition disease. Here, we targeted the development of improved NPP1 inhibitors based on acyclic mimics of Pα,α-phosphorodithioate-substituted adenine nucleotides, 1-4. The latter were obtained in a facile two-step synthesis from adenine-(methoxy)ethanol. Among analogs 1-4, adenine-(methoxy)ethoxy-Pα,α-dithio–triphosphate, 2, was the most potent NPP1 inhibitor both with purified enzyme (IC50 0.645 µM) and in osteoarthritic human chondrocytes (IC50 0.033 µM). Furthermore, it efficaciously (10-fold vs. control) inhibited ATP-induced CPPD in human articular chondrocytes. Importantly, 2 was a highly selective NPP1 inhibitor which showed only minor inhibition of NPP3, CD39 and CD73, and did not inhibit TNAP (tissue nonspecific alkaline phosphatase) activity in human chondrocytes. Furthermore, 2 did not activate P2Y1,2,6 receptors. Analog 2 was not toxic to cultured chondrocytes at 100 µM. Therefore, 2 may be suitable for further development as a drug candidate for the treatment of CPPD arthritis and other NPP1-related diseases.

Fig. 1. Novel adenine nucleotide analogs developed here as NPP1 inhibitors.

References 1) Nassir, Molhm, et al. 2) Nassir, Molhm, et al. 3) Nassir, Molhm, et al.

124 P082 USING FRAGMENT-BASED LEAD DISCOVERY TO GENERATE NEW SCAFFOLDS FOR THE DEVELOPMENT OF FXIIA INHIBITORS

Clara Davoine (1,2), François Simon (1), Charlotte Bouckaert (1), Steve Lanners (1), Marianne Fillet (2), Lionel Pochet (1)

1) Namur Medicine & Drug Innovation Center (NAMEDIC - NARILIS), University of Namur, Belgium, Rue de Bruxelles 61, 5000 Namur, Belgium 2) Laboratory for the Analysis of Medicines (LAM), Department of Pharmacy, CIRM, University of Liege, Belgium, Place du 20 Août 7, 4000 Liège, Belgium

Tackling thrombotic disorders without affecting the hemostatic capacity remains a challenge in medicine. Until now, the direct oral anticoagulants (DOACs) on the market could induce severe bleeding side effects. One of the strategies to find safer antithrombotic therapies is to target coagulation factor XIIa (FXIIa). Indeed, several studies on different animal models suggest that the inhibition of FXII or FXIIa leads to the development of anticoagulants devoided of a bleeding risk with additional anti-inflammatory properties. Also, anti-FXII directed therapies could answer unmet medical needs such as the safe prevention of thrombosis in patients exposed to blood-contacting medical devices [1]. Besides its implication in thrombosis, the inhibition of FXII is attractive as a therapeutic strategy to interfere with excessive vascular leakage in patients suffering from hereditary angioedema [2] and as an emerging research field in neuro-inflammatory and neurodegenerative disorders [3]. The FXII or FXIIa inhibitors currently under development include peptides, proteins, antibodies, and RNA-based technologies. In contrast, only a few data regarding the design of synthetic small molecular-weight inhibitors of FXIIa are available. Our team previously developed 3-carboxamido-benzopyrans [4]. Encouraging results demonstrate that the compounds are anticoagulants and are quite selective for the contact phase pathway [4c]. Importantly, this study showed that aromatic guanidine is an attractive starting point in the design of FXIIa inhibitors. Besides the modulations of the 3-carboxamide coumarins, the search for new chemical scaffolds has been started. To facilitate the chemical exploration, we decided to apply a fragment-based lead discovery approach (FBLD). With this aim in view, we set up a high concentration bioassay as primary screening and we elaborate an initial library of fragments bearing an amidine or a guanidine moiety. The library was further enlarged with available in-house compounds and with structures close to potent serine protease inhibitors described in the literature. For the constitution of this library, computational studies were also undertaken. In this communication, the results of these investigations will be presented.

References 1) a) A.H. Schmaier, E.X. Stavrou, Res Pract Thromb Haemost. (2019), 1–8.; b) B. Tillman, D. Gailani, Semin Thromb Hemost. (2018), 44(1), 60–9. 2) J. Bjorkqvist, S. de Maat, U. Lewandrowski, A. Di Gennaro, C. Oschatz, K. Schonig, M.M. Nothen, C. Drouet, H. Braley, M.W. Nolte, A. Sickmann, C. Panousis, C. Maas, T. Renne, J Clin Invest, 125 (2015) 3132-3146. 3) S. Lorenzano, M. Inglese, T. Koudriavtseva, Editorial: Role of Coagulation Pathways in Neurological Diseases. Front Neurol (2019), 10, 1–3. 4) a) S. Robert, C. Bertolla, B. Masereel, J.M. Dogné, L. Pochet, Journal of Medicinal Chemistry, 51 (2008) 3077-3080; b) C. Bouckaert, S. Serra, G. Rondelet, E. Dolušić, J. Wouters, J.M. Dogné, R. Frédérick, L. Pochet, Eur J of Med Chem, 110 (2016) 181-194; c) C. Bouckaert , S. Zhu, J. W. P. Govers-Riemslag, M. Depoorter, S. L. Diamond, L. Pochet, Thromb Res, 157 (2017) 126-133.

125 P083 IDENTIFICATION AND IN-VIVO EFFICACY STUDIES OF NOVEL NNMT INHIBITORS

Sven Ruf (1), Mahanandeesha Siddappa Hallur (2), Nisha K. Anchan (2), Indu N. Swamy (2), Karthikai Raj Murugesan (2), Sayantani Sarkar (2), Lokesh Kananti Narasimhulub (2), V.P. Rama Kishore Putta (2), Shama Shaik (2), Devaraj Venkatapura Chandrasekar (2), Vishal Subhash Mane (2), Sanjay Venkatachalapathi Kadnur (2), Juluri Suresh (2), Ravi Kanth Bhamidipati (2), Manvi Singh (2), Raghunadha Reddy Burri (2), Rajendra Kristam (2), Herman Schreuder (1), Joerg Czech (1), Christine Rudolph (1), Alexander Marker (1), Thomas Langer (1), Ramesh Mullangi (2), Takeshi Yura (2), Ramachandraiah Gosu (2), Aimo Kannt (1,3), Saravanakumar Dhakshinamoorthy (2), Sridharan Rajagopal (2)

1) Sanof-Aventis Deutschland GmbH, 65926 Frankfurt am Main, Germany 2) Jubilant Biosys Ltd. Bangalore, 560022 India 3) Institute of Experimental Pharmacology, Medical Faculty Mannheim, University of Heidelberg, D-68167 Mannheim, Germany

Obesity is considered as one of the major risk factors of development of insulin resistence and Type 2 diabetes (T2D). Nicotinamide N-methyl transferase (NNMT), an enzyme that catalyzes the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to nicotinamide (NA) to form N-methylnicotinamide (MNA) is implicated in the regulation of body weight and insulin sensitivity. NNMT is expressed in the liver, adipose and other tissues.1,2 Several reports have suggested the role of NNMT in various disease conditions including metabolic disorders.3-5 Increased expression of NNMT has also been linked to enhanced cell proliferation and disease progression in a wide variety of cancers. It is also known that NNMT is up-regulated in Parkinsons’s disease and in ageing skeletal muscle tissue. 6-8 Recent reports have highlighted the relationship between high expression of NNMT and obesity/T2D 9,10 In our work we identified a novel nicotinamide (NA) derivative, that was able to inhibit the NNMT enzymatic activity in vitro and reduced the in-vivo formation of 1-methyl-nicotinamide (MNA), the primary metabolite of NA by ~80% after 2 h when administered to mice at 50mg/kg p.o.

References 1) Aksoy S, Szumlanski CL, Weinshilboum RM. J Biol Chem. 1994;269,14835–14840 2) Riederer M, Erwa W, Zimmermann R, Frank S, Zechner R. Atherosclerosis 2009;204,412–417 3) Xu J, Moatamed F, Caldwell JS, et al. J Clin Endocrinol Metab. 2003;88,4990–4996 4) Roessler M, Rollinger W, Palme S, et al. Clin Cancer Res. 2005;11,6550–6557 5) Sartini D, Muzzonigro G, Milanese G, Pierella F, Rossi V, Emanuelli M. J Urol. 2006;176,2248–2254 6) Sartini D, Santarelli A, Rossi V, et al. Mol Med. 2007;13,415–421 7) Tomida M, Mikami I, Takeuchi S, Nishimura H, Akiyama H. J Cancer Res Clin Oncol. 2009;135,1223–1229 8) Parsons RB, Smith ML, Williams AC, Waring RH, Ramsden DB . J. Neuropathol Exp Neurol. J. Neuropathol Exp Neurol. 2002;61:111–124 9) Williams AC, Ramsden DB. J Clin Neurosci. 2005;12:6–11. 10 10) Salek RM, Maguire ML, Bentley E, et al. Physiol Genomics. 2007;29:99–108.

126 P084 WANDERING THROUGH EPITRANSCRIPTOMICS DRUG DISCOVERY LAND WITH A BIOPHYSICAL GPS

Gregg Siegal (1), Stijn Gremmen (1), Willem-Jan Waterreus (1), Johan Hollander (1), Marta Carneiro (1), Birgit Zech (2), Gerhard Mueller (2)

1) ZoBio BV, J.H. Oortweg 19, 2333CH, Leiden, NL 2) Gotham Therapeutics, Am Klopferspitz 19a, 82152 Martinsried, Germany

The modulation of enzymes involved in chemical modifications of RNA (epitranscriptomics) is rapidly gaining interest in drug discovery. Gotham Therapeutics and ZoBio initiated a collaboration to develop small-molecule inhibitors/antagonists of proteins that recognize or modify the m6A nucleotide in messenger RNA and thereby regulate protein expression. These epitranscriptomic proteins can be divided into three classes: readers, writers and erasers and we have advanced programs in all three together with Gotham. A synergistic approach across the classes is expected to result in a deep understanding of the common mechanism for recognizing m6A-RNA modification and developing libraries of privileged structures for binding to epitranscriptomic targets. The most advanced program focuses on the “writer” protein complex METTL3/METTL14, a SAM-dependent methyltransferase. The other two programs on undisclosed targets, focus on a protein that recognizes m6A RNA and a demethylase. All three targets were unprecedented at the outset, meaning no biophysical assays, much less tool compounds, were available to initiate a drug discovery campaign. Here I will present how we developed biophysical assays to enable med chem decision making, even before high resolution structural information became available. In particular, I will discuss how we used purely biophysical approaches to develop a biologically relevant screening cascade, which was later confirmed and supplemented with more traditional biochemical assays. Results of fragment screening will be compared to HTS and DNA encoded library screens based on careful characterization of hits from each technique with the biophysical assays. The use of both NMR and crystallography to obtain structural information, with special emphasis on how these two orthogonal techniques synergize, will also be presented. Finally, I will illustrate how synthesis of this information was actually used to make informed medicinal chemistry decisions.

