Hanyue Qiu, Zhuanzhuan Du, Yankun Zhao, Shan Yuan, Song Xi, Tao Zhou, Jiao Yang, Changhui Zhang, Yang Xiong, Yi Xia, Shaolin Zhang, Lin Fu, Ling He, Min Zhang
Journal of medicinal chemistry 2023 Jul 27Molecular 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.
Hanyue Qiu, Zhuanzhuan Du, Yankun Zhao, Shan Yuan, Song Xi, Tao Zhou, Jiao Yang, Changhui Zhang, Yang Xiong, Yi Xia, Shaolin Zhang, Lin Fu, Ling He, Min Zhang. Enantioselective Synthesis and Biological Evaluation of Pyrrolidines Bearing Quaternary Stereogenic Centers. Journal of medicinal chemistry. 2023 Jul 27;66(14):9866-9880
PMID: 37428137
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