(2R,3S)-N-(4-(3-bromoanilino)quinazolin-6-yl)-3-(piperidin-1-ylmethyl)oxirane-2-carboxamide | 1207983-07-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: (2R,3S)-N-(4-(3-bromoanilino)quinazolin-6-yl)-3-(piperidin-1-ylmethyl)oxirane-2-carboxamide
• 英文别名: (2R,3S)-N-[4-(3-bromoanilino)quinazolin-6-yl]-3-(piperidin-1-ylmethyl)oxirane-2-carboxamide
• CAS: 1207983-07-0
• 化学式: C₂₃H₂₄BrN₅O₂
• 分子量: 482.38
• InChiKey: KGIFCCDXPXCPKK-LEWJYISDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  82.7
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  potassium (2R,3S)-3-(piperidin-1-ylmethyl)oxirane-2-carboxylate 、 N4-(3-溴苯基)喹唑啉-4,6-二胺 在 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.67h， 以30%的产率得到(2R,3S)-N-(4-(3-bromoanilino)quinazolin-6-yl)-3-(piperidin-1-ylmethyl)oxirane-2-carboxamide
  参考文献：
  名称：

  Novel Irreversible Epidermal Growth Factor Receptor Inhibitors by Chemical Modulation of the Cysteine-Trap Portion

  摘要：

  Irreversible EGFR inhibitors can circumvent acquired resistance to first-generation reversible, ATP-competitive inhibitors in the treatment of non-small-cell lung cancer. They contain both a driver group, which assures target recognition, and it warhead, generally an acrylamide or propargylamide fragment that binds covalently to Cys797 within the kinase domain of EGFR. We performed it systematic exploration of the role for the warhead group, introducing different cysteine-trapping fragments at position 6 of a traditional 4-anilinoquinazoline scaffold. We found that different reactive groups, including epoxyamides (compounds 3-6) and phenoxyacetamides (compounds 7-9), were able to irreversibly inhibit EGFR. In particular, at significant lower concentrations than gefitinib (1), (2R,3R)-N-(4-(3-bromoanilino)quinazolin-6-yl)-3-(piperidin-1-ylmethyl)oxirane-2-carboxamide (6) inhibited EGFR autophosphorylation and downstream Signaling pathways, Suppressed proliferation, and induced apoptosis in gefitinib-resistant NSCLC H 1975 cells, harboring the T790M mutation in EGFR.

  DOI：

  10.1021/jm901558p

文献信息

• Novel Irreversible Epidermal Growth Factor Receptor Inhibitors by Chemical Modulation of the Cysteine-Trap Portion
  作者：Caterina Carmi、Andrea Cavazzoni、Stefano Vezzosi、Fabrizio Bordi、Federica Vacondio、Claudia Silva、Silvia Rivara、Alessio Lodola、Roberta R. Alfieri、Silvia La Monica、Maricla Galetti、Andrea Ardizzoni、Pier Giorgio Petronini、Marco Mor

  DOI：10.1021/jm901558p

  日期：2010.3.11

  Irreversible EGFR inhibitors can circumvent acquired resistance to first-generation reversible, ATP-competitive inhibitors in the treatment of non-small-cell lung cancer. They contain both a driver group, which assures target recognition, and it warhead, generally an acrylamide or propargylamide fragment that binds covalently to Cys797 within the kinase domain of EGFR. We performed it systematic exploration of the role for the warhead group, introducing different cysteine-trapping fragments at position 6 of a traditional 4-anilinoquinazoline scaffold. We found that different reactive groups, including epoxyamides (compounds 3-6) and phenoxyacetamides (compounds 7-9), were able to irreversibly inhibit EGFR. In particular, at significant lower concentrations than gefitinib (1), (2R,3R)-N-(4-(3-bromoanilino)quinazolin-6-yl)-3-(piperidin-1-ylmethyl)oxirane-2-carboxamide (6) inhibited EGFR autophosphorylation and downstream Signaling pathways, Suppressed proliferation, and induced apoptosis in gefitinib-resistant NSCLC H 1975 cells, harboring the T790M mutation in EGFR.