127 P085 D2AAK2 AS DOPAMINE D2 RECEPTOR ANTAGONIST WITHOUT A PROTONATABLE NITROGEN ATOM – IN SILICO, IN VITRO AND IN VIVO EVALUATION AS A POTENTIAL ANTIPSYCHOTIC

Piotr Stępnicki (1), Katarzyna Targowska-Duda (2), Marta Kruk-Słomka (3), Andrea G. Silva (4), Anna Kozak (1), Tomasz M. Wróbel (1), Grażyna Biała (3), Marián Castro (4), Agnieszka A. Kaczor (1,5)

1) Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodźki St., PL-20093 Lublin, Poland 2) Department of Biopharmacy, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodźki St., PL-20093 Lublin, Poland 3) Department of Pharmacology and Pharmacodynamics, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodźki St., PL-20093 Lublin, Poland 4) 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 5) School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, FI-70211 Kuopio, Finland

Schizophrenia is a chronic mental disorder with complex and still not fully understood pathomechanism. Currently available antipsychotics are often not sufficiently effective against symptoms of the disease. In search for novel potential antipsychotics, structure-based virtual screening was performed in order to identify new antagonists of dopamine D2 receptor [1]. From among ten found novel ligands, four with the best affinities to dopamine D2 receptor were subjected to further in silico, in vitro and behavioral studies to evaluate their potential antipsychotic properties. The compound D2AAK2 (Fig. 1), second of identified hits, lacks a protonatable nitrogen atom, which constitutes a key element of interaction with orthosteric binding site of aminergic G protein-coupled receptors. Instead, it has an amide nitrogen atom with a hydrogen atom, that may interact electrostatically with the conserved Asp(3.32). The D2AAK2 analogues with an alkylated amide nitrogen atom are inactive which can support the orthosteric binding mode. However, its analogues with an additional protonatable nitrogen atom are also inactive which can suggest the allosteric mode of action. Performed in vitro radioligand binding assays and behavioral studies (amphetamine-induced hyperactivity test, elevated plus maze test, passive avoidance test) revealed affinity of the compound to key molecular targets in schizophrenia, and its antipsychotic, anxiogenic and procognitive effects.

References 1) Kaczor AA, Silva AG, Loza MI, Kolb P, Castro M, Poso A. ChemMedChem 2016;11(7):718-29.

128 P086 DEVELOPMENT OF NEXT GENERATION ANTITUBERCULAR BENZOTHIAZINONES BY METABOLISM GUIDED LEAD OPTIMIZATION

Hector Torres-Gomez, Kamil Philip Wojtas, Sebastian Schieferdecker, Francois Keiff, Melanie Joch, Maria Strassburger, Florian Meyer, Florian Kloss

Transfer Group Antiinfectives, Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Insitute, Beutenbergstrasse 11a, 07745, Jena, Germany

Tuberculosis represents a major public health threat with approximately 1.5 million associated deaths annually and an alarming rise of multi drug resistant (MDR) strains. Therefore, the advancement of new effective antitubercular drugs is desperately needed.1 BTZ-043 is a highly potent member of the benzothiazinone (BTZ) class which comprises covalent inhibitors of decaprenylphosphoryl-β-D-ribose 2′-epimerase (DprE1), an essential cell wall target of Mycobacterium tuberculosis.2 Currently, BTZ-043 is undergoing clinical development within a partnership of our group and associates.3,4 Recently, several in vivo studies revealed the formation of an unprecedented transient hydride Meisenheimer complex metabolite.5 Apart from the discovery of a BTZ-specific metabolic feature, this observation provided new starting points for lead optimization endeavors. Through different rational design strategies we were able to address this issue and prepared a series of next generation BTZs showing reduced hydride Meisenheimer complex formation and favorable pharmacological properties.

References 1) WHO Global Tuberculosis Report 2018-Executive Summary, WHO Press Geneva 2) V. Makarov, G. Manina, K. Mikusova, O. Rvabova, B. Saint-Joanis, N. Dhar; M. R. Pasca; S. Buroni; A. P. Lucarelli et al. Science, 2009, 324, 801-804 3) ClinicalTrials.gov Identifiers: NCT03590600, NCT04044001 4) EMA Designation Number: EU/3/18/2029 5) F. Kloss; V. Krchnak; A. Krchnakova; S. Schieferdecker; J. Dreisbach; V. Krone; U. Möllmann; M. Hoelscher; M. J. Miller. Angew. Chemie. Int. Ed. 2017, 56, 2187-2191

129 P087

NOVEL KV7 ION CHANNEL OPENERS FOR THE TREATMENT OF EPILEPSY

D.A. Jeyaraj (1), Sridharan Rajagopal (1), Swapan Kumar Samanta (1), Naveena Madhyastha (1), Bharathi Mohan Kuppusamy (1), Robert W. Dougherty (2), Ravi Kanth Bhamidipati (1), Zainuddin Mohd (1)

1) Jubilant Biosys, Bangalore, Karnataka, India 2) Jubilant Discovery Services, Malvern, PA, United States

Kv7 neuronal voltage gated potassium channels are the molecular mediators of the M current and regulate membrane excitability in the central and peripheral neuronal systems. We report novel small molecule Kv7 openers that show anti-seizure activities in electroshock and pentylenetetrazol induced seizure models, without any influence on Rotarod readouts in mice. Anti-seizure activity was observed in proportion to the unbound concentration of the compound in the brain.

These molecules originated from a high throughput screen using heterodimeric Kv7.2/7.3 channels. Two similar but structurally distinct lead series were identified. The SAR and optimization process of these series will be presented. The results of representative compounds in seizure models will also be shown. Kv7 ion channels are also expressed in the bladder smooth muscle (detrusor) and therefore the impact of individual Kv7 isoforms was investigated in human detrusor tissue using a panel of Kv7 openers with distinct activity profiles against Kv7 isoforms. Effects of the novel Kv7 openers on detrusor contraction will also be shown.

References 1) Mark A. Seefeld et al., Bioorg. Med. Chem. Lett., 2018;28:3793-3797

130 P088 DESIGN, SYNTHESIS AND SAR STUDIES OF BORONIC ACID INHIBITORS FOR THE β-LACTAMASE KPC-2

JINGYUAN ZHOU, PAUL STAPLETON, SHOZEB HAIDER, JESS HEALY, GEOFFREY WELLS

UCL School of Pharmacy, 29-39 Brunswick Sq., London, WC1N 1AX, UK

Multidrug resistance (MDR) has been found in many species of bacteria since the introduction of antibiotics. Resistance can occur via several mechanisms, for example, expression of drug-inactivating enzymes. β-lactamase enzymes such as K. pneumoniae carbapenemase (KPC-2), are the predominant cause of resistance to β-lactam antibiotics. Boronic acid derivatives inhibit β-lactamases by mimicking the tetrahedral transition state of the enzyme complex (Figure 1).

Figure 1a) Mechanism of serine β-lactamases inactivate meropenem. b) Boronic acids bind to serine β-lactamases covalently. This project aims to design and synthesis small molecule inhibitors of KPC-2 based on the scaffold of the known ligand: 3-NPBA, followed by in vitro tests of the compounds against the purified enzyme and bacteria expressing KPC-2 in order to evaluate structure-activity relationships (SAR). Promising inhibitors for KPC-2 have been developed with a scaffold containing a 1,4-disubstituted 1,2,3-triazole (Zhou J. et al., 2018). The compounds in cellulo (disk diffusion and MIC test) have shown successful reversal of resistance to cefotaxime (CTX) and meropenem (MEM) in KPC-2 producing E. coli (over 512-fold more sensitive). Enzyme kinetics data indicate that the compounds have a clear SAR and the best inhibitors has a nanomolar Ki value (32.5 nM).

References 1) Zhou J., Stapleton P., Haider S, Healy J. (2018) Bioorganic & Medicinal Chemistry 26, 2921–2927.

131 132 POSTERS

Others

133 P091 BENZOYLTHIOSEMICARBAZIDES AS PROMISING ANTIMICROBIAL AGENTS TARGETING D-ALANINE-D-ALANINE LIGASE IN BACTERIO

Alice Ameryckx (1), Leopold Thabault (1), Lionel Pochet (2), Francoise Van Bambeke (1), Raphael Frederick (1)

1) Medicinal Chemistry Research Group/Cellular and Molecular Pharmacology, Louvain Drug Research Institute (LDRI), Universite catholique de Louvain, Av. E Mounier 74, 1200 Woluwe-Saint-Lambert, Belgium 2) Department of Pharmacy, Namur Medicine & Drug Innovation Center (NAMEDIC), Namur Research Institute for Life Sciences (NARILIS), University of Namur, Namur, Belgium

As the phenomenon of antibiotic resistance is dramatically increasing these days, searching for new therapeutic targets less vulnerable to this resistance issue appears as a real need.1 The cell wall of bacteria and the enzymes that are involved in its synthesis are promising targets for many antibiotics, which inhibit the late stages of peptidoglycan biosynthetic pathway.2 But the resistance phenomena have revealed the high flexibility in this assembly pathway, and the need to target other enzymes acting on earlier steps of peptidoglycan synthesis.3 D-alanyl-D-alanine ligase (Ddl) is of particular interest as it utilizes a substrate (D-alanine) which is specific for bacterial peptidoglycan biosynthesis and essential for bacterial growth.4 In this work, a series of 37 benzoylthiosemicarbazides inhibitors of D-Ala-D-Ala ligase (Ddl) were designed and synthesized in order to target resistant strains of bacteria. Among these, the 4-(3,4-dichlorophenyl)-1-(2-hydroxybenzoyl)-3-thiosemicarbazide 1 was identified as a very potent Ddl inhibitor with an activity in the micromolar range. This compound, possessing strong antimicrobial activities including against multidrug resistant strains, was proved to act through a bactericidal mechanism and demonstrated very low cytotoxicity on THP-1 human monocytic cell line.

Further structure-activity relationships (SARs) studies provided evidence that the hydroxyl substituent in the 2-position (R1) of the benzoylthiosemicarbazide scaffold is essential for the enzymatic inhibition. The in vivo biochemical mechanism was then determined by UPLC-MS dosage6 of intracellular L-Ala, D-Ala and D-Ala-D-Ala levels in response to 4-(3,4-dichlorophenyl)-1-(2-hydroxybenzoyl)-3-thiosemicarbazide 1. Finally, these encouraging results prompted us to investigate the selectivity of this compound towards various enzymes and receptors. This work thus highlights the thiosemicarbazide motif as very promising for the development of novel antibacterial compounds acting through an interesting mechanism of action, good selectivity and low cytotoxicity.

