3-acetyl-7-((4-(3-methoxyphenyl)pyrimidin-2-yl)amino)-4-morpholino-2H-chromen-2-one

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 香豆素及其衍生物
• 英文名称: 3-acetyl-7-((4-(3-methoxyphenyl)pyrimidin-2-yl)amino)-4-morpholino-2H-chromen-2-one
• 英文别名: 3-acetyl-7-{[4-(3-methoxyphenyl)pyrimidin-2-yl]amino}-4-morpholino-2H-benzopyran-2-one；3-Acetyl-7-[[4-(3-methoxyphenyl)pyrimidin-2-yl]amino]-4-morpholin-4-ylchromen-2-one；3-acetyl-7-[[4-(3-methoxyphenyl)pyrimidin-2-yl]amino]-4-morpholin-4-ylchromen-2-one
• 化学式: C₂₆H₂₄N₄O₅
• 分子量: 472.5
• InChiKey: KBVZMRABFVBGQW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  35
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  103
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  丹皮酚 在 aluminum (III) chloride 、 palladium diacetate 、 sodium hydride 、 caesium carbonate 、 三乙胺 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 、 三氯氧磷 作用下， 以 二氯甲烷 、 甲苯 、 mineral oil 为溶剂， 反应 11.0h， 生成 3-acetyl-7-((4-(3-methoxyphenyl)pyrimidin-2-yl)amino)-4-morpholino-2H-chromen-2-one
  参考文献：
  名称：

  Discovery of coumarin derivatives as potent and selective cyclin-dependent kinase 9 (CDK9) inhibitors with high antitumour activity

  摘要：

  Specific inhibition of CDK9 is considered a promising strategy for developing effective anticancer therapeutics. However, most of the reported CDK9 inhibitors are still at an early stage of development and lack selectivity against other CDKs. Herein, we discovered coumarin derivative 30i as a potent CDK9 inhibitor with high selectivity (8300-fold over CDK7). Binding mode analysis illustrated that the substituent coumarin moiety is a critical group for CDK9 selectivity by occupying a flexible hinge/alpha D region, which is sterically hindered in other CDKs. Compound 30i showed excellent cellular antiproliferative activity, moderate pharmacokinetic property and low hERG inhibition. Moreover, 30i significantly induced tumour growth inhibition in a dose-dependent manner without causing an obvious loss of body weight in an MV4-11 xenograft mice model. Altogether, these results suggest that 30i may serve as a potential acute myeloid leukaemia (AML) therapeutics by selectively targeting CDK9. (C) 2020 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2020.112424

文献信息

• Discovery of coumarin derivatives as potent and selective cyclin-dependent kinase 9 (CDK9) inhibitors with high antitumour activity
  作者：Junyu Xu、Hongmei Li、Xinren Wang、Jianhang Huang、Shuwen Li、Chenhe Liu、Ruinan Dong、Gaoyuan Zhu、Chunqi Duan、Fei Jiang、Yanmin Zhang、Yuqin Zhu、Tianyi Zhang、Yadong Chen、Weifang Tang、Tao Lu

  DOI：10.1016/j.ejmech.2020.112424

  日期：2020.8

  Specific inhibition of CDK9 is considered a promising strategy for developing effective anticancer therapeutics. However, most of the reported CDK9 inhibitors are still at an early stage of development and lack selectivity against other CDKs. Herein, we discovered coumarin derivative 30i as a potent CDK9 inhibitor with high selectivity (8300-fold over CDK7). Binding mode analysis illustrated that the substituent coumarin moiety is a critical group for CDK9 selectivity by occupying a flexible hinge/alpha D region, which is sterically hindered in other CDKs. Compound 30i showed excellent cellular antiproliferative activity, moderate pharmacokinetic property and low hERG inhibition. Moreover, 30i significantly induced tumour growth inhibition in a dose-dependent manner without causing an obvious loss of body weight in an MV4-11 xenograft mice model. Altogether, these results suggest that 30i may serve as a potential acute myeloid leukaemia (AML) therapeutics by selectively targeting CDK9. (C) 2020 Elsevier Masson SAS. All rights reserved.