3-hydroxy-3-n-pentyl-5-(4-methylanilino)indole-2(1H)-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 3-hydroxy-3-n-pentyl-5-(4-methylanilino)indole-2(1H)-one
• 英文别名: 3-hydroxy-3-pentyl-5-(p-tolylamino)indolin-2-one；3-hydroxy-5-(4-methylanilino)-3-pentyl-1H-indol-2-one
• 化学式: C₂₀H₂₄N₂O₂
• 分子量: 324.423
• InChiKey: AQTVFFIENJSPIQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  24
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  61.4
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  5-溴-2-硝基苯乙酸乙酯 在 四(三苯基膦)钯 、 ruthenium(III) chloride trihydrate 、 palladium 10% on activated carbon 、 氢气 、 caesium carbonate 、 溶剂黄146 、 三苯基膦 、 sodium hydroxide 作用下， 以 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 20.0~110.0 ℃ 、400.01 kPa 条件下， 反应 5.0h， 生成 3-hydroxy-3-n-pentyl-5-(4-methylanilino)indole-2(1H)-one
  参考文献：
  名称：

  Dual inhibitors of RAF-MEK-ERK and PI3K-PDK1-AKT pathways: Design, synthesis and preliminary anticancer activity studies of 3-substituted-5-(phenylamino) indolone derivatives

  摘要：

  The dysfunction and mutual compensatory activation of RAF-MEK-ERK and PI3K-PDK1-AKT pathways have been demonstrated as the hallmarks in several primary and recurrent cancers. The strategy of concurrent blocking of these two pathways shows clinical merits on effective cancer therapy, such as combinatory treatments and dual-pathway inhibitors. Herein, we report a novel prototype of dual-pathway inhibitors by means of merging the core structural scaffolds of a MEK1 inhibitor and a PDK1 inhibitor. A library of 43 compounds that categorized into three series (Series I-III) was synthesized and tested for antitumor activity in lung cancer cells. The results from structure-activity relationship (SAR) analysis showed the following order of antitumor activity that 3-hydroxy-5-(phenylamino) indolone (Series III) > 3-alkenyl-5-(phenylamino) indolone (Series I) > 3-alkyl-5-(phenylamino) indolone (Series II). A lead compound 9za in Series III showed most potent antitumor activity with IC50, value of 1.8 +/- 0.8 mu M in A549 cells. Moreover, antitumor mechanism study demonstrated that 9za exerted significant apoptotic effect, and cellular signal pathway analysis revealed the potent blockage of phosphorylation levels of ERK and AKT in RAF-MEK-ERK and PI3K-PDK1-AKT pathways, respectively. The results reported here provide robust experimental basis for the discovery and optimization of dual pathway agents for anti-lung cancer therapy.

  DOI：

  10.1016/j.bmc.2019.01.028

文献信息

• Dual inhibitors of RAF-MEK-ERK and PI3K-PDK1-AKT pathways: Design, synthesis and preliminary anticancer activity studies of 3-substituted-5-(phenylamino) indolone derivatives
  作者：Zutao Yu、Zhuo Chen、Qiongli Su、Shiqi Ye、Hongbo Yuan、Mengni Kuai、Meng Lv、Zhijun Tu、Xiaoping Yang、RangRu Liu、Gaoyun Hu、Qianbin Li

  DOI：10.1016/j.bmc.2019.01.028

  日期：2019.3

  The dysfunction and mutual compensatory activation of RAF-MEK-ERK and PI3K-PDK1-AKT pathways have been demonstrated as the hallmarks in several primary and recurrent cancers. The strategy of concurrent blocking of these two pathways shows clinical merits on effective cancer therapy, such as combinatory treatments and dual-pathway inhibitors. Herein, we report a novel prototype of dual-pathway inhibitors by means of merging the core structural scaffolds of a MEK1 inhibitor and a PDK1 inhibitor. A library of 43 compounds that categorized into three series (Series I-III) was synthesized and tested for antitumor activity in lung cancer cells. The results from structure-activity relationship (SAR) analysis showed the following order of antitumor activity that 3-hydroxy-5-(phenylamino) indolone (Series III) > 3-alkenyl-5-(phenylamino) indolone (Series I) > 3-alkyl-5-(phenylamino) indolone (Series II). A lead compound 9za in Series III showed most potent antitumor activity with IC50, value of 1.8 +/- 0.8 mu M in A549 cells. Moreover, antitumor mechanism study demonstrated that 9za exerted significant apoptotic effect, and cellular signal pathway analysis revealed the potent blockage of phosphorylation levels of ERK and AKT in RAF-MEK-ERK and PI3K-PDK1-AKT pathways, respectively. The results reported here provide robust experimental basis for the discovery and optimization of dual pathway agents for anti-lung cancer therapy.