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Design, synthesis and anticancer activity studies of novel indole derivatives as Bcl-2/Mcl-1 dual inhibitors

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Abstract

A series of novel indole derivatives were designed, synthesized and evaluated for the binding affinity of Bcl-2 family proteins and antiproliferative activity against three selected cancer cell lines (PC-3, Jurkat, and MDA-MB-231). The preliminary structure-activity relationship (SAR) for this indole scaffold was summarized. Among all the compounds, compound 9k showed the best inhibitory activity against Bcl-2 and Mcl-1 proteins with IC50 values of 7.63 µM and 1.53 µM, respectively, which is comparable to the positive control AT-101. The docking study of it with Bcl-2 and Mcl-1 proteins indicated that it could bind to the active pocket of them through Van der Waals forces, hydrogen bond, etc. However, the three compounds with good binding affinity of Bcl-2 protein exhibited weaker antitumor activity compared to AT-101, which need further modification.

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Acknowledgements

This work was supported by grants from National Natural Science Foundation of China (No. 82104123), Natural Science Foundation of Shandong Province (No. ZR2020QH344), and the Project of Shandong Medical and Health Science and Technology (No. 2019WS393).

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  1. These authors contributed equally: Yingfei Liu, Jianjun Li

Authors and Affiliations

  1. Department of Medicinal Chemistry, School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong, 271016, China

    Yingfei Liu, Jianjun Li, Guanghui Zhou, Jiale Zhang, Yu Teng & Tingting Liu

  2. Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250000, China

    Zhushuang Bai

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  1. Yingfei Liu
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Liu, Y., Li, J., Zhou, G. et al. Design, synthesis and anticancer activity studies of novel indole derivatives as Bcl-2/Mcl-1 dual inhibitors. Med Chem Res 32, 99–108 (2023). https://doi.org/10.1007/s00044-022-02991-y

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  • DOI: https://doi.org/10.1007/s00044-022-02991-y

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