(S)-pyrrolidine-2-carboxylic acid N-[4-(5-chloro-benzo[1,3]dioxol-4-ylamino)-7-(2-methoxyethoxy)quinazolin-6-yl]amide | 1155336-45-0

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (S)-pyrrolidine-2-carboxylic acid N-[4-(5-chloro-benzo[1,3]dioxol-4-ylamino)-7-(2-methoxyethoxy)quinazolin-6-yl]amide
• 英文别名: (S)-N-[4-(5-chloro-benzo[1,3]dioxol-4-ylamino)-7-(2-methoxyethoxy)quinazolin-6-yl]pyrrolidine-2-carboxamide；(S)-N-(4-(5-chlorobenzo[d][1,3]dioxol-4-ylamino)-7-(2-methoxyethoxy)quinazolin-6-yl)pyrrolidine-2-carboxamide；(2S)-N-[4-[(5-chloro-1,3-benzodioxol-4-yl)amino]-7-(2-methoxyethoxy)quinazolin-6-yl]pyrrolidine-2-carboxamide
• CAS: 1155336-45-0
• 化学式: C₂₃H₂₄ClN₅O₅
• 分子量: 485.927
• InChiKey: PXVOZEZXKFLOOY-HNNXBMFYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  34
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  116
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  (S)-2-[4-(5-chloro-benzo[1,3]dioxol-4-ylamino)-7-(2-methoxyethoxy)quinazolin-6-ylcarbamoyl]pyrrolidine-2-carboxylic acid tert-butyl ester 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 以48%的产率得到(S)-pyrrolidine-2-carboxylic acid N-[4-(5-chloro-benzo[1,3]dioxol-4-ylamino)-7-(2-methoxyethoxy)quinazolin-6-yl]amide
  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

文献信息

• Structure-based virtual screening of Src kinase inhibitors
  作者：Kyungik Lee、Jongwoo Kim、Ki-Woong Jeong、Ki Won Lee、Yeonjoo Lee、Ji Yeon Song、Maeng Sup Kim、Gwan Sun Lee、Yangmee Kim

  DOI：10.1016/j.bmc.2009.02.054

  日期：2009.4

  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.