DOCSLIB.ORG

Bispidine-Amino Acid Conjugates Act As a Novel Scaffold for the Design of Antivirals That Block Japanese Encephalitis Virus Replication

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Bispidine-Amino Acid Conjugates Act As a Novel Scaffold for the Design of Antivirals That Block Japanese Encephalitis Virus Replication Bispidine-Amino Acid Conjugates Act as a Novel Scaffold for the Design of Antivirals That Block Japanese Encephalitis Virus Replication V. Haridas1*, Kullampalayam Shanmugam Rajgokul2, Sandhya Sadanandan1, Tanvi Agrawal2, Vats Sharvani2, M. V. S. Gopalakrishna1, M. B. Bijesh1, Kanhaiya Lal Kumawat3, Anirban Basu3, Guruprasad R. Medigeshi2* 1 Department of Chemistry, Indian Institute of Technology, New Delhi, India, 2 Vaccine and Infectious Disease Research Center, Translational Health Science and Technology Institute, Gurgaon, India, 3 National Brain Research Center, Manesar, Haryana, India Abstract Background: Japanese encephalitis virus (JEV) is a major cause of viral encephalitis in South and South-East Asia. Lack of antivirals and non-availability of affordable vaccines in these endemic areas are a major setback in combating JEV and other closely related viruses such as West Nile virus and dengue virus. Protein secondary structure mimetics are excellent candidates for inhibiting the protein-protein interactions and therefore serve as an attractive tool in drug development. We synthesized derivatives containing the backbone of naturally occurring lupin alkaloid, sparteine, which act as protein secondary structure mimetics and show that these compounds exhibit antiviral properties. Methodology/Principal Findings: In this study we have identified 3,7-diazabicyclo[3.3.1]nonane, commonly called bispidine, as a privileged scaffold to synthesize effective antiviral agents. We have synthesized derivatives of bispidine conjugated with amino acids and found that hydrophobic amino acid residues showed antiviral properties against JEV. We identified a tryptophan derivative, Bisp-W, which at 5 mM concentration inhibited JEV infection in neuroblastoma cells by more than 100-fold. Viral inhibition was at a stage post-entry and prior to viral protein translation possibly at viral RNA replication. We show that similar concentration of Bisp-W was capable of inhibiting viral infection of two other encephalitic viruses namely, West Nile virus and Chandipura virus. Conclusions/Significance: We have demonstrated that the amino-acid conjugates of 3,7-diazabicyclo[3.3.1]nonane can serve as a molecular scaffold for development of potent antivirals against encephalitic viruses. Our findings will provide a novel platform to develop effective inhibitors of JEV and perhaps other RNA viruses causing encephalitis. Citation: Haridas V, Rajgokul KS, Sadanandan S, Agrawal T, Sharvani V, et al. (2013) Bispidine-Amino Acid Conjugates Act as a Novel Scaffold for the Design of Antivirals That Block Japanese Encephalitis Virus Replication. PLoS Negl Trop Dis 7(1): e2005. doi:10.1371/journal.pntd.0002005 Editor: Kouichi Morita, Institute of Tropical Medicine (NEKKEN), Japan Received May 17, 2012; Accepted November 28, 2012; Published January 17, 2013 Copyright: ß 2013 Haridas et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: TA is supported by the Vaccine Research Innovation Award. This study was supported by institutional grant by the Department of Biotechnology to GRM (Grant # BT/PR14217/MED/30/405/2010 URL: http://dbtindia.nic.in/index.asp)and by the extra-mural support from the Department of Science and Technology to VH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: Two patent applications are pending related to this study with provisional patent application numbers 2784/Del/2011 and 2786/Del/ 2011. * E-mail: [email protected] (VH); [email protected] (GRM) Introduction 4B and 5). Pigs and water birds have been proposed to be the natural hosts of JEV and Culex mosquitoes transmit the disease to Japanese encephalitis virus (JEV) is a mosquito-borne, neuro- humans who are dead-end hosts [1,2]. tropic RNA virus