6-chloro-3-(1-{4-[(3,4,5-trifluorobenzyl)oxy]benzyl}-4-(4-fluorophenyl)-1H-imidazol-5-yl)-1H-indole-2-carboxylic acid

• 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: 6-chloro-3-(1-{4-[(3,4,5-trifluorobenzyl)oxy]benzyl}-4-(4-fluorophenyl)-1H-imidazol-5-yl)-1H-indole-2-carboxylic acid
• 英文别名: 6-chloro-3-[5-(4-fluorophenyl)-3-[[4-[(3,4,5-trifluorophenyl)methoxy]phenyl]methyl]imidazol-4-yl]-1H-indole-2-carboxylic acid
• 化学式: C₃₂H₂₀ClF₄N₃O₃
• 分子量: 605.976
• InChiKey: GCXIQFYOGSTRFW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.4
• 重原子数：
  43
• 可旋转键数：
  8
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  80.1
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  3,4,5-三氟溴苄 在 lithium aluminium tetrahydride 、 potassium carbonate 、 sodium hydroxide 作用下， 以 四氢呋喃 、 乙醇 、 丙酮 为溶剂， 反应 3.5h， 生成 6-chloro-3-(1-{4-[(3,4,5-trifluorobenzyl)oxy]benzyl}-4-(4-fluorophenyl)-1H-imidazol-5-yl)-1H-indole-2-carboxylic acid
  参考文献：
  名称：

  1,4,5-Trisubstituted Imidazole-Based p53–MDM2/MDMX Antagonists with Aliphatic Linkers for Conjugation with Biological Carriers

  摘要：

  The tumor suppressor protein p53, the "guardian of the genome", is inactivated in nearly all cancer types by mutations in the TPS3 gene or by overexpression of its negative regulators, oncoproteins MDM2/MDMX. Recovery of p53 function by disrupting the p53-MDM2/MDMX interaction using small-molecule antagonists could provide an efficient nongenotoxic anticancer therapy. Here we present the syntheses, activities, and crystal structures of the p53-MDM2/MDMX inhibitors based on the 1,4,5-trisubstituted imidazole scaffold which are appended with aliphatic linkers that enable coupling to bioactive carriers. The compounds have favorable properties at both biochemical and cellular levels. The most effective compound 19 is a tight binder of MDM2 and activates p53 in cancer cells that express the wild-type p53, leading to cell cycle arrest and growth inhibition. Crystal structures reveal that compound 19 induces MDM2 dimerization via the aliphatic linker. This unique dimerization-binding mode opens new prospects for the optimization of the p53-MDM2/MDMX inhibitors and conjugation with bioactive carriers.

  DOI：

  10.1021/acs.jmedchem.7b00104

文献信息

• 1,4,5-Trisubstituted Imidazole-Based p53–MDM2/MDMX Antagonists with Aliphatic Linkers for Conjugation with Biological Carriers
  作者：Aleksandra Twarda-Clapa、Sylwia Krzanik、Katarzyna Kubica、Katarzyna Guzik、Beata Labuzek、Constantinos G. Neochoritis、Kareem Khoury、Kaja Kowalska、Miroslawa Czub、Grzegorz Dubin、Alexander Dömling、Lukasz Skalniak、Tad A. Holak

  DOI：10.1021/acs.jmedchem.7b00104

  日期：2017.5.25

  The tumor suppressor protein p53, the "guardian of the genome", is inactivated in nearly all cancer types by mutations in the TPS3 gene or by overexpression of its negative regulators, oncoproteins MDM2/MDMX. Recovery of p53 function by disrupting the p53-MDM2/MDMX interaction using small-molecule antagonists could provide an efficient nongenotoxic anticancer therapy. Here we present the syntheses, activities, and crystal structures of the p53-MDM2/MDMX inhibitors based on the 1,4,5-trisubstituted imidazole scaffold which are appended with aliphatic linkers that enable coupling to bioactive carriers. The compounds have favorable properties at both biochemical and cellular levels. The most effective compound 19 is a tight binder of MDM2 and activates p53 in cancer cells that express the wild-type p53, leading to cell cycle arrest and growth inhibition. Crystal structures reveal that compound 19 induces MDM2 dimerization via the aliphatic linker. This unique dimerization-binding mode opens new prospects for the optimization of the p53-MDM2/MDMX inhibitors and conjugation with bioactive carriers.