References 1) Cassell, G. H.; Mekalanos, J., JAMA 2001, 285 (5), 601-605. 2) Fan, C.; Moews, P. C.; Walsh, C. T.; Knox, J. R., Science 1994, 266 (5184), 439-443. 3) Tytgat, I.; Colacino, E., et al., Curr. Med. Chem. 2009, 16 (20), 2566-2580. 4) (a) Zawadzke, L. E.; Bugg, T. D.; Walsh, C. T., Biochemistry 1991, 30 (6), 1673-1682; (b) Gholizadeh, Y.; Prevost, M., et al., Protein Sci. 2001, 10 (4), 836-844. 5) S. Putty, A. Rai, D. Jamindar, P. Pagano, C. L. Quinn, T. Mima, H. P. Schweizer, W. G. Gutheil, Chem. Biol. Drug. Des. 2011, 78, 757-763

134 P092 THE DESIGN, SYNTHESIS AND EVALUATION OF MECHANISTIC PROBES OF IDO1

Nicholas J. Cundy (1), Tina Tang (3), Richard S. Grainger (1), Sam Butterworth (2), Nicholas M. Barnes (3), Emma L. Raven (4)

1) School of Chemistry, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK 2) School of Pharmacy, University of Manchester, Oxford Road, Manchester, M13 9PL, UK 3) Institute of Clinical Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK 4) School of Chemistry, University of Bristol, Kingsdown, Bristol, BS8 1TS, UK

Degradation of tryptophan by over-expression of IDO1 (indolamine-2,3-dioxygenase) has been linked with the immunosuppressive effect of a number of cancers; therefore inhibition of IDO1 has the potential to provide therapeutic benefit.1 Examples of clinically evaluated competitive IDO1 inhibitors include 1-methyl-D -tryptophan and epacadostat.2 Considerable effort has also been dedicated to unravelling the mechanism by which IDO1 metabolises L-tryptophan.3

Our research aims to build on the current mechanistic understanding of IDO1 to rationally design irreversible inhibitors of IDO1. Through irreversible inhibition we hope to achieve a prolonged effect and allow the immune system to respond to the threat posed by cancerous cells. By mimicking natural substrates of IDO1, and including structural motifs that intercept the natural mechanistic pathway, we propose that inhibition can be achieved using tryptophan analogues A and B or tryptamine analogue C.

This poster will describe synthetic approaches to A-C and the results for the preliminary evaluation for their utility as mechanistic probes.

References 1) C. Uyttenhove, L. Pilotte, I. Theate, V. Stroobant, D. Colau, N. Parmentier, T. Boon and B. J. Van den Eynde, Nat. Med., 2003, 9, 1269. 2) i. S. G. Cady and M. Sono, Arc. Biochem. Biophys., 1991, 291, 326; ii. C. Jochems, M. Fantini, R. I. Fernando, A. R. Kwilas, R. N. Donahue, L. M. Lepone, I. Grenga, Y. S. Kim, M. W. Brechbiel, J. L. Gully, R. A. Madan, C. R. Heery, J. W. Hodge, R. Newton, J. Schlom and K. Y. Tsang, Oncotarget, 2016, 7, 37762. 3) J. Basran, I. Efimov, N. Chauhan, S. J. Thackray, J. L. Krupa, G. Eaton, G. A. Griffith, C. G. Mowat, S. Handa and E. L. Raven, J. Am. Chem. Soc., 2011, 133, 16251.

135 P093 SYNTHESIS AND CHARACTERIZATION OF FUROXAN DERIVATIVES WITH IN VIVO STERILIZING ANTITUBERCULAR ACTIVITY

Guilherme Felipe Santos Fernandes (1), Paula Carolina De Souza (1,2), Leonardo Biancolino Marino (1), Camila Maríngolo Ribeiro (1), Patricia Bento Da Silva (1), Marlus Chorilli (1), (1), Caio Sander Paiva Silva (1), Flávia Aparecida Resende (1), Mariana Cristina Solcia (1), Rone Aparecido De Grandis (1), Sang Hyun Cho (2), Yuehong Wang (2), Scott Gary Franzblau (2), Fernando Rogério Pavan (1), Jean Leandro Dos Santos (1)

1) School of Pharmaceutical Sciences, São Paulo State University, Araraquara, Brazil 2) Institute of Tuberculosis Research, University of Illinois at Chicago, Chicago, Illinois, USA

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), is the infectious disease responsible for the highest number of deaths worldwide. According to the World Health Organization, the disease was responsible for 1.5 million deaths and there were an estimated 10.0 million new cases in 2018. Furthermore, an increased number of multidrug-resistant (MDR) and extensively-drug resistant (XDR) strains has alarmed authorities around the world and is currently, the major global challenge of the scientific community in the fight against the disease. Herein, a series of furoxan derivatives were synthesized followed by in vitro and in vivo characterization of their antitubercular potential against M.tb. Two of these compounds, furoxan (2) and (3) proved to be highly selective and potent against the M.tb (MIC90 values of 1.61 µM and 1.03 µM). Compounds (2) and (3) were also active against non-replicating M.tb with MIC90 values of 6.67 µM and 9.84 µM, respectively. In addition, they also demonstrated active against several M.tb monoresistant strains (MIC90 values ranging from 0.61 to 20.42 µM) and clinical M.tb MDR strains (MIC90 values ranging from 3.09 to 42.95 µM). Compound (3) showed early bactericidal effects in time-kill experiments, which were superior to those of the first- and second-line anti-TB drugs currently used in therapy. Ames test demonstrated that compounds (2) and (3) are not mutagenic under the tested conditions. In vivo studies revealed that compounds (2) and (3) are orally bioavailable and highly effective, leading to a reduction of M.tb to undetectable levels in a mouse model of infection. Altogether, these results indicate that furoxan (2) and (3) are promising lead compounds for the development of a novel chemical class of antitubercular drugs.

136 P094 STUDY OF THE CORRELATION BETWEEN THE GENERATION OF REACTIVE OXYGEN SPECIES WITH THE ELECTROCHEMICAL PROPERTIES OF NEW HOMODIMERS BASED ON THE PHARMACOPHORE AMINO-1,4-NAPHTHOQUINONE

Judith Faúndes (1), Carolina Mascayano (1), Francisco J. Recio (2), Claudia Torrent (1), Yesseny Vásquez-Martínez (3), Juana A. Ibacache (1)

1) Facultad de Química y Biología, Universidad de Santiago de Chile, 9170022, Santiago, Chile 2) Facultad de Química y Farmacia, Universidad Católica de Chile, Santiago, 7820436, Chile 3) Programa Centro de Investigaciones Biomédicas Aplicadas, Escuela de Medicina, Facultad de Ciencias Médicas, Universidad de Santiago de Chile, 9170022 Santiago, Chile

It is known that reactive oxygen species are related to an increase in cell proliferation and differentiation. However, it has also been observed that tumour cells are more vulnerable to being damaged by exogenous reactive oxygen species1,2. For this reason, it is that the synthesis of redox generating agents has become a strategy of interest. In this context, quinones play an important role, because they can be reduced via one electron to form the semiquinone anion radical, or via two electrons to give the hydroquinone, generating reactive oxygen species that can oxidize DNA, lipids and proteins3. Thus, by changing the substituents, the generation of ROS can be modulated by making the quinonic fragment more oxidizing or reducing. Because the quinonic nucleus is the electroactive one, the synthesis of homodimers based on the pharmacophore amino-1,4-naphthoquinone was carried out based on the Twin-Drug strategy, to obtain a more potent and/or selective product than the monomeric entity4. This hypothesis has already been worked on in the laboratory group, obtaining a higher index of selectivity for dimeric compounds5. Therefore, this work will present the evaluation of new homodimers as ROS generating agents in Staphylococcus aureus, and their correlation with formal redox potentials, as preliminary antecedents for their study in human cells and future cytotoxic assays.

References 1) Malhi, S. S., Budhiraja, A., Arora, S., Chaudhari, K. R., Nepali, K., Kumar, R., Murthy, R. S. R. (2012). Intracellular delivery of redox cycler-doxorubicin to the mitochondria of cancer cell by folate receptor targeted mitocancerotropic liposomes. International Journal of Pharmaceutics, 432(1–2), 63–74. 2) Pelicano, H., Carney, D., & Huang, P. (2004). ROS stress in cancer cells and therapeutic implications. Drug Resistance Updates, 7(2), 97–110. 3) Wang, Y., Gray, J. P., Mishin, V., Heck, D. E., Laskin, D. L., & Laskin, J. D. (2010). Distinct Roles of Cytochrome P450 Reductase in Mitomycin c Redox Cycling and Cytotoxicity. Molecular. 4) Contreras, J. M., & Sippl, W. (2008). Homo and Heterodimer Ligands: The Twin Drug Approach. The Practice of Medicinal Chemistry, 380–414 5) Ibacache, J. A., Faundes, J., Montoya, M., Mejías, S., & Valderrama, J. A. (2018). Preparation of novel homodimers derived from cytotoxic isoquinolinequinones. A twin drug approach. Molecules, 23(2).

137 P095 CELLULAR AND MOLECULAR CHANGES ASSOCIATED WITH POTENTIAL TREATMENT OF NEUROPSYCHIATRIC DISORDERS WITH NEW MULTI-TARGET LIGANDS OF AMINERGIC GPCRs

Oliwia Koszła (1), Przemysław Sołek (2), Sylwia Woźniak (1), Magda Kondej (1), Piotr Stępnicki (1), Tomasz M. Wróbel (1), Ewa Kędzierska (3), Agnieszka A. Kaczor (1,4)

1) Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Medical University of Lublin, 4A Chodzki St., 20-093 Lublin, Poland 2) Department of Animal Physiology and Reproduction, Faculty of Biotechnology, University of Rzeszow, Werynia 502, 36-100 Kolbuszowa, Poland 3) Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, 4A Chodzki St., 20-093 Lublin, Poland 4) University of Eastern Finland, Yliopistonranta 1, FI-70211 Kuopio, Finland

Neuropsychiatric disorders are difficult to diagnose and treat, mainly due to their poorly understood pathomechanism. Current treatments are often used to alleviate the most severe symptoms, however there is a risk of damaging the central nervous systems. One strategy to treat neuropsychiatric disorders is to focus on hippocampal neurogenesis. Neurogenesis in the hippocampus reflects the region's unique, large-scale plasticity and can be a potential modulation center for a subset of cognitive and affective behaviors that are affected by many psychiatric disorders. Here we present cytotoxicity and assessment of the proliferation properties of a selected compound using the HT-22 and SH-SY5Y cell lines, its effect on on the production of reactive oxygen and nitrogen species (ROS and RNS, respectively) and on the activation of mechanisms to combat free radicals (reduction of glutathione). We also show the compound’s influence on cell viability and the level of cellular DNA fragmentation. In addition, we present the effect of the compound on the cognitive processes in mice after chronic administration. In conclusion, the studied compound is a promising starting point to develop novel treatments for cognitive symptoms of neuropsychiatric disorders.

