1-(4-(4-([3,6'-biquinolin]-4'-ylamino)-2-(trifluoromethyl)phenyl)piperazin-1-yl)ethanone | 1252048-15-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 1-(4-(4-([3,6'-biquinolin]-4'-ylamino)-2-(trifluoromethyl)phenyl)piperazin-1-yl)ethanone
• 英文别名: 1-[4-[4-[(6-Quinolin-3-ylquinolin-4-yl)amino]-2-(trifluoromethyl)phenyl]piperazin-1-yl]ethanone
• CAS: 1252048-15-9
• 化学式: C₃₁H₂₆F₃N₅O
• 分子量: 541.576
• InChiKey: CSGQJQNLGDSKDJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  40
• 可旋转键数：
  4
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  61.4
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  、 喹啉-3-硼酸 在 bis-triphenylphosphine-palladium(II) chloride 、 sodium carbonate 、 2-二-叔丁膦基-2',4',6'-三异丙基联苯 作用下， 以 1,4-二氧六环 为溶剂， 反应 6.0h， 生成 1-(4-(4-([3,6'-biquinolin]-4'-ylamino)-2-(trifluoromethyl)phenyl)piperazin-1-yl)ethanone
  参考文献：
  名称：

  Discovery of 1-(4-(4-Propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo[h][1,6]naphthyridin-2(1H)-one as a Highly Potent, Selective Mammalian Target of Rapamycin (mTOR) Inhibitor for the Treatment of Cancer

  摘要：

  The mTOR It protein is a master regulator of cell growth and proliferation, and inhibitors of its kinase activity have the potential to become new class of anticancer drugs. Starting from quinoline I, which was identified in a biochemical mTOR assay, we developed a tricyclic benzonaphthyridinone inhibitor 37 (Torin 1), which inhibited phosphorylation of mTORC1 and mTORC2 substrates in cells at concentrations of 2 and 10 nM, respectively. Moreover, Torin I exhibits 1000-fold selectivity for mTOR over P13K (EC50 = 1800 nM) and exhibits 100-fold binding selectivity relative to 450 other protein kinases. Torin was efficacious at a dose of 20 mg/kg in a U87MG xenograft model and demonstrated good pharmacodynamic inhibition of downstream effectors of mTOR in tumor and per tissues. These results demonstrate that Torin I is a useful probe of mTOR-dependent phenomena and that benzo-naphthridinones represent a promising scaffold for the further development of mTOR-specific inhibitors with the potential for clinical utility.

  DOI：

  10.1021/jm101144f

文献信息

• Discovery of 1-(4-(4-Propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo[h][1,6]naphthyridin-2(1<i>H</i>)-one as a Highly Potent, Selective Mammalian Target of Rapamycin (mTOR) Inhibitor for the Treatment of Cancer
  作者：Qingsong Liu、Jae Won Chang、Jinhua Wang、Seong A. Kang、Carson C. Thoreen、Andrew Markhard、Wooyoung Hur、Jianming Zhang、Taebo Sim、David M. Sabatini、Nathanael S. Gray

  DOI：10.1021/jm101144f

  日期：2010.10.14

  The mTOR It protein is a master regulator of cell growth and proliferation, and inhibitors of its kinase activity have the potential to become new class of anticancer drugs. Starting from quinoline I, which was identified in a biochemical mTOR assay, we developed a tricyclic benzonaphthyridinone inhibitor 37 (Torin 1), which inhibited phosphorylation of mTORC1 and mTORC2 substrates in cells at concentrations of 2 and 10 nM, respectively. Moreover, Torin I exhibits 1000-fold selectivity for mTOR over P13K (EC50 = 1800 nM) and exhibits 100-fold binding selectivity relative to 450 other protein kinases. Torin was efficacious at a dose of 20 mg/kg in a U87MG xenograft model and demonstrated good pharmacodynamic inhibition of downstream effectors of mTOR in tumor and per tissues. These results demonstrate that Torin I is a useful probe of mTOR-dependent phenomena and that benzo-naphthridinones represent a promising scaffold for the further development of mTOR-specific inhibitors with the potential for clinical utility.