2-{[(tert-butoxy)carbonyl]amino}-4-(3-methoxyphenyl)thiophene-3-carboxylic acid | 1432511-10-8

• 分子结构分类: 有机化合物 - 有机杂环化合物
• 英文名称: 2-{[(tert-butoxy)carbonyl]amino}-4-(3-methoxyphenyl)thiophene-3-carboxylic acid
• CAS: 1432511-10-8
• 化学式: C₁₇H₁₉NO₅S
• 分子量: 349.408
• InChiKey: QBBJVVKEUPZIIT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.47
• 重原子数：
  24.0
• 可旋转键数：
  4.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  84.86
• 氢给体数：
  2.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  2-{[(tert-butoxy)carbonyl]amino}-4-(3-methoxyphenyl)thiophene-3-carboxylic acid 、 苯甲醇 在 N,N'-羰基二咪唑 作用下， 以 二氯甲烷 为溶剂， 反应 18.0h， 以65%的产率得到benzyl 2-{[(tert-butoxy)carbonyl]amino}-4-(3-methoxyphenyl)thiophene-3-carboxylate
  参考文献：
  名称：

  Synthesis and structure–activity relationships of 2-amino-3-carboxy-4-phenylthiophenes as novel atypical protein kinase C inhibitors

  摘要：

  Recent evidence suggests atypical protein kinase C (aPKC) isoforms are required for both TNF- and VEGF-induced breakdown of the blood-retinal barrier (BRB) and endothelial permeability to 70 kDa dextran or albumin. A chemical library screen revealed a series of novel small molecule phenylthiophene based inhibitors of aPKC isoforms that effectively block permeability in cell culture and in vivo. In an effort to further elucidate the structural requirements of this series of inhibitors, we detail in this study a structure-activity relationship (SAR) built on screening hit 1, which expands on our initial pharmacophore model. The biological activity of our analogues was evaluated in models of bona fide aPKC-dependent signaling including NF kappa B driven-gene transcription as a marker for an inflammatory response and VEGF/TNF-induced vascular endothelial permeability. The EC50 for the most efficacious inhibitors (6, 32) was in the low nanomolar range in these two cellular assays. Our study demonstrates the key structural elements that confer inhibitory activity and highlights the requirement for electron-donating moieties off the C-4 aryl moiety of the 2-amino-3-carboxy-4-phenylthiophene backbone. These studies suggest that this class has potential for further development into small molecule aPKC inhibitors with therapeutic efficacy in a host of diseases involving increased vascular permeability and inflammation. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.03.019
• 作为产物：
  描述：

  3-甲氧基苯乙酮 在 4-二甲氨基吡啶 、 ammonium acetate 、 水 、 溶剂黄146 、 potassium hydroxide 作用下， 以 吡啶 、 乙醇 、 甲苯 为溶剂， 反应 11.17h， 生成 2-{[(tert-butoxy)carbonyl]amino}-4-(3-methoxyphenyl)thiophene-3-carboxylic acid
  参考文献：
  名称：

  Synthesis and structure–activity relationships of 2-amino-3-carboxy-4-phenylthiophenes as novel atypical protein kinase C inhibitors

  摘要：

  Recent evidence suggests atypical protein kinase C (aPKC) isoforms are required for both TNF- and VEGF-induced breakdown of the blood-retinal barrier (BRB) and endothelial permeability to 70 kDa dextran or albumin. A chemical library screen revealed a series of novel small molecule phenylthiophene based inhibitors of aPKC isoforms that effectively block permeability in cell culture and in vivo. In an effort to further elucidate the structural requirements of this series of inhibitors, we detail in this study a structure-activity relationship (SAR) built on screening hit 1, which expands on our initial pharmacophore model. The biological activity of our analogues was evaluated in models of bona fide aPKC-dependent signaling including NF kappa B driven-gene transcription as a marker for an inflammatory response and VEGF/TNF-induced vascular endothelial permeability. The EC50 for the most efficacious inhibitors (6, 32) was in the low nanomolar range in these two cellular assays. Our study demonstrates the key structural elements that confer inhibitory activity and highlights the requirement for electron-donating moieties off the C-4 aryl moiety of the 2-amino-3-carboxy-4-phenylthiophene backbone. These studies suggest that this class has potential for further development into small molecule aPKC inhibitors with therapeutic efficacy in a host of diseases involving increased vascular permeability and inflammation. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.03.019