Synthesis of an alkaloid inspired compound collection
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).
We 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.
Principal Supervisor:
Associate Professor Luca Laraia, DTU Chemistry
Co-supervisor:
Professor Jens Øllgaard Duus, DTU Chemistry
Examiners:
Professor Mads Hartvig Clausen, DTU Chemistry
Associate Professor Rasmus Prætorius Clausen, University of Copenhagen
Associate Professor James Hodgkinson, University of Leicester, UK