N-(4-(3-bromoanilino)quinazolin-6-yl)-3-piperidin-1-ylpropanamide | 1233953-84-8

• 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: N-(4-(3-bromoanilino)quinazolin-6-yl)-3-piperidin-1-ylpropanamide
• 英文别名: N-(4-(3-bromoanilino)quinazolin-6-yl)-3-piperidin-1-ylpropionamide；N-[4-(3-bromoanilino)quinazolin-6-yl]-3-piperidin-1-ylpropanamide
• CAS: 1233953-84-8
• 化学式: C₂₂H₂₄BrN₅O
• 分子量: 454.369
• InChiKey: LILZTFBVEZLTID-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  70.2
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-(4-(3-bromoanilino)quinazolin-6-yl)-3-piperidin-1-ylpropanamide 在 红铝 作用下， 以 四氢呋喃 为溶剂， 反应 16.0h， 以48%的产率得到N⁴-(3-bromophenyl)-N⁶-(3-(piperidin-1-yl)propyl)quinazoline-4,6-diamine
  参考文献：
  名称：

  Long-lasting inhibition of EGFR autophosphorylation in A549 tumor cells by intracellular accumulation of non-covalent inhibitors

  摘要：

  In the present study, a small set of reversible or irreversible 4-anilinoquinazoline EGFR inhibitors was tested in A549 cells at early (1 h) and late (8 h) time points after inhibitor removal from culture medium. A combination of assays was employed to explain the observed long-lasting inhibition of EGFR autophosphorylation. We found that EGFR inhibition at 8 h can be due, besides to the covalent interaction of the inhibitor with Cys797, as for PD168393 (2) and its prodrug 4, to the intracellular accumulation of non-covalent inhibitors by means of an active cell uptake, as for 5 and 6. Compounds 5-6 showed similar potency and duration of inhibition of EGFR autophosphorylation as the covalent inhibitor 2, while being devoid of reactive groups forming covalent bonds with protein thiols. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.08.008
• 作为产物：
  描述：

  2-氰基-4-硝基苯胺 在 氯化亚砜 、 硫酸 、 铁粉 、 溶剂黄146 、 potassium iodide 作用下， 以 1,4-二氧六环 、 乙醇 、 水 为溶剂， 反应 5.0h， 生成 N-(4-(3-bromoanilino)quinazolin-6-yl)-3-piperidin-1-ylpropanamide
  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.
• Long-lasting inhibition of EGFR autophosphorylation in A549 tumor cells by intracellular accumulation of non-covalent inhibitors
  作者：Federica Vacondio、Caterina Carmi、Elena Galvani、Michele Bassi、Claudia Silva、Alessio Lodola、Silvia Rivara、Andrea Cavazzoni、Roberta R. Alfieri、Pier Giorgio Petronini、Marco Mor

  DOI：10.1016/j.bmcl.2013.08.008

  日期：2013.10

  In the present study, a small set of reversible or irreversible 4-anilinoquinazoline EGFR inhibitors was tested in A549 cells at early (1 h) and late (8 h) time points after inhibitor removal from culture medium. A combination of assays was employed to explain the observed long-lasting inhibition of EGFR autophosphorylation. We found that EGFR inhibition at 8 h can be due, besides to the covalent interaction of the inhibitor with Cys797, as for PD168393 (2) and its prodrug 4, to the intracellular accumulation of non-covalent inhibitors by means of an active cell uptake, as for 5 and 6. Compounds 5-6 showed similar potency and duration of inhibition of EGFR autophosphorylation as the covalent inhibitor 2, while being devoid of reactive groups forming covalent bonds with protein thiols. (C) 2013 Elsevier Ltd. All rights reserved.