within the family Flaviviridae, which includes Protein-protein interactions are vital to many cellular events and other pathogens of global significance such as dengue virus and blocking such interactions using synthetic compounds is a very West Nile virus. JEV is endemic to most South- and South-East attractive option for design of new pharmaceuticals. The Asian countries and recurring outbreaks lead to about 30,000 formation of homomeric and heteromeric protein complexes deaths, mostly children, annually. Patients recovering from JEV involves very stringent selection based on chemical complemen- infections suffer from long-term neurological sequelae. Availability tarity. Therefore targeting such interaction requires a structure- of WHO-approved JEV vaccine for pediatric use is limited and based approach. The therapeutic utility of secondary structure there are no clinically approved antivirals for JEV infections. JEV peptide mimetics is under intense investigation particularly to treat genome is a single-stranded positive strand RNA encoding for a cancer and HIV and also to serve as antimicrobial compounds [3– single poly-protein that is cleaved by host and viral proteases into 5]. Protein secondary structure based inhibitors are one of the three structural (Capsid, precursor membrane/membrane and rational ways in achieving this goal. In this study, we describe 3,7- envelope) and seven non-structural proteins (NS1, 2A, 2B, 3, 4A, diazabicyclo[3.3.1]nonane, commonly called bispidine, as a PLOS Neglected Tropical Diseases | www.plosntds.org 1 January 2013 | Volume 7 | Issue 1 | e2005 Identification of a New Flavivirus Inhibitor Author Summary experiments, cells were treated at indicated time-points with indicated concentrations of bispidine derivatives, washed twice Japanese encephalitis virus is a mosquito-borne virus, with phosphate buffered saline (PBS) and incubated with virus which causes encephalitis primarily in children and is a medium (DMEM containing 2% fetal bovine serum with major cause of encephalitis-related deaths in South and additives) containing the required amount of virus or no virus South-East Asian countries. Although new and safe (uninfected controls) for one hour on a rocking platform in CO2 vaccines are available for use, it is neither affordable nor incubator at 37uC. After incubation, virus inoculum was removed readily available in endemic regions. Currently there are no and cells were washed twice with PBS and fresh medium (DMEM- antivirals for JEV treatment and developing new drugs 2% fetal bovine serum with additives) containing the indicated against JEV is the need of the hour. In this study we used concentration of compound/s or equal volume of DMSO was the backbone of the naturally occurring lupin alkaloid, sparteine to synthesize derivatives containing amino acid added onto the cells and continued incubation for indicated residues. We found that the conjugate consisting of the periods. Minocycline treatment was performed as described hydrophobic amino acid tryptophan, Bisp-W, inhibited previously [8], briefly, cells were pre-treated for 1 h with either virus replication in cell culture studies. We show that Bisp- minocycline (20 mM) or Bisp-W (5 mM) and corresponding vehicle W inhibits virus infection at a stage post-entry and at the controls (PBS/DMSO). Cells were infected as above in the level of viral RNA replication suggesting that this absence of compounds and compounds were added after virus compound could serve as a potential therapeutic option adsorption. Culture supernatants were collected and viral titers for treating JEV infection. We believe that the chemical were measured using plaque assays. Intracellular virus titers were scaffold identified in this study could serve as a platform measured by collecting cells by trypsinisation and resuspending for synthesizing more potent antivirals that could be used cells in PBS. Cell suspension was subjected to three freeze-thaw to treat viral encephalitis. cycles by placing in liquid nitrogen and 37uC water-bath consecutively in each