10-chloro-5-(4-methylpiperazin-1-yl)-8H-phthalazino[1,2-b]quinazolin-8-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 10-chloro-5-(4-methylpiperazin-1-yl)-8H-phthalazino[1,2-b]quinazolin-8-one
• 英文别名: 10-chloro-5-(4-methylpiperazin-1-yl)phthalazino[1,2-b]quinazolin-8-one；10-Chloro-5-(4-methylpiperazin-1-yl)quinazolino[2,3-a]phthalazin-8-one；10-chloro-5-(4-methylpiperazin-1-yl)quinazolino[2,3-a]phthalazin-8-one
• 化学式: C₂₀H₁₈ClN₅O
• 分子量: 379.849
• InChiKey: FHNIQJYKZBNXQL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  27
• 可旋转键数：
  1
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  51.5
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2-氨基-5-氯苯甲酰肼 在 三氯氧磷 作用下， 以 乙二醇 、 甲苯 为溶剂， 反应 20.0h， 生成 10-chloro-5-(4-methylpiperazin-1-yl)-8H-phthalazino[1,2-b]quinazolin-8-one
  参考文献：
  名称：

  Phthalazino[1,2-b]quinazolinones as p53 Activators: Cell Cycle Arrest, Apoptotic Response and Bak–Bcl-xl Complex Reorganization in Bladder Cancer Cells

  摘要：

  p53 inactivation is a clinically defined characteristic for cancer treatment-nonresponsiveness. It is therefore highly desirable to develop anticancer agents by restoring p53 function.(1) Herein the synthesized phthalazino[1,2-b]quinazolinones were discovered as p53 activators in bladder cancer cells. 10-Bromo-5-(2-dimethylamino-ethylamino)phthalazino[1,2-b]quinazolin-8-one (5da) was identified as the most promising candidate in view of both its anticancer activity and mechanisms of action. 5da exhibited strong anticancer activity on a broad range of cancer cell lines and significantly reduced tumor growth in xenograft models at doses as low as 6 mg/kg. Furthermore, 5da caused cell cycle arrest at S/G2 phase, induced apoptosis, changed cell size, and led to cell death by increasing the proportion of sub-G1 cells. Molecular mechanism studies suggested that accumulation of phospho-p53 in mitochondria after 5da treatment resulted in conformational activation of Bak, thereby evoking cell apoptosis, finally leading to irreversible cancer cell inhibition. Our present studies furnish new insights into the molecular interactions and anticancer mechanisms of phospho-p53-dependent quinazolinone compound.

  DOI：

  10.1021/acs.jmedchem.6b01769

文献信息

• Phthalazino[1,2-<i>b</i>]quinazolinones as p53 Activators: Cell Cycle Arrest, Apoptotic Response and Bak–Bcl-xl Complex Reorganization in Bladder Cancer Cells
  作者：Guo-Hai Zhang、Jing-Mei Yuan、Gang Qian、Chen-Xi Gu、Kai Wei、Dong-Liang Mo、Jiang-Ke Qin、Yan Peng、Zu-Ping Zhou、Cheng-Xue Pan、Gui-Fa Su

  DOI：10.1021/acs.jmedchem.6b01769

  日期：2017.8.24

  p53 inactivation is a clinically defined characteristic for cancer treatment-nonresponsiveness. It is therefore highly desirable to develop anticancer agents by restoring p53 function.(1) Herein the synthesized phthalazino[1,2-b]quinazolinones were discovered as p53 activators in bladder cancer cells. 10-Bromo-5-(2-dimethylamino-ethylamino)phthalazino[1,2-b]quinazolin-8-one (5da) was identified as the most promising candidate in view of both its anticancer activity and mechanisms of action. 5da exhibited strong anticancer activity on a broad range of cancer cell lines and significantly reduced tumor growth in xenograft models at doses as low as 6 mg/kg. Furthermore, 5da caused cell cycle arrest at S/G2 phase, induced apoptosis, changed cell size, and led to cell death by increasing the proportion of sub-G1 cells. Molecular mechanism studies suggested that accumulation of phospho-p53 in mitochondria after 5da treatment resulted in conformational activation of Bak, thereby evoking cell apoptosis, finally leading to irreversible cancer cell inhibition. Our present studies furnish new insights into the molecular interactions and anticancer mechanisms of phospho-p53-dependent quinazolinone compound.