Design, synthesis and biological evaluation of novel 6-phenyl-1,3a,4,10b-tetrahydro-2H-benzo[c]thiazolo[4,5-e]azepin-2-one derivatives as potential BRD4 inhibitors

  • Bioorg Med Chem. 2020 Aug 1;28(15):115601. doi: 10.1016/j.bmc.2020.115601.
Qifei Li  1 ,  Jieming Li  1 ,  Yan Cai  1 ,  Yuxing Zou  1 ,  Bin Chen  1 ,  Feng Zou  1 ,  Jiaxian Mo  1 ,  Ting Han  1 ,  Weiwei Guo  1 ,  Wenlong Huang  2 ,  Qianqian Qiu  3 ,  Hai Qian  4
Affiliations
  • 1. Center of Drug Discovery, State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, PR China.
  • 2. Center of Drug Discovery, State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
  • 3. Center of Drug Discovery, State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: [email protected].
  • 4. Center of Drug Discovery, State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: [email protected].
PMID: 32631570 DOI: 10.1016/j.bmc.2020.115601
Abstract

Bromodomain-containing protein 4 (BRD4) is a key epigenetic regulator in Cancer, and inhibitors targeting BRD4 exhibit great Anticancer activity. By replacing the methyltriazole ring of the BRD4 Inhibitor I-BET-762 with an N-methylthiazolidone heterocyclic ring, fifteen novel BRD4 inhibitors were designed and synthesized. Compound 13f had a hydrophobic acetylcyclopentanyl side chain, showing the most potent BRD4 inhibitory activity in the BRD4-BD1 inhibition assay (IC50 value of 110 nM), it also significantly suppressed the proliferation of MV-4-11 cells with high BRD4 level (IC50 value of 0.42 μM). Furthermore, the potent apoptosis-promoting and G0/G1 cycle-arresting activity of compound 13f were indicated by flow cytometry. As the downstream-protein of BRD4, c-Myc was in significantly low expression by compound 13f treatment in a dose-dependent manner. All the findings supported that this novel compound 13f provided a perspective for developing effective BRD4 inhibitors.

Keywords
Anti-proliferation; Anti-tumor; Apoptosis; BRD4 inhibitors.
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