cycle. Supernatants were collected by centrifugation at 3,000 rpm for 5 min. at 4uC and used in plaque privileged scaffold for generating potential antiviral agents. We assays as described above. For West Nile virus inhibition studies, chose bispidine moiety, because of its rigidity and high hydropho- cells were infected with an MOI of 1 pfu/cell and supernatants bic surface area, which enables interaction with hydrophobic collected at 22 hours post-infection (h pi) and for Chandipura surfaces of cellular/viral proteins and thus may alter the profile of virus, cells were infected with an MOI of 0.1 pfu/cell and protein interaction network. We envisioned that, when appended supernatants collected at 8 h pi. Viral titers were estimated by with amino acids, bispidine scaffold can orient the amino acids in plaque assay on Vero cells as described above. rigid geometrical arrangement and thus would be an ideal scaffold to generate various ligands for inhibiting protein-protein interac- Cytotoxicity assay tions [6]. We validated this hypothesis by using JEV as a model Cells were infected as described above and cytotoxicity was and show that one of the derivatives of bispidine exhibits potent assessed by lactate dehydrogenase release assay using CytoTox 96 inhibitory activity against JEV replication suggesting that bispidine Non-Radioactive Cytotoxicity Assay kit as per the manufacturer’s can be used to develop novel therapeutics
Load more

Recommended publications
  • Sparteine Surrogate and (-)- Sparteine
    This is a repository copy of Gram-Scale Synthesis of the (-)-Sparteine Surrogate and (-)- Sparteine. White Rose Research Online URL for this paper: https://eprints.whiterose.ac.uk/124708/ Version: Accepted Version Article: Firth, James D, Canipa, Steven J, O'Brien, Peter orcid.org/0000-0002-9966-1962 et al. (1 more author) (2018) Gram-Scale Synthesis of the (-)-Sparteine Surrogate and (-)- Sparteine. Angewandte Chemie International Edition. pp. 223-226. ISSN 1433-7851 https://doi.org/10.1002/anie.201710261 Reuse Items deposited in White Rose Research Online are protected by copyright, with all rights reserved unless indicated otherwise. They may be downloaded and/or printed for private study, or other acts as permitted by national copyright laws. The publisher or other rights holders may allow further reproduction and re-use of the full text version. This is indicated by the licence information on the White Rose Research Online record for the item. Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request. [email protected] https://eprints.whiterose.ac.uk/ COMMUNICATION Gram-Scale Synthesis of the (–)-Sparteine Surrogate and (–)- Sparteine James D. Firth,[a] Steven J. Canipa,[a] Leigh Ferris[b] and Peter O’Brien*[a] Abstract: An 8-step, gram-scale synthesis of the (–)-sparteine to a greatly enhanced reactivity of the s-BuLi/sparteine surrogate surrogate (22% yield, with just 3 chromatographic purifications) and a complex. For example, the high reactivity of the s-BuLi/sparteine 10-step, gram-scale synthesis of (–)-sparteine (31% yield) are surrogate complex was required for one of the steps in Aggarwal’s reported.
    [Show full text]
  • Bispidine Derivatives
    Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 161 Bispidine Derivatives Synthesis and Interactions with Lewis Acids LAURI TOOM ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6214 UPPSALA ISBN 91-554-6509-9 2006 urn:nbn:se:uu:diva-6735 ! " # $$% & '&( ) * ) ) +* *, -* . / *, - 0, $$%, , 1 * 2 . * 0. ", " , &%&, 3 , , 214 5&6((36%($565, 2 * * * * * ) 76 8 9 , ,&: ; < , -* * = * ) ) * * * ) . * * , -* * * ) )) . * . * 8 ) . * ) 0. , " * * .* * ) ** * 8 .** > * , " ) . * ) . * 8 * .** * ) , . * * ) * . * ** , -* ) * ) * * 8 * ?6 * 4 , 1 ;@6 < . * * * * * , = ) ;A 6 < * 9B;A 6 <+C%;D 6E<3: . , 4 ) ! " # ! "$ ! " % &'(! ! )*'&+,- ! F 0 - $$% 2114 &%(&6%&3 214 5&6((36%($565 ' ''' 6%7 ( ;* 'GG ,=,G H I ' ''' 6%7 (< List of Papers Included in this Thesis This thesis is based on the following papers, which are referred to in the text by their Roman numerals: I. Toom, L., Grennberg, H., Gogoll, A. Microwave-Assisted Raney Nickel Reduction of Bispidinone Thioketals to N,N’-Dialkyl- bispidines. Accepted for publication in Synthesis. II. Toom, L., Kütt, A., Kaljurand, I., Leito
