1-(6-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)-5-methoxyindolin-1-yl)prop-2-en-1-one | 1453199-11-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 1-(6-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)-5-methoxyindolin-1-yl)prop-2-en-1-one
• CAS: 1453199-11-5
• 化学式: C₃₀H₂₄ClN₅O₄S
• 分子量: 586.071
• InChiKey: QCWIBKPNEJLGKE-UHFFFAOYSA-N

物化性质

• 沸点：
  812.7±75.0 °C(predicted)
• 密度：
  1.42±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.82
• 重原子数：
  41.0
• 可旋转键数：
  7.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  106.42
• 氢给体数：
  1.0
• 氢受体数：
  8.0

反应信息

• 作为反应物：
  描述：

  1-(6-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)-5-methoxyindolin-1-yl)prop-2-en-1-one 在 甲醇 、 caesium carbonate 作用下， 以 四氢呋喃 为溶剂， 以7.8 mg的产率得到1-(6-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)-5-methoxyindolin-1-yl)prop-2-en-1-one
  参考文献：
  名称：

  Structure- and Reactivity-Based Development of Covalent Inhibitors of the Activating and Gatekeeper Mutant Forms of the Epidermal Growth Factor Receptor (EGFR)

  摘要：

  A novel series of small-molecule inhibitors has been developed to target the double mutant form of the epidermal growth factor receptor (EGFR) tyrosine kinase, which is resistant to treatment with gefitinib and erlotinib. Our reported compounds also show selectivity over wild-type EGFR. Guided by molecular modeling, this series was evolved to target a cysteine residue in the ATP binding site via covalent bond formation and demonstrates high levels of activity in cellular models of the double mutant form of EGFR. In addition, these compounds show significant activity against the activating mutations, which gefitinib and erlotinib target and inhibition of which gives rise to their observed clinical efficacy. A glutathione (GSH)-based assay was used to measure thiol reactivity toward the electrophilic functionality of the inhibitor series, enabling both the identification of a suitable reactivity window for their potency and the development of a reactivity quantitative structure-property relationship (QSPR) to support design.

  DOI：

  10.1021/jm400822z
• 作为产物：
  描述：

  1-苯磺酰基吲哚-3-硼酸频哪醇酯 在 四(三苯基膦)钯 、 palladium diacetate 、 sodium carbonate 、 caesium carbonate 、 N,N-二异丙基乙胺 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 、 三氟乙酸 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 水 、 乙腈 为溶剂， 反应 2.0h， 生成 1-(6-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)-5-methoxyindolin-1-yl)prop-2-en-1-one
  参考文献：
  名称：

  Structure- and Reactivity-Based Development of Covalent Inhibitors of the Activating and Gatekeeper Mutant Forms of the Epidermal Growth Factor Receptor (EGFR)

  摘要：

  A novel series of small-molecule inhibitors has been developed to target the double mutant form of the epidermal growth factor receptor (EGFR) tyrosine kinase, which is resistant to treatment with gefitinib and erlotinib. Our reported compounds also show selectivity over wild-type EGFR. Guided by molecular modeling, this series was evolved to target a cysteine residue in the ATP binding site via covalent bond formation and demonstrates high levels of activity in cellular models of the double mutant form of EGFR. In addition, these compounds show significant activity against the activating mutations, which gefitinib and erlotinib target and inhibition of which gives rise to their observed clinical efficacy. A glutathione (GSH)-based assay was used to measure thiol reactivity toward the electrophilic functionality of the inhibitor series, enabling both the identification of a suitable reactivity window for their potency and the development of a reactivity quantitative structure-property relationship (QSPR) to support design.

  DOI：

  10.1021/jm400822z