References 1) Heckers S, Konradi C (2002) Hippocampal neurons in schizophrenia. J Neural Transm 109:891–905. https://doi.org/10.1007/s007020200073

138 P096 DESIGN, SYNTHESIS, IN VITRO ANTICANCER EVALUATION,KINASE INHIBITORY EFFECTS, AND PHARMACOKINETIC PROFILE OF NEW 1,3,4-TRIARYLPYRAZOLE DERIVATIVES POSSESSING TERMINAL SULFONAMIDE

Karim I. Mersal (1), Mohammed S. Abdelmaksood (2), Chang Hyun Oh (1)

1) Center for Biomaterials, Korea Institute of Science and Technology(KIST), Cheongryang,Seoul,Republic of Korea; Department of Biomolecular Science, University of Science and Technology (UST), Daejeon, Yuseong-gu Republic of Korea 2) Medicinal & Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre (NRC), Dokki, Giza, Egypt 3)

The current study represents the design and synthesis of a novel series of 1,3-diaryl-4-sulfonamidoarylpyrazole derivatives. This series consists of 34 compounds with different substituted ethyl and propyl sulfonamide side chains(compounds 1a-q & compounds 2a-q) and it was evaluated for its antiproliferative activity against NCI-60 cell line panel. Compounds from this series showed the highest mean inhibition percentage at 10µM single dose testing and were selected to be tested at 5 dose mode. The IC50s of the most potent compounds were determined over the 60 cell lines. The most potent compound exhibited potency against various cell lines with IC 50 0.33µM against A498 renal cancer cell line. The most potent compound was evaluated over a panel of 20 kinases to explore its molecular target(s) and the IC50 for this compound was defined for the most sensitive kinases. In vitro stability and in vivo pharmacokinetic profile for this compound were also evaluated.

References 1) Design, synthesis, in vitro anticancer evaluation, kinase inhibitory effects, and pharmacokinetic profile of new 1,3,4-triarylpyrazole derivatives possessing terminal sulfonamide moiety 2) Abdel-Maksoud MS, Kim MR, El-Gamal MI, et al. Design, synthesis, in vitro antiproliferative evaluation, and kinase inhibitory effects of a new series of imidazo[2,1- b] thiazole derivatives. Eur J Med Chem 2015;95:453–63. 3) Gamal El-Din MM, El-Gamal MI, Abdel-Maksoud MS, et al. Synthesis and in vitro antiproliferative activity of new 1,3,4- oxadiazole derivatives possessing sulfonamide moiety. Eur J Med Chem 2015;90:45–52. 4) Gamal El-Din MM, El-Gamal MI, Abdel-Maksoud MS, et al. Design, synthesis, and in vitro antiproliferative and kinase inhibitory effects of pyrimidinylpyrazole derivatives terminating with arylsulfonamido or cyclic sulfamide substituents. J Enz Inhibit Med Chem 2016;31:111–22. 5) Sharma A, Shah SR, Illum H, Dowell J. Vemurafenib: targeted inhibition of mutated BRAF for treatment of advanced melanoma and its potential in other malignancies. Drugs 2012; 72:2207–22. 6) Rheault TR, Stellwagen JC, Adjabeng GM, et al. Discovery of Dabrafenib: a selective inhibitor of Raf kinases with antitumor activity against B-Raf-driven tumors. ACS Med Chem Lett 2013;4:358–62. 7) Karoulia Z, Gavathiotis E, Poulikakos PI. New perspectives for targeting RAF kinase in human cancer. Nature Rev Cancer 2017;17:676–91. 8) El-Gamal MI, Sim TB, Hong JH, et al. Synthesis of 1H-pyrazole- 1-carboxamide derivatives and their antiproliferative activity against melanoma cell line. Arch Pharm Chem Life Sci 2011;344:197–204. 9) El-Gamal MI, Oh CH. Design and synthesis of 3-(3-chloro-4- substituted phenyl)-4-(pyridin-4-yl)-1H-pyrazole-1-carboxamide derivatives and their antiproliferative activity against melanoma cell line. Bull Korean Chem Soc 2011;32:821–8. 10) Choi WK, El-Gamal MI, Choi HS, et al. New diarylureas and diarylamides containing 1,3,4-triarylpyrazole scaffold: Synthesis, antiproliferative evaluation against melanoma cell lines, ERK kinase inhibition and molecular docking studies. Eur J Med Chem 2011;46:5754–62. 11) Choi WK, El-Gamal MI, Choi HS, et al. Synthesis and antiproliferative activity of new aminoisoquinolinylurea derivatives against melanoma cell line. Bull Korean Chem Soc 2012;33: 2991–8.

139 P097 THIENO-FUSED 7-DEAZAPURINE RIBONUCLEOSIDES: SYNTHESIS AND BIOLOGICAL ACTIVITIES

Michal Tichý (1), Michal Hocek (1,2)

1) Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Gilead Sciences & IOCB Research Center, Flemingovo nam. 2, CZ-16610 Prague 6, Czech Republic 2) Department of Organic Chemistry, Faculty of Science, Charles University in Prague, Hlavova 8, CZ-12843 Prague 2, Czech Republic

Inspired by recent discoveries of highly potent and selective deazapurine nucleoside cytostatics bearing hetaryl groups in position 7,1,2 we designed a few types of (het)aryl-fused 7-deazapurine ribonucleosides. First class of such tricyclic nucleosides, pyrimidoindole nucleosides, was not cytotoxic, however, few derivatives showed interesting antiviral activities.3,4 In order to investigate the effect of the size of the fused ring on biological activities, we designed three series of isomeric thieno-fused 7-deazapurine ribonucleosides bearing various groups in position 4 of the pyrimidine ring, which were synthesized in 5–6 steps starting from simple 4,6-dichloropyrimidine and 2- or 3-iodothiophene by a sequence involving Negishi coupling, nucleophilic azidation, cyclization of tetrazoles, glycosylation and Suzuki or Stille coupling or by nucleophilic substitution.5 Several compounds from all series (especially methyl, methoxy and methylsulfanyl derivatives) exerted sub-micromolar cytostatic activities against broad panel of leukemia and cancer cell lines with lower toxicity to normal fibroblasts. Detailed synthesis, biological activities as well as new results from investigation of mechanism of action will be discussed on the poster.

This work was supported by the Academy of Sciences of the Czech Republic (RVO 61388963 and the Praemium Academiae award to M. Hocek), by the Czech Science Foundation (16-001785) and by Gilead Sciences, Inc.

References 1) Bourderioux, A.; Nauš, P.; Perlíková, P.; Pohl, R.; Pichová, I.; Votruba, I.; Džubák, P.; Konečný, P.; Hajdúch, M.; Stray, K. M.; Wang, T.; Ray, A. S.; Feng, J. Y.; Birkus, G.; Cihlar, T.; Hocek, M. J. Med. Chem. 2011, 54, 5498–5507. 2) Nauš, P.; Caletková, O.; Konečný, P.; Džubák, P.; Bogdanová, K.; Kolář, M.; Vrbková, J.; Slavětínská, L.; Tloušt’ová, E.; Perlíková, P.; Hajdúch, M.; Hocek, M. J. Med. Chem. 2014, 57, 1097–1110. 3) Tichý, M.; Pohl, R.; Xu, H. Y.; Chen, Y. L.; Yokokawa, F.; Shi, P. Y.; Hocek, M. Bioorg. Med. Chem. 2012, 20, 6123–6133. 4) Tichý, M.; Pohl, R.; Tloušt’ová, E.; Weber, J.; Bahador, G.; Lee, Y. J.; Hocek, M. Bioorg. Med. Chem. 2013, 21, 5362–5372. 5) Tichý, M.; Smoleń, S.; Tloušťová, E.; Pohl, R.; Oždian, T.; Hejtmánková, K.; Lišková, B.; Gurská, S.; Džubák, P.; Hajdúch, M.; Hocek, M. J. Med. Chem. 2017, 60, 2411–2424.

140 P098 SYNTHESIS OF NOVEL HETERO-FUSED 7-DEAZAPURINE RIBONUCLEOSIDES

Lucia Veselovska (1), Michal Hocek (1,2)

1) Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, CZ-16610 Prague 6, Czech Republic 2) Dept. of Organic Chemistry, Faculty of Science, Charles University, Hlavova 8,CZ-12843 Prague 2, Czech Republic

Many substituted 7-deazapurine ribonucleosides and their analogs displayed various biological activities, and some of them are even used as clinical antiviral drugs. [[1]] Methodical study of modified 7‑deazapurine ribonucleosides in our group led to the discovery of different groups of potent cytostatic compounds – substituted 7‑deazapurine ribonucleosides with a fused hetaryl ring such as benzene, furan, thiophene, or 5-methylpyrrole. Several compounds showed significant nanomolar cytostatic or cytotoxic activities against cancer cells and promising antiviral activities against Dengue and HCV viruses. [2] These results inspired us to synthesize and examine biological activities of new type of 7‑deazapurine ribonucleosides: pyrido-fused compounds, possessing nitrogen atom in four different positions in the fused pyridine ring. The desired tricyclic modified ribonucleosides were synthesised in 6–7 steps starting from corresponding chloro-nitropyridines. All final nucleosides were tested for their biological activities.

This work was supported by the Czech Academy of Sciences (Praemium Academiae award to M. Hocek), by the Czech Science Foundation (16-00178S and 19-08124S) and by Gilead Sciences, Inc.

References 1) De Clercq, E.; Li, G. Approved Antiviral Drugs over the Past 50 Years. Clin. Microbiol. Rev. 2016, 29, 695−747. 2) a) Tichý, M.; Pohl, R.; Xu, H. Y.; Chen, Y.-L.; Yokokawa, F.; Shi, P.-Y.; Hocek, M. Bioorg. Med. Chem. 2012, 20, 6123–6133; b) Tichý, M.; Pohl, R.; Tloušťová, E.; Weber, J.; Bahador, G.; Lee, Y.-J.; Hocek, M. Bioorg. Med. Chem. 2013, 21, 5362–5372; c) Tichý, M.; Smoleń, S.; Tloušťová, E.; Pohl, R.; Oždian, T.; Hejtmánková, K.; Lišková, B.; Gurská, S.; Džubák, P.; Hajdúch, M.; Hocek, M. J. Med. Chem. 2017, 60, 2411–2424; d) Tokarenko, A.; Lišková, B.; Smoleń, S.; Táborská, N.; Tichý, M.; Gurská, S.; Perlíková, P.; Frydrych, I.; Tloušťová, E.; Znojek, P.; Mertlíková-Keiserová, H.; Poštová Slavětínská, L.; Pohl, R.; Klepetářová, B.; Khalid, N.; Wenren, Y.; Laposa, R. R.; Džubák, P.; Hajdúch, M.; Hocek, M. J. Med. Chem. 2018, 61, 9347-9359.