    [Show full text]
  • Acylbispidinols
    Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 12 December 2018 doi:10.20944/preprints201812.0149.v1 Peer-reviewed version available at Nanomaterials 2019, 9, 89; doi:10.3390/nano9010089 Article Supramolecular Organogels Based on N-Benzyl, N’-Acylbispidinols Alexey V. Medved'ko1, Alexander I. Dalinger1, Vyacheslav N. Nuriev1, Vera S. Semashko1, Andrei V. Filatov2, Alexander A. Ezhov3,4, Andrei V. Churakov5, Judith A. K. Howard6, Andrey A. Shiryaev7,8, Alexander E. Baranchikov1,5, Vladimir K. Ivanov5,9 and Sergey Z. Vatsadze1* 1 Faculty of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russian Federation; [email protected] 2 Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation 3 Faculty of Physics, Lomonosov Moscow State University, 119991 Moscow, Russian Federation 4 Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences, 119991 Moscow, Russian Federation 5 Kurnakov Institute of General and Inorganic Chemistry of the Russian Academy of Sciences, 119991 Moscow, Russian Federation 6 Department of Chemistry, University of Durham, Durham, DH1 3LE, UK 7 Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, 119071 Moscow, Russian Federation 8 Institute of geology of ore deposits, petrography, mineralogy and geochemistry, Russian Academy of Sciences, 119017 Moscow, Russian Federation 9 Faculty of Material Science, Lomonosov Moscow State University, 119991 Moscow, Russian Federation * Correspondence: [email protected] ; Tel.: +7-903-748-7892 Abstract: The acylation of unsymmetrical N-benzylbispidinols in aromatic solvents without external base led to formation of supramolecular gels, which possess different thickness and stability depending on the substituents in para-positions of benzylic group and nature of acylating agent as well as on the nature of the solvent used.
    [Show full text]
  • Supramolecular Organogels Based on N-Benzyl, N'-Acylbispidinols
    nanomaterials Article Supramolecular Organogels Based on N-Benzyl, N0-Acylbispidinols Alexey V. Medved’ko 1, Alexander I. Dalinger 1, Vyacheslav N. Nuriev 1, Vera S. Semashko 1, Andrei V. Filatov 2, Alexander A. Ezhov 3,4 , Andrei V. Churakov 5, Judith A. K. Howard 6, Andrey A. Shiryaev 7,8 , Alexander E. Baranchikov 1,5 , Vladimir K. Ivanov 5,9 and Sergey Z. Vatsadze 1,* 1 Faculty of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia; [email protected] (A.V.M.); [email protected] (A.I.D.); [email protected] (V.N.N.); [email protected] (V.S.S.); [email protected] (A.E.B.) 2 Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russia; fi[email protected] 3 Faculty of Physics, Lomonosov Moscow State University, 119991 Moscow, Russia; [email protected] 4 Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences, 119991 Moscow, Russia 5 Kurnakov Institute of General and Inorganic Chemistry of the Russian Academy of Sciences, 119991 Moscow, Russia; [email protected] (A.V.C.); [email protected] (V.K.I.) 6 Department of Chemistry, University of Durham, Durham DH1 3LE, UK; [email protected] 7 Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, 119071 Moscow, Russia; [email protected] 8 Institute of Geology of Ore Deposits, Petrography, Mineralogy and Geochemistry, Russian Academy of Sciences, 119017 Moscow, Russia 9 Faculty of Material Science, Lomonosov Moscow State University, 119991 Moscow, Russia * Correspondence: [email protected]; Tel.: +7-903-748-7892 Received: 10 December 2018; Accepted: 3 January 2019; Published: 11 January 2019 Abstract: The acylation of unsymmetrical N-benzylbispidinols in aromatic solvents without an external base led to the formation of supramolecular gels, which possess different thicknesses and degrees of stability depending on the substituents in para-positions of the benzylic group as well as on the nature of the acylating agent and of the solvent used.
