3-[5-{4-(3-Chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl}thiophene-2-yl] acrylic acid tert-butyl ester | 1152131-76-4

• 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: 3-[5-{4-(3-Chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl}thiophene-2-yl] acrylic acid tert-butyl ester
• 英文别名: 3-[5-{4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl}thiophene-2-yl]acrylic acid tert-butyl ester；3-(5-{4-[3-chloro-4-(3-fluorobenzyloxy)phenyl-amino]quinazolin-6-yl}thiophene-2-yl)acrylic acid tert-butyl ester；Tert-butyl 3-[5-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]quinazolin-6-yl]thiophen-2-yl]prop-2-enoate
• CAS: 1152131-76-4
• 化学式: C₃₂H₂₇ClFN₃O₃S
• 分子量: 588.102
• InChiKey: KCSJFJSHANFKAA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.3
• 重原子数：
  41
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  102
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  3-[5-{4-(3-Chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl}thiophene-2-yl] acrylic acid tert-butyl ester 在 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 12.5h， 生成 3-[5-{4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl}thiophene-2-yl]-N-(tetrahydropyran-2-yloxy)acrylamide
  参考文献：
  名称：

  Novel Chimeric Histone Deacetylase Inhibitors: A Series of Lapatinib Hybrides as Potent Inhibitors of Epidermal Growth Factor Receptor (EGFR), Human Epidermal Growth Factor Receptor 2 (HER2), and Histone Deacetylase Activity

  摘要：

  Reversible lysine-specific acetylation has been described as an important posttranslational modification, regulating chromatin structure and transcriptional activity in the case of core histone proteins. Histone deacetylases (HDAC) are considered as a promising target for anticancer drug development, with 2a as pan-HDAC inhibitor approved for cutanous T-cell lymphoma therapy and several other HDAC inhibitors currently in preclinical and clinical development. Protein kinases are a well-established target for cancer therapy with the EGFR/HER2 inhibitor 5 approved for treatment of advanced, HER2 positive breast cancer as a prominent example. In the present report, we present a novel strategy for cancer drug development by combination of EGFR/HER2 kinase and HDAC inhibitory activity in one molecule. By combining the structural features of 5 with an (E)-3-(aryl)-N-hydroxyacrylamide motif known from HDAC inhibitors like 1 or 3, we obtained selective inhibitors for both targets with potent cellular activity (target inhibition and cytotoxicity) of selected compounds 6a and 6c. By combining two distinct pharmacologically properties in one molecule, we postulate a broader activity spectrum and less likelihood of drug resistance in cancer patients.

  DOI：

  10.1021/jm100665z
• 作为产物：
  描述：

  6-碘-4(H)-喹唑啉酮 在 bis(triphenylphosphine)palladium(II) dichloride 、 sodium carbonate 、 三乙胺 、 sodium hydroxide 、 三氯氧磷 作用下， 以 乙二醇二甲醚 、 乙醇 、 二氯甲烷 、 水 、 甲苯 为溶剂， 反应 3.0h， 生成 3-[5-{4-(3-Chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl}thiophene-2-yl] acrylic acid tert-butyl ester
  参考文献：
  名称：

  Novel Chimeric Histone Deacetylase Inhibitors: A Series of Lapatinib Hybrides as Potent Inhibitors of Epidermal Growth Factor Receptor (EGFR), Human Epidermal Growth Factor Receptor 2 (HER2), and Histone Deacetylase Activity

  摘要：

  Reversible lysine-specific acetylation has been described as an important posttranslational modification, regulating chromatin structure and transcriptional activity in the case of core histone proteins. Histone deacetylases (HDAC) are considered as a promising target for anticancer drug development, with 2a as pan-HDAC inhibitor approved for cutanous T-cell lymphoma therapy and several other HDAC inhibitors currently in preclinical and clinical development. Protein kinases are a well-established target for cancer therapy with the EGFR/HER2 inhibitor 5 approved for treatment of advanced, HER2 positive breast cancer as a prominent example. In the present report, we present a novel strategy for cancer drug development by combination of EGFR/HER2 kinase and HDAC inhibitory activity in one molecule. By combining the structural features of 5 with an (E)-3-(aryl)-N-hydroxyacrylamide motif known from HDAC inhibitors like 1 or 3, we obtained selective inhibitors for both targets with potent cellular activity (target inhibition and cytotoxicity) of selected compounds 6a and 6c. By combining two distinct pharmacologically properties in one molecule, we postulate a broader activity spectrum and less likelihood of drug resistance in cancer patients.

  DOI：

  10.1021/jm100665z