(5-chloro-benzo[1,3]dioxol-4-yl)(7-fluoro-6-nitro-quinazolin-4-yl)amine | 1155336-39-2

• 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: (5-chloro-benzo[1,3]dioxol-4-yl)(7-fluoro-6-nitro-quinazolin-4-yl)amine
• CAS: 1155336-39-2
• 化学式: C₁₅H₈ClFN₄O₄
• 分子量: 362.704
• InChiKey: YLZZJNCCUJGOCO-UHFFFAOYSA-N

物化性质

• 沸点：
  498.7±45.0 °C(predicted)
• 密度：
  1.685±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  25.0
• 可旋转键数：
  3.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  99.41
• 氢给体数：
  1.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  乙二醇甲醚 、 (5-chloro-benzo[1,3]dioxol-4-yl)(7-fluoro-6-nitro-quinazolin-4-yl)amine 在 potassium trimethylsilonate 作用下， 以 二甲基亚砜 为溶剂， 反应 4.0h， 以52%的产率得到(5-chloro-benzo[1,3]dioxol-4-yl)[7-(2-methoxyethoxy)-6-nitro-quinazolin-4-yl]amine
  参考文献：
  名称：

  Structure-based virtual screening of Src kinase inhibitors

  摘要：

  Src is an important target in multiple processes associated with tumor growth and development, including proliferation, neovascularization, and metastasis. In this study, hit identification was performed by virtual screening of commercial and in-house compound libraries. Docking studies for the hits were performed, and scoring functions were used to evaluate the docking results and to rank ligand-binding affinities. Subsequently, hit optimization for potent and selective candidate Src inhibitors was performed through focused library design and docking analyses. Consequently, we report that a novel compound '43' with an IC50 value of 89 nM, representing (S)-N-(4-(5-chlorobenzo[d][1,3]dioxol-4-ylamino)-7-(2-methoxyethoxy)quinazolin-6-yl)pyrrolidine-2-carboxamide, is highly selective for Src in comparison to EGFR (IC50 ratio > 80-fold) and VEGFR-2 (IC50 ratio > 110-fold). Compound 43 exerted anti-proliferative effects on Src-expressing PC3 human prostate cancer and A431 human epidermoid carcinoma cells, with calculated IC50 values of 1.52 and 0.78 mu M, respectively. Moreover, compound 43 (0.1 mu M) suppressed the phosphorylation of extracellular signal-regulated kinases and p90 ribosomal S6 kinase, downstream molecules of Src, in a time-dependent manner, in both PC3 and A431 cell lines. The docking structure of compound 43 with Src disclosed that the chlorobenzodioxole moiety and pyrrolidine ring of C-6 quinazoline appeared to fit tightly into the hydrophobic pocket of Src. Additionally, the pyrrolidine NH forms a hydrogen bond with the carboxyl group of Asp348. These results confirm the successful application of virtual screening studies in the lead discovery process, and suggest that our novel compound 43 can be an effective Src inhibitor candidate for further lead optimization. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2009.02.054
• 作为产物：
  描述：

  4-氯-7-氟-6-硝基喹唑啉 、 5-氯苯并[1,3]二恶茂-4-胺 在 盐酸 作用下， 以 水 、 异丙醇 为溶剂， 反应 2.0h， 以89%的产率得到(5-chloro-benzo[1,3]dioxol-4-yl)(7-fluoro-6-nitro-quinazolin-4-yl)amine
  参考文献：
  名称：

  Structure-based virtual screening of Src kinase inhibitors

  摘要：

  Src is an important target in multiple processes associated with tumor growth and development, including proliferation, neovascularization, and metastasis. In this study, hit identification was performed by virtual screening of commercial and in-house compound libraries. Docking studies for the hits were performed, and scoring functions were used to evaluate the docking results and to rank ligand-binding affinities. Subsequently, hit optimization for potent and selective candidate Src inhibitors was performed through focused library design and docking analyses. Consequently, we report that a novel compound '43' with an IC50 value of 89 nM, representing (S)-N-(4-(5-chlorobenzo[d][1,3]dioxol-4-ylamino)-7-(2-methoxyethoxy)quinazolin-6-yl)pyrrolidine-2-carboxamide, is highly selective for Src in comparison to EGFR (IC50 ratio > 80-fold) and VEGFR-2 (IC50 ratio > 110-fold). Compound 43 exerted anti-proliferative effects on Src-expressing PC3 human prostate cancer and A431 human epidermoid carcinoma cells, with calculated IC50 values of 1.52 and 0.78 mu M, respectively. Moreover, compound 43 (0.1 mu M) suppressed the phosphorylation of extracellular signal-regulated kinases and p90 ribosomal S6 kinase, downstream molecules of Src, in a time-dependent manner, in both PC3 and A431 cell lines. The docking structure of compound 43 with Src disclosed that the chlorobenzodioxole moiety and pyrrolidine ring of C-6 quinazoline appeared to fit tightly into the hydrophobic pocket of Src. Additionally, the pyrrolidine NH forms a hydrogen bond with the carboxyl group of Asp348. These results confirm the successful application of virtual screening studies in the lead discovery process, and suggest that our novel compound 43 can be an effective Src inhibitor candidate for further lead optimization. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2009.02.054