    [Show full text]
  • Transition Metal Complexes of 3,7-Diazabicyclo[3.3.1]Nonane Derivatives
    Transition Metal Complexes of 3,7-Diazabicyclo[3.3.1]nonane Derivatives: Complex Stabilities and Oxidation Reactivity of Cobalt (II) and Vanadium (IV) Inaugural-Dissertation zur Erlangung der Doktorwürde der Naturwissenschaftlich-Mathematischen Gesamtfakultät der Ruprecht-Karls-Universität Heidelberg vorgelegt von Shigemasa Kuwata aus Hyogo, Japan 2005 Abbreviations Abbreviations s second(s) h hour(s) min minute(s) CT charge transfer IR infrared spectroscopy NMR nuclear magnetic resonance UV-Vis ultraviolet -visible XRD X-ray diffraction CV cyclic voltammetry EPR electron paramagnetic resonance IC inhibitory concentration MeOH methanol EtOH ethanol THF tetrahydrofuran ε extinction coefficient FAB fast atom bombardment ESI electrospray ionization ls low spin hs high spin sod superoxide dismutase eq equivalent acac acetylacetonato I Abbreviations OOO OOO OOO O O O O O O N N N N N N N N N N NPy2 1 6Me-NPy2 1 Npy3 2 N N N OOO OOO OOO O O O O O O N N N N N N N N N N N2Py2 1 6Me-N2Py2 1 N2Py3u 3 N N N N OOO OOO OOO O O O O O O N N N N N N N N N N2Py3o 4 PY4AEa4 N N OOO O O N N N N N2Py4 4 II Abbreviations References 1 U. Holzgrabe, E. Ericyas, Arch. Pharm.,1992, 325, 657. 2 A. Lienke, Doctor dissertation, Ruprecht-Karls-Universität, 1998. 3 M. Merz, Doctor dissertation, Ruprecht-Karls-Universität, 2002. 4 H. Brörzel, Doctor dissertation, Ruprecht-Karls-Universität, 2000. III Abbreviations IV Index Index Abstract 1 Zussamenfassung 7 1. Introduction 13 2.
    [Show full text]
  • And Tetra-Dentate Bispidine-Derived Ligands in the Copper (II)-Catalyzed Asymmetric Henry Reaction
    Application of chiral bi- and tetra-dentate bispidine-derived ligands in the Copper (II)-catalyzed asymmetric Henry reaction Arianna Rossetti,a Stefano Landoni,a,b Fiorella Meneghetti,*b Carlo Castellano,c Matteo Mori,b Greta Colombo Dugonia and Alessandro Sacchetti*a The application of a number of chiral bispidine-based ligands in the copper-catalyzed enantioselective Henry reaction is here reported. Results showed good conversion rates and low to moderate enantiomeric ratios, depending on the substituents on the bispidine core. Enantioselectivities of selected ligands were rationalized on the basis of single-crystal X-ray analyses, NMR studies and computational tools. Following our recent interest in the conformational behavior of chiral Introduction bispidines,10 we decided to investigate new potential applications of Reactions involving the formation of a new C-C bond are the most chiral bispidines in the nitroaldol additions in order to explore the valuable and interesting in organic synthesis. One of the most enantioselection in connection with the ligand asymmetry. common approaches is to exploit the reaction between a carbanion Therefore, we prepared and screened a library of heterogeneous and an electrophilic carbon. The Henry reaction, also known as bispidine ligands in the reaction of nitromethane with aldehydes, 1 nitroaldol reaction, refers to the addition of a nitroalkane anion on under different conditions with diverse metals. The mode of a carbonyl carbon to afford a β-nitro alcohol. These compounds are chelation of selected ligands was further investigated by NMR and of great interest as intermediates for the synthesis of different supported by crystallographic data and computational study to products after the transformation of either the nitro or the hydroxyl assess the role of the ligand in the stereochemical outcome of the 2 function.
    [Show full text]
  • Perspective Dalton Trans 20
    2,4-Substituted bispidines as rigid hosts for versatile applications: from κ-opioid receptor to metal coordination Aline Nonat, Amandine Roux, Maryame Sy, Loic J Charbonniere To cite this version: Aline Nonat, Amandine Roux, Maryame Sy, Loic J Charbonniere. 2,4-Substituted bispidines as rigid hosts for versatile applications: from κ-opioid receptor to metal coordination. Dalton Transactions, Royal Society of Chemistry, 2019, 48 (44), pp.16476-16492. 10.1039/c9dt03480c. hal-02439628 HAL Id: hal-02439628 https://hal.archives-ouvertes.fr/hal-02439628 Submitted on 16 Sep 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Please do not adjust margins Journal Name ARTICLE 2,4-substituted bispidines as rigid hosts for versatile applications: from κ-opioid receptor to metal coordination Received 00th January 20xx, a a,b a a Accepted 00th January 20xx Aline M. Nonat,* Amandine Roux, Maryame Sy, and Loïc J. Charbonnière DOI: 10.1039/x0xx00000x Bispidones (3,7-diazabicyclo[3.3.1]nonan-9-one) are bicyclic analogues of the natural antiarrythmic agent, spartein. They www.rsc.org/ can straightforwardly be obtained from two successive Mannich reactions. Reduction of the ketone gives the corresponding bispidol.
