2-(4-chloro-2-methyl-1H-indol-3-yl)acetic acid | 6127-20-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 2-(4-chloro-2-methyl-1H-indol-3-yl)acetic acid
• 英文别名: 4-Chlor-2-methyl-indol-3-essigsaeure；(4-chloro-2-methyl-indol-3-yl)-acetic acid；(4-Chlor-2-methyl-indol-3-yl)-essigsaeure
• CAS: 6127-20-4
• 化学式: C₁₁H₁₀ClNO₂
• 分子量: 223.659
• InChiKey: DVYFYPAMPUDXFH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  15
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  53.1
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  2-(4-chloro-2-methyl-1H-indol-3-yl)acetic acid 、 N-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)-2-hydroxyacetamide 在 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 4.0h， 以65 mg的产率得到2-((3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)amino)-2-oxoethyl 2-(4-chloro-2-methyl-1H-indol-3-yl)acetate
  参考文献：
  名称：

  Depsipeptides Featuring a Neutral P1 Are Potent Inhibitors of Kallikrein-Related Peptidase 6 with On-Target Cellular Activity

  摘要：

  Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease that belongs to the family of tissue kallikreins (KLKs). Many KLKs are investigated as potential biomarkers for cancer as well as therapeutic drug targets for a number of pathologies. KLK6, in particular, has been implicated in neurodegenerative diseases and cancer, but target validation has been hampered by a lack of selective inhibitors. This work introduces a class of depsipeptidic KLK6 inhibitors, discovered via high-throughput screening, which were found to function as substrate mimics that transiently acylate the catalytic serine of KLK6. Detailed structure-activity relationship studies, aided by in silico modeling, uncovered strict structural requirements for potency, stability, and acyl-enzyme complex half-life. An optimized scaffold, DKFZ-251, demonstrated good selectivity for KLK6 compared to other KLKs, and on-target activity in a cellular assay. Moreover, DKFZ-633, an inhibitor-derived activity based probe, could be used to pull down active endogenous KLK6.

  DOI：

  10.1021/acs.jmedchem.8b01106
• 作为产物：
  描述：

  4-氯-2-甲基-1H-吲哚 在 正丁基锂 、 lithium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 水 为溶剂， 反应 22.0h， 生成 2-(4-chloro-2-methyl-1H-indol-3-yl)acetic acid
  参考文献：
  名称：

  Depsipeptides Featuring a Neutral P1 Are Potent Inhibitors of Kallikrein-Related Peptidase 6 with On-Target Cellular Activity

  摘要：

  Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease that belongs to the family of tissue kallikreins (KLKs). Many KLKs are investigated as potential biomarkers for cancer as well as therapeutic drug targets for a number of pathologies. KLK6, in particular, has been implicated in neurodegenerative diseases and cancer, but target validation has been hampered by a lack of selective inhibitors. This work introduces a class of depsipeptidic KLK6 inhibitors, discovered via high-throughput screening, which were found to function as substrate mimics that transiently acylate the catalytic serine of KLK6. Detailed structure-activity relationship studies, aided by in silico modeling, uncovered strict structural requirements for potency, stability, and acyl-enzyme complex half-life. An optimized scaffold, DKFZ-251, demonstrated good selectivity for KLK6 compared to other KLKs, and on-target activity in a cellular assay. Moreover, DKFZ-633, an inhibitor-derived activity based probe, could be used to pull down active endogenous KLK6.

  DOI：

  10.1021/acs.jmedchem.8b01106

文献信息

• Piper; Stevens, Journal of Organic Chemistry, 1962, vol. 27, p. 3134,3136
  作者：Piper、Stevens

  DOI：——

  日期：——
• Preparation of Some Substituted 2-Methyl-3-indoleacetic Acids^1,2
  作者：Frank J. Stevens、Don H. Higginbotham

  DOI：10.1021/ja01637a053

  日期：1954.4

表征谱图