Design, synthesis and biological evaluation of hydantoin derivatives as Mcl-1 selective inhibitors

• Published in: Bioorganic chemistry 2022-04, Vol.121, p.105643-105643, Article 105643
• Main Authors: Liang, Xiao, Li, Xue, Zhao, Zhiyuan, Nie, Yiming, Yao, Zefu, Ren, Wandi, Yang, Xinying, Hou, Xuben, Fang, Hao
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Apoptosis; Cancer; Cell Line, Tumor; Drug Design; Hydantoin derivatives; Hydantoins - pharmacology; Mcl-1 inhibitors; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2022.105643

[Display omitted] •Hydantoin derivatives were designed and synthesized as Mcl-1 inhibitors.•Several compounds exhibited good binding affinities against Mcl-1 and possess selectivity over Bcl-xL and Bcl-2.•The most potent compound M24 exhibited good anti-proliferative activity and induce apoptosis in HepG2 cells. As a member of Bcl-2 protein family, myeloid cell leukemia-1 (Mcl-1) plays a critical role in cell apoptosis and has become a promising anti-cancer drug target. Herein, we designed and synthesized a series of hydantoin derivatives as novel Mcl-1 inhibitors based on our previously developed lead compound. Among them, compound M23 and M24 exhibited good binding affinities against Mcl-1 with Ki values of 0.49 μM and 0.33 μM respectively. Especially, compound M23 exhibited good selectivity over Bcl-xL, whereas compound M24 possessed good selectivity over both Bcl-2 and Bcl-xL. Furthermore, we also investigated the effects of these new Mcl-1 inhibitors on cell proliferation, apoptosis and mitochondrial membrane potential, as well as the stability in plasma.