((2R,3S,4R,5R)-5-(2-amino-7-(2-methylbenzyl)-6-oxo-1H-purin-1-ium-9(6H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷酸
• 英文名称: ((2R,3S,4R,5R)-5-(2-amino-7-(2-methylbenzyl)-6-oxo-1H-purin-1-ium-9(6H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate
• 化学式: C₁₈H₂₁N₅O₈P
• 分子量: 466.367
• InChiKey: GJVCYMNRTXNUKB-LSCFUAHRSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  -2.58
• 重原子数：
  32.0
• 可旋转键数：
  6.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  202.69
• 氢给体数：
  4.0
• 氢受体数：
  11.0

反应信息

• 作为产物：
  描述：

  guanosine 5'-monophosphate disodium 、 2-甲基苄溴 以 二甲基亚砜 为溶剂， 反应 24.0h， 以71%的产率得到((2R,3S,4R,5R)-5-(2-amino-7-(2-methylbenzyl)-6-oxo-1H-purin-1-ium-9(6H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate
  参考文献：
  名称：

  Design, synthesis and evaluation of analogs of initiation factor 4E (eIF4E) cap-binding antagonist Bn7-GMP

  摘要：

  Aberrant regulation of cap-dependent translation has been frequently observed in the development of cancer. Association of the cap-binding protein eIF4E with N-7-methylated guanosine capped mRNA is the rate limiting step governing translation initiation; and therefore represents an attractive process for cancer drug discovery. Previously, replacement of the 7-Me group of the Me-7-guanosine monophosphate with a benzyl group has been found to increase binding affinity to eIF4E. Recent X-ray crystallographic studies have revealed that the cap-binding pocket undergoes a unique structural change in order to accommodate the benzyl group. To explore the structure-activity relationships governing the affinity of N-7-benzylated guanosine monophosphate (Bn-7-GMP) for eIF4E, we virtually screened a library of 80 Bn-7-GMP analogs utilizing CombiGlide as implemented in Schrodinger (R). A subset library of substituted Bn-7-GMP analogs was synthesized and their dissociation constants (K-d) were determined. Due to the poor correlation between docking/scoring results and experimental binding affinities, three-dimensional quantitative structure-activity relationship (3D-QSAR) calculations were performed. Two highly predictive and self-consistent CoMFA (comparative molecular field analysis) and CoMSIA (comparative molecular similarity indices analysis) models were derived and optimized. These models may be useful for the future design of eIF4E cap-binding antagonists. (C) 2009 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2009.11.054

文献信息

• Design, synthesis and evaluation of analogs of initiation factor 4E (eIF4E) cap-binding antagonist Bn7-GMP
  作者：Yan Jia、Ting-Lan Chiu、Elizabeth A. Amin、Vitaly Polunovsky、Peter B. Bitterman、Carston R. Wagner

  DOI：10.1016/j.ejmech.2009.11.054

  日期：2010.4

  Aberrant regulation of cap-dependent translation has been frequently observed in the development of cancer. Association of the cap-binding protein eIF4E with N-7-methylated guanosine capped mRNA is the rate limiting step governing translation initiation; and therefore represents an attractive process for cancer drug discovery. Previously, replacement of the 7-Me group of the Me-7-guanosine monophosphate with a benzyl group has been found to increase binding affinity to eIF4E. Recent X-ray crystallographic studies have revealed that the cap-binding pocket undergoes a unique structural change in order to accommodate the benzyl group. To explore the structure-activity relationships governing the affinity of N-7-benzylated guanosine monophosphate (Bn-7-GMP) for eIF4E, we virtually screened a library of 80 Bn-7-GMP analogs utilizing CombiGlide as implemented in Schrodinger (R). A subset library of substituted Bn-7-GMP analogs was synthesized and their dissociation constants (K-d) were determined. Due to the poor correlation between docking/scoring results and experimental binding affinities, three-dimensional quantitative structure-activity relationship (3D-QSAR) calculations were performed. Two highly predictive and self-consistent CoMFA (comparative molecular field analysis) and CoMSIA (comparative molecular similarity indices analysis) models were derived and optimized. These models may be useful for the future design of eIF4E cap-binding antagonists. (C) 2009 Elsevier Masson SAS. All rights reserved.