(2SR,3RS)-4-(3-chloro-4-fluorophenyl)-5-oxo-N-(pyridin-3-ylmethyl)-3-(m-tolyl)-morpholine-2-carboxamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 恶嗪烷类
• 英文名称: (2SR,3RS)-4-(3-chloro-4-fluorophenyl)-5-oxo-N-(pyridin-3-ylmethyl)-3-(m-tolyl)-morpholine-2-carboxamide
• 英文别名: (2S,3R)-4-(3-chloro-4-fluorophenyl)-3-(3-methylphenyl)-5-oxo-N-(pyridin-3-ylmethyl)morpholine-2-carboxamide
• 化学式: C₂₄H₂₁ClFN₃O₃
• 分子量: 453.9
• InChiKey: SPZPQUXKSZKZDO-PKTZIBPZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  71.5
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  在 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 N,N-二甲基甲酰胺 、 氯苯 为溶剂， 反应 34.17h， 生成 (2SR,3RS)-4-(3-chloro-4-fluorophenyl)-5-oxo-N-(pyridin-3-ylmethyl)-3-(m-tolyl)-morpholine-2-carboxamide
  参考文献：
  名称：

  Design, in silico prioritization and biological profiling of apoptosis-inducing lactams amenable by the Castagnoli-Cushman reaction

  摘要：

  Five lactam chemotypes amenable by the Castagnoli-Cushman reaction of imines and cyclic anhydrides have been investigated for their ability to activate p53 tumor suppressing transcription factor thus induce apoptosis in p53(+) cancer cells. A virtual library of 1.07 million chemically diverse compounds based on these scaffolds was subjected to in silico screening first. The compounds displaying high docking score were visually prioritized to identify the best-fitting compounds, i.e. the ones which adequately mimic the interactions of clinical candidate inhibitor Nutlin-3a. These 38 compounds were synthesized and tested for apoptosis induction in p53(+) H116 cancer cells to identify 9 potent apoptosis-inducers (two of them exceeding the activity of Nutlin-3a) which belonged to four different chemotypes. The activation of p53 involved in the proapoptotic activity observed was supported by effective induction of EGFP expression in human osteocarcinoma U2OS-pLV reporter cell line. Moreover, the two most potent apoptosis inducers displayed antiproliferative profile identical to several known advanced p53 activators: they inhibited the growth of p53(+/+) HCT116 cells in much lower concentration range compared to p53(+/+) HCT116 cells. (C) 2018 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2018.04.036