141 P099 INVESTIGATION OF THE EFFECT OF THE LENGTH OF THE THIRD INTRACELLULAR LOOP (ICL3) IN DOPAMINE D2 RECEPTOR ON PREFERENCIAL COUPLING WITH Gαi1 AND Gαi2 PROTEINS

Justyna Zuk (1), Damian Bartuzi (1), Agnieszka A. Kaczor (1,2)

1) Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy with Division of Medical Analytics, Medical University, 4A Chodzki St., PL-20093 Lublin, Poland 2) School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, FI-70211 Kuopio, Finland

Dopamine receptors belong to family A of GPCRs that are involved in many diseases, including schizophrenia, Parkinson’s and Alzheimer’s disease. In 2018 the crystal structure of dopamine D2 receptor in an inactive conformation in complex with risperidone - atypical antipsychotic drug1 was released. It gives new possibilities in the design of new drugs acting through this receptor. However, the full structures of D2LONG and D2SHORT isoforms, can only be obtained with the methods of molecular modeling. There are some research indicating that the 29-amino acid insertion in ICL3 of D2LONG allows it to interact specifically with Gαi22. The aim of study was to create the D2LONG and D2SHORT models in complex with Gαi1 and Gαi2 protein and to investigate the properties of the constructed complexes. The homology models of D2LONG and D2SHORT receptors in active conformation in complex with the respective G proteins were built using Modeller. Yasara software was used to generate the model of the short and long IL3. Dopamine was docked with Molegro software. The most probable docking pose of dopamine was took into account based on available literature data on interactions between dopamine and D2 receptor3. The complexes were immersed in an asymmetric membrane consisting of 8 types of lipids in the proportions appropriate for lipid rafts. These systems were subjected to production phase of equilibration and 1μs molecular dynamics in three replicas each. The results of our MD simulations confirm a preferential interaction of the D2S and D2L isoforms with Gαi1 and Gαi2, respectively. Our results can be used for drug design directed to dopamine D2 receptors, which may result in the discovery of more effective and safer therapeutics. The above research is part of the project implemented by OPUS 2017/27/B/NZ7/01767.

References 1) Wang, S.; Che, T.; Levit, A.; Shoichet, B. K.; Wacker, D.; Roth, B. L. Structure of the D2 Dopamine Receptor Bound to the Atypical Antipsychotic Drug Risperidone. Nature 2018, 555 (7695), 269–273 2) Montmayeur, J. P.; Guiramand, J.; Borrelli, E. Preferential Coupling between Dopamine D2 Receptors and G-Proteins. Mol. Endocrinol. 1993, 7 (2), 161–170. https://doi.org/10.1210/mend.7.2.7682286. 3) Wang, J.; Wolf, R. M.; Caldwell, J. W.; Kollman, P. A.; Case, D. A. Development and Testing of a General Amber Force Field. J Comput Chem 2004, 25 (9), 1157–1174. https://doi.org/10.1002/jcc.20035.

142 LIST OF ABSTRACTS

143 ALIHODZIC Sulejman MACROLIDE INSPIRED MACROCYCLES AS A PROMISING TEMPLATES FOR P041 CHALLENGING TARGETS

AMERYCKX Alice BENZOYLTHIOSEMICARBAZIDES AS PROMISING ANTIMICROBIAL AGENTS P091 TARGETING D-ALANINE-D-ALANINE LIGASE IN BACTERIO

ARANZAZU GIRALDO SYNTHESIS OF N-(2-HALOPYRAZOLYL-2-HYDROXYETHYL)IMIDAZOLES AS P001 Sandra Lorena POTENTIAL ANTIFUNGAL AGENTS

BIELAWSKA Anna EFFECT OF 2ND AND 3RD GENERATION PAMAM DENDRIMERS ON PRO- P021 INFLAMMATORY CYTOKINES IN HUMAN KERATINOCYTES AND FIBROBLASTS

BIELAWSKI Krzysztof CYTOTOXICITY OF 2ND AND 3RD GENERATION PAMAM DENDRIMERS IN P022 HUMAN KERATINOCYTES AND FIBROBLASTS

BRICELJ Alesa DEVELOPMENT OF OSMI-4-BASED BIOCHEMICAL PROBES FOR OGT P031

BUCHSTALLER Hans-Peter TARGETING TRANSCRIPTION FACTORS ALLOSTERICALLY – NOVEL, POTENT P071 HYPOXIA-INDUCIBLE FACTOR-2a (HIF-2a) INHIBITORS

CARVALHO DE MATOS NEW STRATEGIES FOR NEURODEGENERATIVE DRUG DISCOVERY: BUILDING P072 Maria Joao C. P. PRECISE CONJUGATES ABLE TO CROSS THE BLOOD BRAIN BARRIER

CERNAK Timothy EXPLORING AN INTERFACE OF SYNTHESIS AND DATA SCIENCE PL18

CHESSARI Gianni ELECTROSTATICS - DRIVING FORCES IN STRUCTURE-BASED DRUG DESIGN P073 AND SYNTHESIS

CLARK Peter A CHEMOSELECTIVE, REGIOSPECIFIC, METAL-, AZIDE- AND HALOGEN-FREE P002 SYNTHESIS OF 1,2,3-TRIAZOLES

CUNDY Nicholas THE DESIGN, SYNTHESIS AND EVALUATION OF MECHANISTIC PROBES OF P092 IDO1

DAMIENS Audrey BIO-SOURCED ANTIFUNGAL AGENTS FOR CROP PROTECTION WITH NO P042 IMPACT ON ENVIRONMENT AND HUMAN HEALTH

DEJMEK Milan FROM NORBORNYL-BASED CARBANUCLEOSIDES TO CYCLIN-DEPENDENT P074 KINASE 2 INHIBITORS

DI Li STRUCTURAL ATTRIBUTES INFLUENCING UNBOUND TISSUE DISTRIBUTION PL01

DOS SANTOS FERNANDES SYNTHESIS AND CHARACTERIZATION OF FUROXAN DERIVATIVES WITH IN P093 Guilherme Felipe VIVO STERILIZING ANTITUBERCULAR ACTIVITY

DOUTHWAITE James ENANTIOSELECTIVE C-H BORYLATION CONTROLLED BY A CHIRAL COUNTER- P003 CATION

DUDKIN Vadim INTRACELLULAR AND TISSUE SPECIFIC TARGETING OF THERAPEUTIC PL22 MODALITIES

DUERR Katharina MEMBRANE PROTEINS AT THE SGC: CHALLENGES AND SUCCESS STORIES PL09

FAUNDES ANAZCO Judith STUDY OF THE CORRELATION BETWEEN THE GENERATION OF REACTIVE P094 OXYGEN SPECIES WITH THE ELECTROCHEMICAL PROPERTIES OF NEW HOMODIMERS BASED ON THE PHARMACOPHORE AMINO-1,4- NAPHTHOQUINONE

144 FRANCIS Stuart DISCOVERY OF SMALL MOLECULE FASCIN 1 INHIBITORS USING FRAGMENT- OC01 BASED DRUG DISCOVERY

FRECH Matthias TITLE TO BE ANNOUNCED PL10

GADEMANN Karl CAPTURING BIOLOGICAL ACTIVITY IN NATURAL PRODUCT FRAGMENTS: PL14 SUCCESS AND LIMITATIONS

GAICH Tanja CONCISE SYNTHESIS OF COMPLEX TAXANE DITERPENE PL15 CANATAXPROPELLANE BY PHOTOCHEMICAL DEAROMATIZATION

GOETZKE Friedrich ENANTIO- AND DIASTEREOSELECTIVE SUZUKI-MIYAURA COUPLING WITH P004 Wieland RACEMIC BICYCLES

GRZYBOWSKI Bartosz A. ORGANIC SYNTHESIS ON A COMPUTER: SHOULD MEDICINAL CHEMISTS PL17 CARE?

GUERIN Théo ECOCATALYZED SYNTHESIS OF VALUABLE THERAPEUTIC MOLECULES P005

HAELSIG Karl THE TOTAL SYNTHESIS OF (–)-CURVULAMINE P050

HAMANN Lawrence G. EXPANDING THE DRUGGABLE GENOME THROUGH CEREBLON-MEDIATED KL02 PROTEIN DEGRADATION

HAUSCH Felix SELECTIVE FKBP51 LIGANDS BY CONFORMATION-SPECIFIC BINDING P043

HAUT Franz-Lucas THE HIGH-PRESSURE MEDIATED CYCLOADDITION OF THIOCARBONYL P007 YLIDES: APPLICATIONS AND LIMITATIONS

HAYES Martin METABOLISM OF STRAINED RINGS: TALES OF THE UNEXPECTED PL02

HEINRICH Timo DISCOVERY AND OPTIMIZATION OF NEXT GENERATION REVERSIBLE P075 METHIONINE AMINOPEPTIDASE-2 INHIBITORS - IDENTIFICATION OF METHIONINE M8891, A CLINICAL COMPOUND FOR THE TREATMENT OF CANCER

HENNIG Michael CRYO-EM AND X-RAY FREE ELECTRON LASER ENABLED STRUCTURE BASED P023 DRUG DISCOVERY ON CHALLENGING MEMBRANE PROTEIN TARGETS

HERETSCH Philipp A RADICAL WAY TO ABEO-STEROIDS PL08

HIMMELBAUER Martin RATIONAL DESIGN AND OPTIMIZATION OF A NOVEL CLASS OF P076 MACROCYCLIC ASK1 INHIBITORS

IZZO Flavia COMBATING THE POST-ANTIBIOTIC ERA" : ARE THERE NOVEL STRUCTURES P044 AND MODE OF ACTIONS?"

JAHNKE Wolfgang DISCOVERY OF ABL001, AN ALLOSTERIC INHIBITOR OF BCR-ABL: PL11 FRAGMENTS, BIOPHYSICS, STRUCTURE AND CHEMISTRY

KARMAKAR JOY TOWARD A SELECTIVE SYN-BIMANE FLUORESCENT PROBE FOR ALDOLASE P008 CLASS-1

KAYUKOVA Lyudmila HITS FOR THE CREATING OF ANTI-TUBERCULOSIS AND ANTI-DIABETIC P077 LEAD-COMPOUNDS AMONG β-AMINOPROPIOAMIDOXIMES DERIVATIVES

KONDEJ Magda SYNTHESIS, PHARMACOLOGICAL AND STRUCTURAL STUDIES OF MULTI- P009 TARGET INDOLE DERIVATIVES

145 KOPPITZ Marcus DISCOVERY AND OPTIMIZATION OF PYRIDYL-CYCLOALKYL-CARBOXYLIC P078 ACIDS AS INHIBITORS OF MICROSOMAL PROSTAGLANDIN E SYNTHASE-1 FOR THE TREATMENT OF ENDOMETRIOSIS

KOSZLA Oliwia CELLULAR AND MOLECULAR CHANGES ASSOCIATED WITH POTENTIAL P095 TREATMENT OF NEUROPSYCHIATRIC DISORDERS WITH NEW MULTI- TARGET LIGANDS OF AMINERGIC GPCRs

