RSC Prize Lecture: 'Natural Product Synthesis: A Crucible for New Method Development and Drug Discovery' - 25th April
17 April 2023
Join us in a RSC Prize Lecture with Professor Dame Margaret Brimble FRS (University of Auckland).
Speaker: Dame Margaret Brimble FRS (University of Auckland)
Time & Location: 11:00AM - 12:00PM, 25th April, Chemistry Building - LT4
Title: 'Natural Product Synthesis: A Crucible for New Method Development and Drug Discovery'
Abstract: Read below or click the following link for the Word file of the abstract: RSC Prize Lecture: Professor Dame Margaret Brimble (Office document, 76kB)
Natural products have long been regarded as “Nature’s medicine chest” providing invaluable platforms for developing front-line drugs. The chemical structures of natural products have evolved over several millennia for a specific biochemical purpose and their molecular frameworks can be considered privileged scaffolds.(1) This lecture will showcase the synthesis of bioactive natural products and peptides from our own research(2) as examples of underexplored novel structural chemotypes for drug discovery.
Inspired by their complex architecture and potential as pharmaceutical lead compounds, the spirocyclic imine class of marine toxins (e.g. portimine and 13-desMe spirolide C) have attracted the attention of our research group.3 The total syntheses of these natural products have challenged the repertoire of existing synthetic methods. Examples of new synthetic methods developed by our group(3) whilst engaging in the total synthesis of these unique bioactive natural products will be highlighted.
Due to the on-going global expansion of antimicrobial resistant (AMR) infections, and the declining proportion of FDA-approved antimicrobial drugs over the past three decades, AMR is now recognised worldwide as one of the greatest threats facing humankind in the 21st century. Antimicrobial peptides and proteins (AMPs) exist widely throughout nature and protect organisms from infection by destroying a broad range of pathogens. Due to the unique and non-specific bactericidal mechanism of action of AMPs, AMPs have a lower tendency to elicit antibiotic resistance than conventional antibiotics and are potentially useful therapeutic agents. The chemical synthesis and biological activity of several representative examples of antimicrobial peptides/proteins will also be described.(4)
1 “Natural Product Derived Privileged Scaffolds in Drug Discovery,” E. K. Davison, M.A. Brimble, Current Opinion in Chemical Biology, 2019, 52, 1-8.
2 “Total Synthesis of (±)-Leonuketal,” P.S. Grant, D.P. Furkert, M.A. Brimble, Org. Lett., 2020, 22, 8735–8740; “Asymmetric Total Synthesis of the Naturally Occurring Antibiotic Anthracimycin,” E. K. Davison, J. L. Freeman, W. Zhang, W. M. Wuest, D. P. Furkert, M. A. Brimble, Org. Lett., 2020, 22, 5550-5554.
3 “Synthesis of the C4-C16 Polyketide Fragment of Portimines A and B,” X. Ding, H.R.M. Aitken, E.S. Pearl, D.P. Furkert, M.A. Brimble, J. Org. Chem., 2021, 86, 12840–12850; “Convenient Access to 5-Membered Cyclic Iminium Ions: Evidence for a Stepwise [4+2] Cycloaddition Mechanism,” J.L. Freeman, M.A. Brimble, D.P. Furkert, Org. Biomol. Chem., 2019, 17, 2705-2714; “Cyclic Enecarbamates as Precursors of alpha,beta-Unsaturated Iminium Ions: Reactivity and Synthesis of 6,6-Spirocyclic Ring Systems,” Z. Wang, N. Krogsgaard-Larsen, B. Daniels, D.P. Furkert, M.A. Brimble, J. Org. Chem., 2016, 81, 10366-10375.
3 “N-Vinyl Acrylamides: Versatile Heterobifunctional Electrophiles for Thiol–Thiol Bioconjugations,” M. Ahangarpour, I. Kavianinia, P. Hume, P.W.R. Harris, M.A. Brimble, J. Am. Chem. Soc., 2022, 144, 30, 13652–13662. “Highly Diastereoselective Synthesis of syn-1,3-Dihydroxyketone Motifs from Propargylic Alcohols via Unusual Spiroepoxide Intermediates,” X.-B. Ding, D.P. Furkert, M.A. Brimble, Angew. Chem. Int. Ed., 2019, 58, 11830-11835; “Unexpected Direct Synthesis of N-Vinyl Amides Through Vinyl Azide-Enolate [3+2] Cycloaddition” H. Choi, H.J. Shirley, P.A. Hume, M.A. Brimble, D.P. Furkert, Angew. Chem. Int. Ed., 2017, 56,
7420-7424; “A Catalytic Asymmetric Ene Reaction For Direct Preparation of a-Hydroxy-1,4-Diketones As Intermediates In Natural Product Synthesis,” H.R.M. Aitken, D. P. Furkert, M.A. Brimble, Synlett, 2020, 31, 687-690; “Intermolecular Diels-Alder Cycloaddition/Cross-coupling Sequences of 2-Bromo-1,3-Butadienes,” H. Choi, H. Shirley, H.R.M. Aitken, T. Schulte, T. Söhnel, P. Hume, M.A. Brimble, D.P. Furkert, Org. Lett., 2020, 22, 1022-1027; “A Highly Efficient N-Mesityl Thiazolylidene for the Aliphatic Stetter Reaction: Stereoelectronic Quantification for Comparison of N-Heterocyclic Carbene Organocatalysts,” E.S. Pearl, D.M.J. Fellner, T. Söhnel, D.P. Furkert, M.A. Brimble, Asian J. Org. Chem., 2021, 10, 2869-2875;
4 “Photoinduced Thiol–Ene Chemistry: A Versatile Toolbox for Peptide-Based Drug Design,” M. Ahangarpour, I. Kavianinia, P.W.R. Harris, M.A. Brimble, Chem. Soc. Rev., 2021, 50, 898-944; “Development of Peptide-Based Antibiotics,” C. C. Hanna, Y. O. Hermant, P. W. R. Harris, M.A. Brimble, Acc. Chem. Res.,” 2021, 54, 1878–1890; “CLipP”ing on Lipids to Generate Antibacterial Lipopeptides,” V. Yim, I. Kavianinia, M. K. Knottenbelt, S. A. Ferguson, G. M. Cook, S. Swift, A. Chakraborty, J. R. Allison, A.J. Cameron, P.W.R. Harris, M.A. Brimble, Chem. Sci., 2020, 11, 5759-5765; “Total Synthesis and Conformational Study of The Anti-tubercular Cyclic Peptide Callyaerin A Bearing a Rare Rigidifying (Z)-2,3-Diaminoacrylamide Moiety,” M.A. Brimble, S. Zhang, L.M. De Leon Rodriguez, I.K.H. Leung, G. M. Cook, P.W.R. Harris, Angew. Chem. Int. Ed., 2018, 57, 3631-3635; “Total Chemical Synthesis of Glycocin F and Analogues: S-Glycosylation Confers Improved Antimicrobial Activity,” Z. Amso, S.W. Bisset, S.-H. Yang, P.W.R. Harris, T.H. Wright, C.D. Navo, M.L. Patchett, G.E. Norris, M.A. Brimble, Chem. Sci., 2018, 9, 1686-1691.