    [Show full text]
  • PDF (04Chapter4.Pdf)
    51 Chapter 4 New Ligands for Enantioselective Oxidations: N-Heterocyclic Carbenes 4.1 Unselective Ligand Systems for Pd-catalyzed Alcohol Ox- idations In 1977 Blackburn and Schwartz[68] reported the PdCl2/NaOAc-catalyzed aerobic oxidation of sec- ondary alcohols sans copper salts and byproducts (other than water). The reaction proceeds at mild ◦ (25-38 C) temperatures under 1 atm O2, though precipitation of palladium was observed at long reaction times. Since then, organic ligands have been identified which improve various aspects of the reaction. Several are reviewed here (Table 4.1), and any could be considered a starting point in an effort to design enantioselectivity into the unselective process. The pyridine/Pd(OAc)2 system reported by Uemura et al.[28] extended the substrate scope to include primary and aliphatic alcohols. Reaction rates are also accelerated. Ligand screens by Uemura[28] and also Stoltz[31] and Sigman[32] identified other nitrogenous molecules which ostensibly behave as less efficient analogues of pyridine. Employing triethylamine did result in faster reaction rates at low temperatures[69]. Molecular sieves are included in the reaction mixture and serve to disproportionate (or at least sequester) the primary product hydrogen peroxide, driving the reaction to completion. This element of the protocol has been retained by subsequent catalysts operating in organic solvents. A water-soluble phenanthroline derivative reported by Sheldon and coworkers[29] removes the 52 necessity of mixing oxygen and organic solvents, rendering the reaction safer and environmentally friendlier. The large rates observed in this system are likely due to the high temperature and the ability of the polar solvent to abstract anions and create vacancies on Pd.
    [Show full text]
  • 2.2. Department of Homogeneous Catalysis
    Homogeneous Catalysis 2.2. Department of Homogeneous Catalysis Director: Benjamin List (born 1968) Further group leaders: Martin Klußmann (born 1974) Nuno Maulide (born 1979) left the Institute in September 2013 Klaus-Richard Pörschke (born 1949) Homogeneous Catalysis Curriculum Vitae: Benjamin List 1968 Born in Frankfurt/Main, Germany 1993 Chemistry Diploma, Freie Universität Berlin 1997 Ph.D., Johann Wolfgang Goethe-Universität Frankfurt, with Prof. J. Mulzer 1997-1998 Postdoc, Scripps Research Institute, La Jolla, USA, with Prof. R. Lerner 1999-2003 Assistant Professor (Tenure Track), Scripps Research Institute, La Jolla, USA 2003-2005 Group Leader at the Max-Planck-Institut für Kohlenforschung 2004- Honorary Professor at the Universität zu Köln 2005- Director at the Max-Planck-Institut für Kohlenforschung 2012- Managing Director of the Max-Planck-Institut für Kohlenforschung Awards and Honors 1997-1998 Feodor-Lynen Fellowship of the Alexander von Humboldt Foundation 1994-1995 NaFoeG-Graduate Fellowship of the Senate of Berlin 2000 Synthesis-Synlett Journal Award 2003 Carl-Duisberg-Memorial Award 2004 Degussa Prize for Chiral Chemistry 2004 Lieseberg Prize 2004 Lecturer Award of the German Chemical Industry Fund 2005 Visiting Professorship, Gakushuin University, Tokyo, Japan 2005 Society of Synthetic Chemistry, Japan: 2005 Lectureship Award 2005 AstraZeneca European Lecturer 2005 Novartis Young Investigator Award 2006 JSPS Fellowship, Japan 2006 100 Masterminds of Tomorrow, Germany 2006 Wiechert Lectureship, FU Berlin, Germany 2007
    [Show full text]
  • Download (7MB)
    Mathieson, Michael (2014) Studies towards the synthesis of hexacyclinic acid. PhD thesis. http://theses.gla.ac.uk/5750/ Copyright and moral rights for this thesis are retained by the author A copy can be downloaded for personal non-commercial research or study, without prior permission or charge This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the Author The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the Author When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given Glasgow Theses Service http://theses.gla.ac.uk/ [email protected] Studies towards the Synthesis of Hexacyclinic Acid Michael Mathieson (MChem) A thesis submitted in part fulfilment of the requirements of the degree of Doctor of Philosophy School of Chemistry College of Science & Engineering University of Glasgow November 2014 Contents Acknowledgements...................................................................... 