KRÖMER Matous NUCLEOSIDES MODIFIED ON SUGAR AND BASE: SYNTHESIS AND P079 BIOLOGICAL PROFILING

LEVELL Julian EARLY DRUG DISCOVERY EFFORTS TOWARDS THE IDENTIFICATION OF P080 NOVEL EP300/CBP HAT INHIBITORS

LEVELL Julian THE BIG IMPACT OF SMALL CHANGES : TOWARDS BEST-IN-CLASS EZH2 AND OC08 LSD1 INHIBITORS

LOPEZ Irakusne ARTIFICIAL INTELLIGENCE: WILL IT CHANGE THE WAY WE RESEARCH? P061

MAHJOUR Babak A HIGH-THROUGHPUT EXPERIMENTATION SOFTWARE FOR THE INVENTION P064 OF NEW COUPLING REACTIONS

MATVIYUK Tatiana NEW COVALENT pROBES: FRAGMENT-BASED DISCOVERY OF POTENT BRD-4 P011 INHIBITORS

MCGRATH Andrew DISCOVERY AND DEVELOPMENT OF A NOVEL ESTERIFICATION REACTION P012 ENABLED BY HIGH-THROUGHPUT EXPERIMENTATION

MERSAL Karim DESIGN, SYNTHESIS, IN VITRO ANTICANCER EVALUATION,KINASE P096 INHIBITORY EFFECTS, AND PHARMACOKINETIC PROFILE OF NEW 1,3,4- TRIARYLPYRAZOLE DERIVATIVES POSSESSING TERMINAL SULFONAMIDE

MIES Thomas BIOMIMETIC MEROTERPENOID SYNTHESES: SCOPE AND LIMITATIONS OF P051 POLYENE CYCLIZATIONS APPLIED TO THE SYNTHESIS OF HONGOQUERCIN ANALOGUES

MOON Hyung-In INHIBITORY EFFECTS OF CERAMIDE FROM BRASSICA NAPUS ON THE P045 ATOPIC FUNCTION VIA THE REGULATION OF HUMAN KALLIKREIN 5 AND 7 PROTEASE

NASSIR Molhm DEVELOPMENT OF NPP1 INHIBITORS AS POTENTIAL DRUGS FOR THE P081 TREATMENT OF OSTEOARTHRITIS/CPPD DISEASE

NENCKA Radim SYNTHESIS OF NON-HYDROLYSABLE “SUPER SUBSTRATES” OF P046 PHOSPHATIDYLINOSITOL 4-KINASES

NICEWICZ David NEW AVENUES IN SYNTHESIS ENABLED BY ORGANIC PHOTOREDOX PL06 CATALYSIS

NOVAK Alexander A BIOMIMETIC SYNTHESIS ELUCIDATES THE ORIGIN OF PREUISOLACTONE A P013

ODEGARD Valerie SBT6050, A HER2-DIRECTED TLR8 IMMUNOTAC™ THERAPEUTIC, IS A PL23 POTENT HUMAN MYELOID CELL AGONIST WITH TUMOR-LOCALIZED ACTIVITY

PEMBERTON Nils DISCOVERY OF AZD3458 A HIGHLY SELECTIVE PI3Kγ INHIBITOR: OC06 COMBINING STRUCTURE, HDX-MS AND BINDING KINETICS TO UNDERSTAND THE MODE OF ACTION

PHILLIPS Andy TARGETED PROTEIN DEGRADATION PL12

146 POCHET Lionel USING FRAGMENT-BASED LEAD DISCOVERY TO GENERATE NEW SCAFFOLDS P082 FOR THE DEVELOPMENT OF FXIIA INHIBITORS

POCOCK Ian SYNTHESIS AND APPLICATIONS OF 4,5-DISUBSTITUTED CARBAZOLES P014

REISMAN Sarah E. NECESSITY IS THE MOTHER OF INVENTION: NATURAL PRODUCTS AND THE KL01 CHEMISTRY THEY INSPIRE

RITTER Tobias LATE-STAGE FUNCTIONALIZATIONS PL07

RUF Sven IDENTIFICATION AND IN-VIVO EFFICACY STUDIES OF NOVEL NNMT P083 INHIBITORS

SAFINA Brian DISCOVERY OF TUMOR-TARGETED TLR7/8 IMMUNE-STIMULATING PL21 ANTIBODY CONJUGATES (ISAC): A NEW CLASS OF IMMUNO-ONCOLOGY THERAPEUTICS

SANDFORT Frederik DEAMINATIVE STRATEGY FOR VISIBLE-LIGHT-MEDIATED C–B AND C–C P015 BOND FORMATION VIA ELECTRON-DONOR-ACCEPTOR COMPLEXES

SARPONG Richmond BREAK-IT-TO-MAKE-IT STRATEGIES FOR COMPLEX MOLECULE SYNTHESIS PL05

SCHADT Simone PREDICTING ADME - REALITY, VISION OR FANTASY? PL04

SCHAEFFLER Michael NOVEL MODE OF ACTION MOLECULE OSW-1 ABOLISHES THE GRP78 P047

SEGALL Matthew PRACTICAL APPLICATION OF DEEP LEARNING TO DRUG DISCOVERY P062 PROJECT DATA

SHAH Falgun LEVERAGING IN SILICO ADMET PROFILES AND ANCILLARY PHARMACOLOGY PL03 TO INFLUENCE PRIORITIZATION OF HIT SERIES WITH HIGHER PROBABILITY OF SUCCESS

SIEGAL Greg WANDERING THROUGH EPITRANSCRIPTOMICS DRUG DISCOVERY LAND P084 WITH A BIOPHYSICAL GPS

SPIEGEL David USING SMALL MOLECULES TO ENGINEER AND EXPLORE HUMAN IMMUNITY PL20

STEADMAN Vicky THE DISCOVERY OF A POTENT AND ORALLY BIOAVAILABLE MACROCYCLIC OC07 CYCLOPHILIN INHIBITOR BASED ON THE STRUCTURAL SIMPLIFICATION OF SANGLIFEHRIN A

STEINEBACH Christian FOUR E3 LIGASES, ONE TARGET: TOWARDS NOVEL CDK6 PROTACS OC02

STEPNICKI Piotr D2AAK2 AS DOPAMINE D2 RECEPTOR ANTAGONIST WITHOUT A P085 PROTONATABLE NITROGEN ATOM – IN SILICO, IN VITRO AND IN VIVO EVALUATION AS A POTENTIAL ANTIPSYCHOTIC

STRIETH-KALTHOFF Felix DISCOVERY AND RATIONALIZATION OF ENERGY-TRANSFER-ENABLED P010 CYCLIZATION REACTIONS USING A COMBINED SCREENING APPROACH

THOMPSON James INVESTIGATING THE CHAMELEONIC PROPERTIES OF RGD INTEGRIN OC05 ANTAGONISTS FOR THE TREATMENT OF IPF

TICHY Michal THIENO-FUSED 7-DEAZAPURINE RIBONUCLEOSIDES: SYNTHESIS AND P097 BIOLOGICAL ACTIVITIES

TORRES-GOMEZ Hector DEVELOPMENT OF NEXT GENERATION ANTITUBERCULAR P086 BENZOTHIAZINONES BY METABOLISM GUIDED LEAD OPTIMIZATION

147 TRAUNER Dirk CONTROLLING THE FATE AND FUNCTION OF PROTEINS WITH KL03 PHOTOPHARMACOLOGY

VAN BEELEN Eric SMALL SCALE PURIFICATION OF CONSTITUENTS FROM COMPLEX NATURAL P048 PRODUCT EXTRACTS USING SUB-2μm CHROMATOGRAPHY

VAN BEELEN Eric INCREASED ROBUSTNESS AND THROUGHPUT IN COMPOUND P063 PURIFICATION USING SFC AND INTELLIGENT DECISION MAKING SOFTWARE

VAN BEELEN Eric THE EFFECTS OF SFC PREPARATIVE SCALE-UP ON THROUGHPUT, PURITY P065 AND RECOVERY OF AN IMPURITY IN AN API MIXTURE

VANDERWAL Christopher SYNTHESIS OF COMPLEX ANTIPLASMODIAL ISOCYANOTERPENES PL16

VERMA Vishal DISCOVERY OF GDC-0334: A POTENT AND ORALLY BIOAVAILABLE CLINICAL OC04 CANDIDATE FOR THE INHIBITION OF TRPA1

VESELOVSKA Lucia SYNTHESIS OF NOVEL HETERO-FUSED 7-DEAZAPURINE RIBONUCLEOSIDES P098

WEIN Lukas SYNTHESIS OF (–)-MITREPHORONE A VIA A BIOINSPIRED LATE STAGE C–H P049 OXIDATION OF (–)-MITREPHORONE B

WILLIAMS Benjamin USING ION-PAIRING TO CONTROL REGIOSELECTIVITY IN IRIDIUM- P006 CATALYSED C-H BORYLATION OF ARENES

WILLIAMS Simon TOTAL SYNTHESIS OF CHIVOSAZOLE F OC03

WINTER Georg CHEMICAL GENOMICS APPROACHES TO TARGETED PROTEIN PL13 DEGRADATION

YURA Takeshi NOVEL KV7 ION CHANNEL OPENERS FOR THE TREATMENT OF EPILEPSY P087

ZENTGRAF Matthias ACCELERATING R&D WITH AUGMENTED INTELLIGENCE PL19

ZHOU JINGYUAN DESIGN, SYNTHESIS AND SAR STUDIES OF BORONIC ACID INHIBITORS FOR P088 THE -LACTAMASE KPC-2

ZUK Justyna INVESTIGATION OF THE EFFECT OF THE LENGTH OF THE THIRD P099 INTRACELLULAR LOOP (ICL3) IN DOPAMINE D2 RECEPTOR ON PREFERENCIAL COUPLING WITH GΑI1 AND GΑI2 PROTEINS

148 LIST OF AUTHORS

149 Lastname & firstname initial Abstract nr BRUCELLE F. P080 ABDELMAKSOOD M. S. P096 BUCHSTALLER H.-P. P071 ABEL B. P010 BURRI R. R. P083 ADAMO J. PL23 BUTTERWORTH S. P092 ADENOV M. P077 CAI R. OC07 ALBERS J. P071 CALDERINE M. P075 ALEX A P010 CANNIZZARO C. OC07 ALIHODZIC S. P041 CARNEIRO M. P084 ALOTAIBI A. P014 CASTRO M. P085, P009 AMERYCKX A. P091 CERNAK T. P012, P064, PL18 ANCHAN N. K. P083 CHANDRASEKAR D. V. P083 ANDERLUH M. P031 CHANG J. R. PL23 ANGYAL P. P049 CHESSARI G. P073 APPLEBY T. OC07 CHILDS M. PL23 ARAD U. P081 CHIN G. OC07 AUBIN A. P065, P048, P063 CHINGISSOVA L. P077 AUSTIN C. OC07 CHIVA J.-Y. OC07 BAE K. S. P045 CHO S. H. P093 BAITURSYNOVA G. P077 CHORILLI M. P093 BARNES N. M. P092 CLARK P. R. P002 BARRETT A. G. P051 COMEAU M. R. PL23 M. CONDUIT G. P062 BARTUZI D. P099 CROFT D. OC01 BARTYZEL A. P009 CUMMINGS R. P080 BAUM P. PL23 CUNDY N. J. P092 BAYLISS M. P063 CZARNOMYSY R. P022, P021 BECKER F. P075 CZECH J. P083 BERGANDER K. P010 DA SILVA P. B. P093 BERGES N. P071 DAMIENS A. P042 BHAMIDIPATI R. K. P083, P087 DANILIUC C. G. P010 BIAŁA G. P085, P009 DAVOINE C. P082 BIELAWSKA A. P021 DE GRANDIS R. A. P093 BIELAWSKI K. P022, P021 DE SOUZA P. C. P093 BILLAMBOZ M. P042 DEAN D. OC07 BISMILDA V. P077 DEJMEK M. P046, P074 BLAKEMORE C. OC07 DHAKSHINAMOORTHY S. P083 BLUME B. P075 DI L. PL01 BOMKE J. P075 DIRIAN K. P010 BOMMI-REDDY A. P080 DOS SANTOS J. L. P093 BORGES F. P072 DOUGHERTY R. W. P087 BOUCKAERT C. P082 DOUTHWAITE J. L. P003 BOUŘA E. P046 DRAČÍNSKÝ M. P046, P074 BOWER J. OC01 DRYSDALE M. OC01 BRENDER T. PL23 DUBOSE R. PL23 BREVIK J. PL23 DUDKIN V. PL22 BRICELJ A. P031 DUECKER F. L. PL08

