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

Qifei Li; Jieming Li; Yan Cai; Yuxing Zou; Bin Chen; Feng Zou; Jiaxian Mo; Ting Han; Weiwei Guo; Wenlong Huang; Qianqian Qiu; Hai Qian

doi:10.1016/j.bmc.2020.115601

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. Epub 2020 Jun 20.

Authors

Qifei Li¹, Jieming Li¹, Yan Cai¹, Yuxing Zou¹, Bin Chen¹, Feng Zou¹, Jiaxian Mo¹, Ting Han¹, Weiwei Guo¹, Wenlong Huang², Qianqian Qiu³, Hai Qian⁴

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Benzazepines / chemical synthesis
Benzazepines / metabolism
Benzazepines / pharmacology*
Binding Sites
Cell Cycle Proteins / antagonists & inhibitors*
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Design
Drug Screening Assays, Antitumor
G1 Phase Cell Cycle Checkpoints / drug effects
Humans
Molecular Docking Simulation
Protein Binding
Thiazoles / chemical synthesis
Thiazoles / metabolism
Thiazoles / pharmacology*
Transcription Factors / antagonists & inhibitors*
Transcription Factors / metabolism

Substances

Antineoplastic Agents
BRD4 protein, human
Benzazepines
Cell Cycle Proteins
Thiazoles
Transcription Factors