PhD Defence - Ruwei Yao "Synthesis of an alkaloid inspired compound collection"

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



Professor Jens Øllgaard Duus, DTU Chemistry



Professor Mads Hartvig Clausen, DTU Chemistry
Associate Professor Rasmus
Prætorius Clausen, University of Copenhagen

Associate Professor James Hodgkinson, University of Leicester, UK


Fri 10 Feb 23
13:00 - 16:00


Technical University of Denmark
Building 303A, Aud. 44