150 DUNBAR N. OC07 HAJDÚCH M. P079 DÜRR K. L. PL09 HALLUR M. S. P083 ECKERT U. P075 HAMANN L. G. KL02 ENYEDY I. P076 HANSEN K. P075 FAN L.-Q. PL23 HARROP W. P048 FAÚNDES J. P094 HAUSCH F. P043 FERNANDES C. P072 HAUT F.-L. P007 FILLET M. P082 HAYES M. PL02 FISCHER B. P081 HEALY J. P088 FLETCHER S. P. P004 HEINRICH T. P075 FLIRI H. OC07 HEINZE R. C. PL08 FRANCIS S. OC01 HELMUELLER S. P065 FRANZBLAU S. G. P093 HENKEL C. P010 FREDERICK R. P091 HENNIG M. P023 FRIESE-HAMIM M. P075 HERETSCH P. PL08 GADEMANN K. PL14 HESSON T. P076 GAICH T. PL15 HIGHTON A. OC07 GARDBERG A. P080 HIMMELBAUER M. P076 GENOV G. R. P003 HOBZA P. P074 GHINET A. P005 HOCEK M. P097, P098, P079 GIBSON D. C. P003 HOJMAN A. S. P071 GIBSON L. OC03 HOLLANDER J. P084 GILFILLAN R. P076 HŘEBABECKÝ H. P046 GLORIUS F. P010, P015 HUHN A. P080 GOBEC M. P031 HUI H. OC07 GOETZKE F. W. P004 IBACACHE J. A. P094 GOHLKE A. OC01 IRWIN B. P062 GÓMEZ-SUÁREZ A. P010 IZZO F. P044 GONZALEZ LOPEZ DE F. P076 JABLONSKI J.-A. P048 TURISO JAGDEV K. P014 GOODWIN G. OC01 JAHNKE W. PL11 GOSU R. P083 JAIME P. P001 GRAINGER R. S. P092, P014 JAMES M. J. P015 GRAY C. OC01 JANSA P. OC07 GREMMEN S. P084 JEYARAJ D. P087 GRIGGLESTONE C. P013 JI M. OC07 GRYNSZPAN F. P008 JIN H. OC07 GRZYBOWSKI B. PL17 JIN J. OC03 GUERIN T. P005 JOCH M. P086 GULDI D. M. P010 JOHNSON J. L. P076 GULYAYEV A. P077 JONES H. P076 GUNERA J. P075 JORDA R. P074 GÜTSCHOW M. OC02, P031 JUAN X. P050 HABIGER C. P007 KACZOR A. A. P095, P085, P009, HAELSIG K. P050 P099 HAIDER S. P088 KADNUR S. V. P083

151 KAHNT A. P010 LI M. OC03 KAN J. OC03 LICLICAN A. OC07 KANNT A. P083 LINDEMANN R. P071 KARKI K. OC07 LINDNER S. OC02 KARMAKAR J. P008 LISTAKHAVA I. P079 KAYUKOVA L. P077 LOI E. M. P031 KEATS A. OC07 LOPEZ I. P061 KĘDZIERSKA E. P095, P009 LOZA M. I. P009 KEIFF F. P086 LUZZIO M. J. P076 KERR W. J. OC05 MACDONALD L. OC01 KIM Y. M. P045 MACHESKY L. OC01 KING K. P076 MACKMAN R. OC07 KLAUCK F. J. R. P015 MADHYASTHA N. P087 KLÍMA M. P046 MAGAUER T. P007, P049 KLOSS F. P086 MAHJOUR B. P064 KNEHANS T. P071 MAIMONE T. P050 KNOLLE W. P010 MANE V. S. P083 KOHL R. P075 MARCOTTE D. J. P076 KONDEJ M. P095, P009 MARINO L. B. P093 KONZCAL J. OC01 MARKER A. P083 KOPPITZ M. P078 MASCAYANO C. P094 KÖPRÜLÜOĞLU C. P074 MATOS M. J. P072 KOSZŁA O. P095, P009 MATOSIUK D. P009 KOZAK A. P085 MATVIYUK T. P011 KRAUS F. P044 MCGRATH A. P012 KRIER M. P071 MCKINNON H. OC01 KRISTAM R. P083 MERSAL K. I. P096 KRÖMER M. P079 METZ H. PL23 KRÖNKE J. OC02 MEYER F. P086 KRUK-SŁOMKA M. P085 MEZNA M. OC01 KRYŠTOF V. P074 MIES T. P051 KUÇERA R. P004 MIHAI M. T. P006 KUPPUSAMY B. M. P087 MISH M. OC07 LAHDENPERÄ A. S. K. P003 MOHD Z. P087 LANGER T. P083 MOON H.-I. P045 LANNERS S. P082 MORTIMORE M. P004 LATCHMAN Y. PL23 MUELLER G. P084 LAYTON C. P065 MULLANGI R. P083 LAZARIDES L. OC07 MÜLLER C. E. P081 LECOMTE M. P071 MURRAY B. OC07 LEE Y.-J. OC07 MURUGAN P. P076 LEHMANN M. P075 MURUGESAN K. R. P083 LEIENDECKER M. P071 MUSIL D. P075 LEPŠÍK M. P074 NARASIMHULUB L. K. P083 LEUTHNER B. P075, P071 NASSIR M. P081 LEVELL J. OC08, P062, P080 NENCKA R. P046, P074

152 NG Y. L. D. OC02 SAMANTA S. K. P087 NICEWICZ D. PL06 SAMARIN K. PL15 NOVAK A. P013 SANDFORT F. P015 NOWAK M. P071 SANDRA LORENA A.-G. P001 ODEGARD V. PL23 SANGI M. OC07 OH C. H. P096 SANTORO J. C. P076 PAIVA SILVA C. S. P093 SANTOS R. OC07 PAKULSKA U. P071 SANTOS FERNANDES G. F. P093 PANNIFER A. OC01 SANVOISIN J. OC07 PARRY C. OC01 SARKAR S. P083 PATERSON I. OC03 SARPONG R. PL05 PAUL N. OC01 SAVCHENKO T. P011 PAVAN F. R. P093 SCHADT S. PL04 PEMBERTON N. OC06 SCHAEFFLER M. P047 PETTIT S. OC07 SCHIEFERDECKER S. P086 PFALZGRAF J. P075 SCHINDLER C. P071 PHILLIPS A. PL12 SCHMITZ U. OC07 PHIPPS R. J. P003, P006 SCHNEIDER F. PL15 PIETERS R. J. P031 SCHREUDER H. P083 PLIETKER B. P044 SCHRIER A. OC07 POCHET L. P082, P091 SCHULTZ B. OC07 POCOCK I. A. P014 SCHUTTELKOPF A. OC01 POULLENNEC K. OC07 SEENISAMY J. P075 POY F. P080 SEGALL M. P062 PRALIYEV K. P077 SERGAZY S. P077 PRIOR C. P014 SETTER B. PL23 PRITCHARD J. M. OC05 SHAFIQ K. P012 PUGLIESE A. OC01 SHAH F. PL03 PUTTA V. R. K. P083 SHAIK S. P083 PYUN P. OC07 SHULGAU Z. P077 RAJAGOPAL S. P083, P087 SIAH A. P042 RAVEN E. L. P092 SIEGAL G. P084 RECIO F. J. P094 SIEGEL D. OC07 REISMAN S. E. KL01 SIEGL C. P075 RESENDE F. A. P093 SILVA A. G. P085, P009 RIBEIRO C. M. P093 SIMON F. P082 RITTER T. PL07 SIMS R. P080 RODRIGUEZ- F. P072 SINGH M. P083 ENRIQUEZ SMITH S. W. PL23 ROHDICH F. P075 SOLCIA M. C. P093 RUDOLPH C. P083 SOŁEK P. P095 RUF S. P083 SOSIČ I. OC02, P031 RUNCO J. P065 SPEARS M. P063 ŠÁCHA P. P074 SPERANDIO D. OC07 SAFINA B. PL21 SPIEGEL D. PL20 ŠÁLA M. P074 SPILKER K. P076

153 SPUCK D. P075 WILLIAMS S. OC03 STAPLETON P. P088 WILSON J. P080 STEADMAN V. OC07 WINSHIP D. PL23 STEINEBACH C. OC02, P031 WINTER G. PL13 STEPAN G. OC07 WOJTAS K. P. P086 STĘPNICKI P. P095, P085, P009 WOŹNIAK S. P095 STEVENS B. PL23 WRÓBEL T. M. P095, P085, P009 STRASSBURGER M. P086 WURST K. P049 STRIETH-KALTHOFF F. P010, P015 XIN Z. P076 SURESH J. P083 XU H. PL23 SWAMY I. N. P083 YANG H. OC07 TAN P. PL23 YERALIYEVA L. P077 TANG T. P092 YURA T. P083 TARGOWSKA-DUDA K. P085 ZANELLA S. PL15 TEDERS M. P010 ZARĘBSKI A. P071 THABAULT L. P091 ZECH B. P084 THOMPSON J. D. OC05 ZENKE F. P075 TIAN Y. OC07 ZENTGRAF M. PL19 TICHÝ M. P097 ZHEMERA A. P011 TOKSANBAEVA B. P077 ZHOU J. P088 TOMKINSON N. C. P002 ZOZULYA S. P011 O. ZUK J. P099 TORRENT C. P094 TORRES-GOMEZ H. P086 TRAUNER D. P013, KL03 UMEHARA K. PL04 URIARTE E. P072 UZAKOVA A. P077 VAN BAMBEKE F. P091 VAN BEELEN E. P065, P048, P063 VANDERWAL C. PL16 VÁSQUEZ-MARTÍNEZ Y. P094 VERMA V. OC04 VESELOVSKA L. P098 VIÑA D. P072 WANG Y. P093 WATERLOT C. P005 WATERREUS W.-J. P084 WATT G. OC07 WEGENER A. P075, P071 WEIN L. A. P049 WEISHEIT L. P049 WELLS G. P088 WHITEHEAD T. P062 WILLIAMS G. D. P002 WILLIAMS B. D. P006

