Synthesis and biological evaluation of N-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)benzenesulfonamide derivatives as new BET bromodomain inhibitors for anti-hematologic malignancies activities

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• 作者：Li Liu ; Yongxia Zhu ; Zhihao Liu ; Tinghong Ye ; Weiqiong Zuo…
• 关键词：BET inhibitor ; BRD4 ; Anti ; proliferation activity ; Benzomorpholinone ; Structure–activity relationship
• 刊名：Molecular Diversity
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：21
• 期：1
• 页码：125-136
• 全文大小：
• 刊物类别：Chemistry and Materials Science
• 刊物主题：Biochemistry, general; Organic Chemistry; Polymer Sciences; Pharmacy;
• 出版者：Springer International Publishing
• ISSN：1573-501X
• 卷排序：21

文摘

The bromodomain and extra-terminal proteins (BETs), in particular BRD4, has been reported to play important roles in cancer, inflammation, obesity, cardiovascular disease, and neurological disorders. In this paper, a series of benzomorpholinone derivatives were synthesized and biologically evaluated as BETs inhibitors. Detailed structure–activity relationship studies led to the discovery of several new potent compounds, of which 15h and 15i displayed \(\text {IC}_{50}\) values of 2.8 and 4.5 \({\upmu }\text {M}\) against BRD4 (D1), respectively, and showed good anti-proliferation activities against four hematologic malignancies cell lines at low-micromolar concentrations, including MV4-11, OCI-LY10, Pfeifer, and Su-DHL-6 cells. This chemotype could be further optimized with respect to its potency and drug-like properties in the future.