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

  • Bioorg Chem. 2022 Apr;121:105643. doi: 10.1016/j.bioorg.2022.105643.
Xiao Liang  1 ,  Xue Li  2 ,  Zhiyuan Zhao  1 ,  Yiming Nie  1 ,  Zefu Yao  1 ,  Wandi Ren  3 ,  Xinying Yang  3 ,  Xuben Hou  4 ,  Hao Fang  5
Affiliations
  • 1. Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Science, Cheeloo College of Medicine, Shandong University, Ji'nan, Shandong 250012, PR China.
  • 2. Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, PR China.
  • 3. Department of Pharmaceutical Analysis, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji'nan, Shandong 250012, PR China.
  • 4. Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Science, Cheeloo College of Medicine, Shandong University, Ji'nan, Shandong 250012, PR China. Electronic address: [email protected].
  • 5. Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Science, Cheeloo College of Medicine, Shandong University, Ji'nan, Shandong 250012, PR China. Electronic address: [email protected].
PMID: 35150958 DOI: 10.1016/j.bioorg.2022.105643
Abstract

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.

Keywords
Apoptosis; Cancer; Hydantoin derivatives; Mcl-1 inhibitors.
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