154 LIST OF PARTICIPANTS

155 ALIHODZIC Sulejman FIDELTA, Croatia AMERYCKX Alice UCLOUVAIN, Belgium ARANZAZU GIRALDO Sandra Lorena UNIVERSITY OF LOS ANDES, Colombia ASHCRAFT Luke CYTOKINETICS, United States AVKIRAN Timur LIFEARC, United Kingdom BIELAWSKA Anna MEDICAL UNIVERSITY OF BIALYSTOK, Poland BIELAWSKI Krzysztof MEDICAL UNIVERISTY OF BIALYSTOK, Poland BÖHLER Christof ACTIVATE SCIENTIFIC, Germany BRICELJ Alesa UNIVERSITY OF LJUBJANA, Slovenia BUCHSTALLER Hans-Peter MERCK, Germany CARVALHO DE MATOS Maria Joao C. P. UNIVERSITY OF SANTIAGO DE COMPOSTELA, Spain CAVALLI Elfie IMPERIAL COLLEGE LONDON, United Kingdom CERNAK Timothy UNIVERSITY OF MICHIGAN, United States CHEOL-MIN Park ULSAN NATIONAL INSTITUTE OF SCIENCES, Korea, South CHESSARI Gianni ASTEX PHARMACEUTICALS, United Kingdom CHOI Subin ULSAN NATIONAL INSTITUTE OF SCIENCES, Korea, South CIULLI Alessio UNIVERSITY OF DUNDEE, United Kingdom CLAFFEY Michelle CLAFFEY LEADERSHIP, United States CLAIBORNE Christopher F. HOFFMANN-LA ROCHE, Switzerland CLARK Peter GSK/UNIVERSITY OF STRATHCLYDE, United Kingdom CLOSE Joshua BLUEPRINT MEDICINES, United States CUNDY Nicholas UNIVERSITY OF BIRMINGHAM, United Kingdom DAMIENS Audrey YNCREA, France DE NANTEUIL Florian FIRMENICH, Switzerland DEJMEK Milan IOCB, Czech Republic DETERING Carsten SCHRÖDINGER, Germany DI Li PFIZER, United States DOS SANTOS FERNANDES Guilherme Felipe SAO PAULO STATE UNIVERSITY, Brazil DOUTHWAITE James UNIVERSITY OF CAMBRIDGE, United Kingdom DUDKIN Vadim JANSSEN, United States DUERR Katharina UNIVERSITY OF OXFORD, United Kingdom EL GIHANI Moharem PIRAMAL PHARMA SOLUTIONS, United Kingdom ERHARD Thomas ABBVIE, Germany FAUNDES ANAZCO Judith UNIVERSITY OF SANTIAGO DE CHILE, Chile

156 FERREIRA Claudio OPTIBRIUM, United Kingdom FESSARD Thomas C. SPIROCHEM, Switzerland FRANCIS Stuart CRUK BEATSON INSTITUTE, United Kingdom FRECH Matthias MERCK, Germany FREDERICK Raphaël UCLOUVAIN, Belgium FUCHSS Thomas MERCK, Germany GADEMANN Karl UNIVERSITY OF ZÜRICH, Switzerland GAICH Tanja UNIVERSITY OF KONSTANZ, Germany GASTREICH Marcus BIOSOLVEIT, Germany GAUL Christoph NOVARTIS, Switzerland GOBBI Luca F. HOFFMANN-LA ROCHE, Switzerland GOETZKE Friedrich Wieland UNIVERSITY OF OXFORD, United Kingdom GONCHARENKO Kristina SPIROCHEM, Switzerland GRZYBOWSKI Bartosz A. UNIST, Korea, South GUERIN Théo YNCREA, France GUICHOU Jean-François CBS INSERM U1054, France HAELSIG Karl UC BERKELEY, United States HAMANN Lawrence G. BRISTOL-MYERS SQUIBB, United States HARTMANN Sascha MERCACHEM-SYNCOM, United Kingdom HAUSCH Felix TU DARMSTADT, Germany HAUT Franz-Lucas UNIVERSITY OF INNSBRUCK, Austria HAYES Martin ASTRAZENECA, Sweden HEINRICH Timo MERCK, Germany HELM Mark UNIVERSITY OF MAINZ, Germany HENNIG Michael LEADXPRO, Switzerland HERETSCH Philipp FU BERLIN, Germany HIMMELBAUER Martin BIOGEN, United States HOEGENAUER Klemens NOVARTIS, Switzerland HOFFMANN Remy JUBILANT CHEMSYS, India HOFMANN Andrea WATERS, Austria HOHN Christoph BOEHRINGER INGELHEIM, Germany ILKEI Viktor GEDEON RICHTER, Hungary IZZO Flavia UNIVERSITY OF STUTTGART, Germany JAHNKE Wolfgang NOVARTIS, Switzerland

157 JASCHKE Andres UNIVERSITY OF HEIDELBERG, Germany JENN Stephan NOVALIX, France JOCHUM Tobias ABCR, Germany KALGUTKAR Amit PFIZER, United States KARMAKAR Joy ARIEL UNIVERSITY, Israel KAYUKOVA Lyudmila JSC AB BEKTUROV INSTITUTE OF CHEMICAL SCIENCES, Kazakhstan KOCH Guido TOPADUR PHARMA, Switzerland KONDEJ Magda MEDICAL UNIVERSITY OF LUBLIN, Poland KOPPITZ Marcus BAYER, Germany KOSZLA Oliwia MEDICAL UNIVERSITY OF LUBLIN, Poland KRAWINKLER Karl Heinz NOVARTIS, Switzerland KRÖMER Matous IOCB, Czech Republic LARUELLE Chris GALAPAGOS, Belgium LEVELL Julian CONSTELLATION PHARMACEUTICALS, United States LINDER Michael MSD ANIMAL HEALTH INNOVATION, Germany LOPEZ Irakusne MESTRELAB RESEARCH, Spain MAGAUER Thomas UNIVERSITY OF INNSBRUCK, Austria MAHJOUR Babak UNIVERSITY OF MICHIGAN, United States MAIER Raimund IRIS BIOTECH, Germany MARIN Julien NOVALIX, France MARQUARDT Jutta ABCR, Germany MASON Chris OXFORD INSTRUMENTS, United Kingdom MATVIYUK Tatiana ENAMINE, Ukraine MAZUNIN Dmitry F. HOFFMANN-LA ROCHE, Switzerland MCGRATH Andrew UNIVERSITY OF MICHIGAN, United States MEDLEY Jonathan GILEAD SCIENCES, United States MERSAL Karim KIST, Korea, South MIES Thomas IMPERIAL COLLEGE LONDON, United Kingdom MOLNAR Laszlo NANGENEX, Hungary MOON Hyung-In SKEDERM COSMETIC R&D CENTER, Korea, South MURATORE Michael JANSSEN, Belgium NANTERMET Philippe MERCK SHARP & DOHME, United States NASSIR Molhm BAR ILAN UNIVERSITY, Israel

158 NENCKA Radim IOCB, Czech Republic

NICEWICZ David UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL, United States NOVAK Alexander NEW YORK UNIVERSITY, United States ODEGARD Valerie SILVERBACK THERAPEUTICS, United States PAESSENS Lutz NOVALIX, Germany PAIVA Stacey-Lynn NATURE RESEARCH, United Kingdom PEMBERTON Nils ASTRAZENECA, Sweden PENA PIÑON Miguel Ángel NOVALIX, France PHILLIPS Andy C4 THERAPEUTICS, United States POCHET Lionel UNAMUR, Belgium POCOCK Ian UNIVERSITY OF BIRMINGHAM, United Kingdom PRICE Stephen FIDELTA, Croatia REISMAN Sarah E. CALIFORNIA INSTITUTE OF TECHNOLOGY, United States RINGOM Rune RECIPHARM OT-CHEMISTRY, Sweden RIPA Lena ASTRAZENECA, Sweden RITTER Tobias MAX PLANCK INSTITUTE, Germany ROSAR Vera ACTIVATE SCIENTIFIC, Germany RUECKRICH Thomas MERCK, Austria RUF Sven SANOFI-AVENTIS, Germany SAFINA Brian BOLT BIOTHERAPEUTICS, United States SANDFORT Frederik UNIVERSITY OF MUNSTER, Germany SARPONG Richmond UC BERKELEY, United States SCHADT Simone F. HOFFMANN-LA ROCHE, Switzerland SCHAEFFLER Michael CFM OSKAR TROPITZSCH, Germany SCHWERTZ Geoffrey UCB, Belgium SEGALL Matthew OPTIBRIUM, United Kingdom SHAH Falgun MERCK SHARP & DOHME, United States SIEGAL Greg ZOBIO, The Netherlands SIMIC Oliver NOVARTIS, Switzerland SPIEGEL David YALE UNIVERSITY, United States STEADMAN Vicky EUROFINS DISCOVERY, United Kingdom STEINEBACH Christian UNIVERSITY OF BONN, Germany STEPAN Antonia F. F. HOFFMANN-LA ROCHE, Switzerland

159 STEPNICKI Piotr MEDICAL UNIVERSITY OF LUBLIN, Poland STOJANOVIC Aleksandar NOVARTIS, Switzerland STRIETH-KALTHOFF Felix UNIVERSITY OF MUNSTER, Germany TAL Daniel WEIZMANN INSTITUTE, Israel THOMPSON James GSK/UNIVERSITY OF STRATHCLYDE, United Kingdom TICHY Michal IOCB, Czech Republic TORMAKANGAS Olli ORION CORPORATION, Finland TORRES-GOMEZ Hector LEIBNIZ-HKI, Germany TRAUNER Dirk NEW YORK UNIVERSITY, United States TRIESELMANN Thomas BOEHRINGER INGELHEIM, Germany UMEHARA Kenichi F. HOFFMANN-LA ROCHE, Switzerland VAN BEELEN Eric WATERS, France VAN HIJFTE Luc MERCACHEM-SYNCOM, The Netherlands VANDERWAL Christopher UCI, United States VERMA Vishal GENENTECH, United States VESELOVSKA Lucia IOCB, Czech Republic VYSKOCIL Stepan TAKEDA, United States WEIN Lukas UNIVERSITY OF INNSBRUCK, Austria WILLIAMS Benjamin UNIVERSITY OF CAMBRIDGE, United Kingdom WILLIAMS Scott D. CHEMMEDCHEM/WILEY-VCH, Canada WILLIAMS Simon SYNGENTA, Switzerland WINTER Georg CEMM, Austria YURA Takeshi JUBILANT BIOSYS, India ZAVIALOV Kirill BIOCAD, Russia ZENTGRAF Matthias BOEHRINGER INGELHEIM, Germany ZHOU Jingyuan UNIVERSITY COLLEGE LONDON, United Kingdom ZUK Justyna MEDICAL UNIVERSITY OF LUBLIN, Poland

160