4 Author’s Declaration....................................................................5 Abstract...................................................................................6 Abbreviations ..............................................................................7 1 – Introduction .........................................................................9 1.1 – Hexacyclinic acid and (−)-FR182877.................................10
    [Show full text]
  • Synthesis and Catalytic Applications of 1,2,4- Triazoles in Oxidative Processes
    University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Doctoral Dissertations Graduate School 8-2012 Synthesis and Catalytic Applications of 1,2,4- Triazoles in Oxidative Processes Ashesh Shirish Belapure [email protected] Follow this and additional works at: https://trace.tennessee.edu/utk_graddiss Recommended Citation Belapure, Ashesh Shirish, "Synthesis and Catalytic Applications of 1,2,4- Triazoles in Oxidative Processes. " PhD diss., University of Tennessee, 2012. https://trace.tennessee.edu/utk_graddiss/1480 This Dissertation is brought to you for free and open access by the Graduate School at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. To the Graduate Council: I am submitting herewith a dissertation written by Ashesh Shirish Belapure entitled "Synthesis and Catalytic Applications of 1,2,4- Triazoles in Oxidative Processes." I have examined the final electronic copy of this dissertation for form and content and recommend that it be accepted in partial fulfillment of the equirr ements for the degree of Doctor of Philosophy, with a major in Chemistry. Shane Foister, Major Professor We have read this dissertation and recommend its acceptance: Shawn R. Campagna, Craig E. Barnes, Thomas A. Zawodzinski Accepted for the Council: Carolyn R. Hodges Vice Provost and Dean of the Graduate School (Original signatures are on file with official studentecor r ds.) To the Graduate Council: I am submitting herewith a dissertation written by Ashesh S. Belapure entitled “Catalytic applications of 1,2,4-triazoles in oxidative processes”.
    [Show full text]
  • Application of Direct Imine Acylation Methodology in the Synthesis of Nitrogen Heterocycles and Natural Products
    Application of Direct Imine Acylation Methodology in the Synthesis of Nitrogen Heterocycles and Natural Products Sarah J. Chambers PhD University of York Chemistry September 2016 Abstract This thesis describes the use of direct imine acylation (DIA) methodology in a range of different applications. Firstly, the attempted synthesis of (±)-cytisine is described (Chapter 2). The use of DIA methodology in the formation of the pyridone ring scaffold of (±)-cytisine has been explored. In the most advanced synthesis towards (±)- cytisine achieved in this project, the generation of N-acyliminium ions from imine A and subsequent nucleophilic addition of organometallic allyl reagents was developed to give diene B. O O 1. T3P (50% in THF) N DIPEA, cinnamic acid Ph N N N 2. allyltrimethyl silane, R Lewis acid N NH A R B (±)-cytisine R = Boc or CO2Et DIA methodology has also been utilised in the synthesis of spirocyclic products from simple indole acids C and imines D (Chapter 3). The reaction provides a broad range of products E in good yields and the indole acid starting materials C are readily synthesised using Fischer indole methodology. The stereoselectivity of the reaction, derivatisation of the products E and 3D shape analysis are also described. O O O T3P (50% N N n n n X OH in THF), Spiro- N DIPEA X cyclisation X R R1 H R R1 R R1 N H N N C D H E 1 R = OMe, F, Br, Me; R = H, Me, Ph; X = C or N; n = 1 or 2 Finally, work towards the synthesis of (±)-aspidospermidine, using the spirocyclisation methodology developed in this project, is introduced (Chapter 4).
    [Show full text]