N-(4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethoxyquinolin-6-yl)acrylamide | 1360430-63-2

• 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: N-(4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethoxyquinolin-6-yl)acrylamide
• 英文别名: N-[4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethoxyquinolin-6-yl]prop-2-enamide
• CAS: 1360430-63-2
• 化学式: C₂₁H₁₆ClFN₄O₂
• 分子量: 410.835
• InChiKey: ATIKKYRDCUPFAU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  87
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  N-(3-氰基-7-乙氧基-4-羟基喹啉-6-基)乙酰胺 在 盐酸 、 吡啶盐酸盐 、 N,N-二异丙基乙胺 、 三氯氧磷 作用下， 以 四氢呋喃 、 二乙二醇二甲醚 、 水 、 N,N-二甲基甲酰胺 、 异丙醇 为溶剂， 生成 N-(4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethoxyquinolin-6-yl)acrylamide
  参考文献：
  名称：

  Irreversible Inhibition of Epidermal Growth Factor Receptor Activity by 3-Aminopropanamides

  摘要：

  Irreversible epidermal growth factor receptor (EGFR) inhibitors contain a reactive warhead which covalently interacts with a conserved cysteine residue in the kinase domain. The acrylamide fragment, a commonly employed warhead, effectively alkylates Cys797 of EGFR, but its reactivity can cause rapid metabolic deactivation or nonspecific reactions with off-targets. We describe here a new series of irreversible inhibitors containing a 3-aminopropanamide linked in position 6 to 4-anilinoquinazoline or 4-anilinoquinoline-3-carbonitrile driving portions. Some of these compounds proved to be as efficient as their acrylamide analogues in inhibiting EGFR-TK (TK = tyrosine kinase) autophosphorylation in A549 lung cancer cells. Moreover, several 3-aminopropanamides suppressed proliferation of gefitinib-resistant H1975 cells, harboring the T790M mutation in EGFR, at significantly lower concentrations than did gefitinib. A prototypical compound, N-(4-(3-bromoanilino)quinazolin-6-yl)-3-(dimethylamino)propanamide (5), did not show covalent binding to cell-free EGFR-TK in a fluorescence assay, while it underwent selective activation in the intracellular environment, releasing an acrylamide derivative which can react with thiol groups.

  DOI：

  10.1021/jm201507x

文献信息

• Irreversible Inhibition of Epidermal Growth Factor Receptor Activity by 3-Aminopropanamides
  作者：Caterina Carmi、Elena Galvani、Federica Vacondio、Silvia Rivara、Alessio Lodola、Simonetta Russo、Stefania Aiello、Fabrizio Bordi、Gabriele Costantino、Andrea Cavazzoni、Roberta R. Alfieri、Andrea Ardizzoni、Pier Giorgio Petronini、Marco Mor

  DOI：10.1021/jm201507x

  日期：2012.3.8

  Irreversible epidermal growth factor receptor (EGFR) inhibitors contain a reactive warhead which covalently interacts with a conserved cysteine residue in the kinase domain. The acrylamide fragment, a commonly employed warhead, effectively alkylates Cys797 of EGFR, but its reactivity can cause rapid metabolic deactivation or nonspecific reactions with off-targets. We describe here a new series of irreversible inhibitors containing a 3-aminopropanamide linked in position 6 to 4-anilinoquinazoline or 4-anilinoquinoline-3-carbonitrile driving portions. Some of these compounds proved to be as efficient as their acrylamide analogues in inhibiting EGFR-TK (TK = tyrosine kinase) autophosphorylation in A549 lung cancer cells. Moreover, several 3-aminopropanamides suppressed proliferation of gefitinib-resistant H1975 cells, harboring the T790M mutation in EGFR, at significantly lower concentrations than did gefitinib. A prototypical compound, N-(4-(3-bromoanilino)quinazolin-6-yl)-3-(dimethylamino)propanamide (5), did not show covalent binding to cell-free EGFR-TK in a fluorescence assay, while it underwent selective activation in the intracellular environment, releasing an acrylamide derivative which can react with thiol groups.