methyl hydrogen ((4-(7-(2-(4-chlorophenoxy)ethyl)-2-(methylamino)-6-oxo-6,7-dihydro-1H-purin-8-yl)phenyl)difluoromethyl)phosphonate | 1373822-45-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: methyl hydrogen ((4-(7-(2-(4-chlorophenoxy)ethyl)-2-(methylamino)-6-oxo-6,7-dihydro-1H-purin-8-yl)phenyl)difluoromethyl)phosphonate
• 英文别名: [[4-[7-[2-(4-chlorophenoxy)ethyl]-2-(methylamino)-6-oxo-1H-purin-8-yl]phenyl]-difluoromethyl]-methoxyphosphinic acid
• CAS: 1373822-45-7
• 化学式: C₂₂H₂₁ClF₂N₅O₅P
• 分子量: 539.863
• InChiKey: JASJFFXSYCTEMP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  36
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  127
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  methyl hydrogen ((4-(7-(2-(4-chlorophenoxy)ethyl)-2-(methylamino)-6-oxo-6,7-dihydro-1H-purin-8-yl)phenyl)difluoromethyl)phosphonate 在 三甲基溴硅烷 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 以4.5%的产率得到((4-(3-(2-(4-chlorophenoxy)ethyl)-6-(methylamino)-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl)phenyl)difluoromethyl)-phosphonic acid
  参考文献：
  名称：

  Structure-Guided Design, Synthesis, and Evaluation of Guanine-Derived Inhibitors of the eIF4E mRNA–Cap Interaction

  摘要：

  The eukaryotic initiation factor 4E (eIF4E) plays a central role in the initiation of gene translation and subsequent protein synthesis by binding the 5' terminal mRNA cap structure. We designed and synthesized a series of novel compounds that display potent binding affinity against eIF4E despite their lack of a ribose moiety, phosphate, and positive charge as present in m7-GMP. The biochemical activity of compound 33 is 95 nM for eIF4E in an SPA binding assay. More importantly, the compound has an IC50 of 2.5 mu M for inhibiting cap-dependent mRNA translation in a rabbit reticular cell extract assay (RRL-IVT). This series of potent, truncated analogues could serve as a promising new starting point toward the design of neutral eIF4E inhibitors with physicochemical properties suitable for cellular activity assessment.

  DOI：

  10.1021/jm300037x
• 作为产物：
  描述：

  (diethoyphosphinyldifluoromethyl)benzoic acid 在 甲醇 、 三乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 7.0h， 生成 methyl hydrogen ((4-(7-(2-(4-chlorophenoxy)ethyl)-2-(methylamino)-6-oxo-6,7-dihydro-1H-purin-8-yl)phenyl)difluoromethyl)phosphonate
  参考文献：
  名称：

  Structure-Guided Design, Synthesis, and Evaluation of Guanine-Derived Inhibitors of the eIF4E mRNA–Cap Interaction

  摘要：

  The eukaryotic initiation factor 4E (eIF4E) plays a central role in the initiation of gene translation and subsequent protein synthesis by binding the 5' terminal mRNA cap structure. We designed and synthesized a series of novel compounds that display potent binding affinity against eIF4E despite their lack of a ribose moiety, phosphate, and positive charge as present in m7-GMP. The biochemical activity of compound 33 is 95 nM for eIF4E in an SPA binding assay. More importantly, the compound has an IC50 of 2.5 mu M for inhibiting cap-dependent mRNA translation in a rabbit reticular cell extract assay (RRL-IVT). This series of potent, truncated analogues could serve as a promising new starting point toward the design of neutral eIF4E inhibitors with physicochemical properties suitable for cellular activity assessment.

  DOI：

  10.1021/jm300037x

文献信息

• Structure-Guided Design, Synthesis, and Evaluation of Guanine-Derived Inhibitors of the eIF4E mRNA–Cap Interaction
  作者：Xiaoqi Chen、David J. Kopecky、Jeff Mihalic、Shawn Jeffries、Xiaoshan Min、Julie Heath、Jeff Deignan、SuJen Lai、Zice Fu、Cristiano Guimaraes、Shanling Shen、Shyun Li、Sheree Johnstone、Stephen Thibault、Haoda Xu、Mario Cardozo、Wang Shen、Nigel Walker、Frank Kayser、Zhulun Wang

  DOI：10.1021/jm300037x

  日期：2012.4.26

  The eukaryotic initiation factor 4E (eIF4E) plays a central role in the initiation of gene translation and subsequent protein synthesis by binding the 5' terminal mRNA cap structure. We designed and synthesized a series of novel compounds that display potent binding affinity against eIF4E despite their lack of a ribose moiety, phosphate, and positive charge as present in m7-GMP. The biochemical activity of compound 33 is 95 nM for eIF4E in an SPA binding assay. More importantly, the compound has an IC50 of 2.5 mu M for inhibiting cap-dependent mRNA translation in a rabbit reticular cell extract assay (RRL-IVT). This series of potent, truncated analogues could serve as a promising new starting point toward the design of neutral eIF4E inhibitors with physicochemical properties suitable for cellular activity assessment.