methyl N-(dibenzo[b,d]furan-4-carbonyl)-S-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)-L-cysteinate | 1354017-79-0

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 2-芳基苯并呋喃类黄酮
• 英文名称: methyl N-(dibenzo[b,d]furan-4-carbonyl)-S-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)-L-cysteinate
• CAS: 1354017-79-0
• 化学式: C₃₂H₃₉NO₄S
• 分子量: 533.732
• InChiKey: QVJSKEFOZXPQBH-AQLGRYSTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.01
• 重原子数：
  38.0
• 可旋转键数：
  13.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  68.54
• 氢给体数：
  1.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  methyl N-(dibenzo[b,d]furan-4-carbonyl)-S-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)-L-cysteinate 在 甲醇 、 lithium hydroxide 作用下， 反应 2.0h， 生成 (R)-2-(dibenzo[b,d]furan-4-carboxamido)-3-(((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)thio)propanoic acid
  参考文献：
  名称：

  Amide-modified prenylcysteine based Icmt inhibitors: Structure–activity relationships, kinetic analysis and cellular characterization

  摘要：

  Human protein isoprenylcysteine carboxyl methyltransferase (hIcmt) is the enzyme responsible for the alpha-carboxyl methylation of the C-terminal isoprenylated cysteine of CaaX proteins, including Ras proteins. This specific posttranslational methylation event has been shown to be important for cellular transformation by oncogenic Ras isoforms. This finding led to interest in hIcmt inhibitors as potential anti-cancer agents. Previous analog studies based on N-acetyl-S-farnesylcysteine identified two prenylcysteine-based low micromolar inhibitors (1a and 1b) of hIcmt, each bearing a phenoxyphenyl amide modification. In this study, a focused library of analogs of 1a and 1b was synthesized and screened versus hIcmt, delineating structural features important for inhibition. Kinetic characterization of the most potent analogs 1a and 1b established that both inhibitors exhibited mixed-mode inhibition and that the competitive component predominated. Using the Cheng-Prusoff method, the K-i values were determined from the IC50 values. Analog 1a has a K-IC of 1.4 +/- 0.2 mu M and a K-IU of 4.8 +/- 0.5 mu M while 1b has a K-IC of 0.5 +/- 0.07 mu M and a K-IU of 1.9 +/- 0.2 mu M. Cellular evaluation of 1b revealed that it alters the subcellular localization of GFP-KRas, and also inhibits both Ras activation and Erk phosphorylation in Jurkat cells. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.10.087
• 作为产物：
  描述：

  反,反-氯化法呢酯 在 氨 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 5.25h， 生成 methyl N-(dibenzo[b,d]furan-4-carbonyl)-S-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)-L-cysteinate
  参考文献：
  名称：

  Amide-modified prenylcysteine based Icmt inhibitors: Structure–activity relationships, kinetic analysis and cellular characterization

  摘要：

  Human protein isoprenylcysteine carboxyl methyltransferase (hIcmt) is the enzyme responsible for the alpha-carboxyl methylation of the C-terminal isoprenylated cysteine of CaaX proteins, including Ras proteins. This specific posttranslational methylation event has been shown to be important for cellular transformation by oncogenic Ras isoforms. This finding led to interest in hIcmt inhibitors as potential anti-cancer agents. Previous analog studies based on N-acetyl-S-farnesylcysteine identified two prenylcysteine-based low micromolar inhibitors (1a and 1b) of hIcmt, each bearing a phenoxyphenyl amide modification. In this study, a focused library of analogs of 1a and 1b was synthesized and screened versus hIcmt, delineating structural features important for inhibition. Kinetic characterization of the most potent analogs 1a and 1b established that both inhibitors exhibited mixed-mode inhibition and that the competitive component predominated. Using the Cheng-Prusoff method, the K-i values were determined from the IC50 values. Analog 1a has a K-IC of 1.4 +/- 0.2 mu M and a K-IU of 4.8 +/- 0.5 mu M while 1b has a K-IC of 0.5 +/- 0.07 mu M and a K-IU of 1.9 +/- 0.2 mu M. Cellular evaluation of 1b revealed that it alters the subcellular localization of GFP-KRas, and also inhibits both Ras activation and Erk phosphorylation in Jurkat cells. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.10.087