BEGIN:VCALENDAR VERSION:2.0 PRODID:-//DTU.dk//NONSGML DTU.dk//EN CALSCALE:GREGORIAN BEGIN:VEVENT DTSTART:20230210T120000Z DTEND:20230210T150000Z SUMMARY:PhD Defence - Ruwei Yao "Synthesis of an alkaloid inspired compound collection" X-ALT-DESC;FMTTYPE=text/html:
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Pseudo-natural products, defined as the non-biogenic fusion of natural product fragments, have emerged as an inspiration for rapidly identifying novel biologically active molecules. We synthesized a library of 64 pseudo-natural products, which contain ten structurally diverse spirocycles based on tropane and quinuclidine alkaloid scaffolds. The library has a high Fsp3 content and Lipinski’s rule-of-five compliance, making it highly drug-like. Through targeted screening we discover unnatural quinoxaline-fused tropanes targeting the 5-HT2A serotonin receptor. Additionally, we identify and further optimize a lead 5HT2B/C antagonist derived from chromanone-fused quinuclidines with a surprising selectivity profile against a panel of aminergic G-protein coupled receptors (GPCRs), alongside α4β2 and α3β4 nicotinic acetylcholine receptors (nAChRs).
\nWe extended this strategy to identify other aminergic G-protein coupled receptors (GPCRs) modulators in the central nervous system (CNS). Herein, we reported the synthesis of a library containing 22 analogues based on quinolizidine alkaloid scaffolds. Biological screening against dopamine receptors revealed that the unnatural quinoline-fused quinolizidines are new chemotype ligands at the dopamine 2 receptor (D2R), which does not often exist in naturally occurring quinolizidines. We further identified our lead compounds can exhibit high selectivity over α4β2 and α3β4 nAChRs.
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Principal Supervisor:
\nAssociate Professor Luca Laraia, DTU Chemistry
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Co-supervisor:
\nProfessor Jens Øllgaard Duus, DTU Chemistry
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Examiners:
\nProfessor Mads Hartvig Clausen, DTU Chemistry
\nAssociate Professor Rasmus Prætorius Clausen, University of Copenhagen
Associate Professor James Hodgkinson, University of Leicester, UK
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