2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-2-oxo-1,4-dihydro-2H-benzo[c]thiazolo[4,5-e]azepin-4-yl)-N-(4-hydroxyphenyl)acetamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯氮卓类
• 英文名称: 2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-2-oxo-1,4-dihydro-2H-benzo[c]thiazolo[4,5-e]azepin-4-yl)-N-(4-hydroxyphenyl)acetamide
• 英文别名: 2-[6-(4-chlorophenyl)-8-methoxy-1-methyl-2-oxo-4H-[1,3]thiazolo[5,4-d][2]benzazepin-4-yl]-N-(4-hydroxyphenyl)acetamide
• 化学式: C₂₇H₂₂ClN₃O₄S
• 分子量: 520.008
• InChiKey: UZCVEDFYQWREOP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  36.0
• 可旋转键数：
  5.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  92.92
• 氢给体数：
  2.0
• 氢受体数：
  7.0

反应信息

• 作为产物：
  描述：

  4-chloro-3-methyl-2-oxo-2,3-dihydrothiazole-5-carbaldehyde 在 4-二甲氨基吡啶 、 四(三苯基膦)钯 、 甲酸铵 、 sodium hydride 、 sodium carbonate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 水 为溶剂， 反应 29.5h， 生成 2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-2-oxo-1,4-dihydro-2H-benzo[c]thiazolo[4,5-e]azepin-4-yl)-N-(4-hydroxyphenyl)acetamide
  参考文献：
  名称：

  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

  摘要：

  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 mu M). 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.

  DOI：

  10.1016/j.bmc.2020.115601

文献信息

• 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
  作者：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

  日期：2020.8

  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 mu M). 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.