Enantioselective Synthesis and Biological Evaluation of Pyrrolidines Bearing Quaternary Stereogenic Centers

Molecular complexity plays an increasingly
important role in the
modern pharmaceutical industry. Setting up multiple stereogenic centers
in privileged substructures may give rise to improved or even unprecedented
bioactivities; however, this area remains largely unexplored due to
the tremendous synthetic challenges. Herein, we report a series of
multisubstituted pyrrolidines with four continuous stereogenic centers,
including up to two aza-QSCs (quaternary stereogenic centers). Systematic
evaluations, including phenotypic screening, molecular docking, molecular
dynamics, bioinformatics, and bioactivity analysis, have been performed
to screen entities with pharmacological properties of interest. Among
them, compound 4m with two QSCs was identified to be
a potent antiproliferation agent through disturbing mitosis exit,
and the presence of QSCs was found to be crucial for anticancer efficacy.
This work illustrates that the introduction of QSCs in privileged
scaffolds not only helps to expand the unpatented chemical space
but also provides new opportunities for the discovery of novel therapeutic
agents.