benzyl 3-(2-amino-9-benzyl-6-(cyclohexylmethoxy)-9H-purin-8-yl)-2-methylbenzoate | 1520101-50-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: benzyl 3-(2-amino-9-benzyl-6-(cyclohexylmethoxy)-9H-purin-8-yl)-2-methylbenzoate
• CAS: 1520101-50-1
• 化学式: C₃₄H₃₅N₅O₃
• 分子量: 561.684
• InChiKey: XTBRQMQYPDENJH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.75
• 重原子数：
  42.0
• 可旋转键数：
  9.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  105.15
• 氢给体数：
  1.0
• 氢受体数：
  8.0

反应信息

• 作为反应物：
  描述：

  benzyl 3-(2-amino-9-benzyl-6-(cyclohexylmethoxy)-9H-purin-8-yl)-2-methylbenzoate 在 盐酸 、 palladium 10% on activated carbon 、 氢气 、 溶剂黄146 作用下， 以 水 为溶剂， 20.0 ℃ 、101.33 kPa 条件下， 反应 13.0h， 以24%的产率得到3-(2-amino-6-cyclohexylmethoxy-9H-purin-8-yl)-2-methylbenzoic acid
  参考文献：
  名称：

  8-Substituted O⁶-Cyclohexylmethylguanine CDK2 Inhibitors: Using Structure-Based Inhibitor Design to Optimize an Alternative Binding Mode

  摘要：

  Evaluation of the effects of purine C-8 substitution within a series of CDK1/2-selective O-6-cyclohexylmethylguanine derivatives revealed that potency decreases initially with increasing size of the alkyl substituent. Structural analysis showed that C-8 substitution is poorly tolerated, and to avoid unacceptable steric interactions, these compounds adopt novel binding modes. Thus, 2-amino-6-cyclohexylmethoxy-8-isopropyl-9H-purine adopts a "reverse" binding mode where the purine backbone has flipped 180 degrees. This provided a novel lead chemotype from which we have designed more potent CDK2 inhibitors using, in the first instance, quantum mechanical energy calculations. Introduction of an ortho-tolyl or ortho-chlorophenyl group at the purine C-8 position restored the potency of these "reverse" binding mode inhibitors to that of the parent 2-amino-6-cyclohexylmethoxy-9H-purine. By contrast, the corresponding 8-(2-methyl-3-sulfamoylphenyl)-purine derivative exhibited submicromolar CDK2-inhibitory activity by virtue of engineered additional interactions with Asp86 and Lys89 in the reversed binding mode, as confirmed by X-ray crystallography.

  DOI：

  10.1021/jm401555v
• 作为产物：
  描述：

  溴甲苯 在 copper(l) iodide 、 palladium diacetate 、 potassium carbonate 、 caesium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 12.0h， 生成 benzyl 3-(2-amino-9-benzyl-6-(cyclohexylmethoxy)-9H-purin-8-yl)-2-methylbenzoate
  参考文献：
  名称：

  8-Substituted O⁶-Cyclohexylmethylguanine CDK2 Inhibitors: Using Structure-Based Inhibitor Design to Optimize an Alternative Binding Mode

  摘要：

  Evaluation of the effects of purine C-8 substitution within a series of CDK1/2-selective O-6-cyclohexylmethylguanine derivatives revealed that potency decreases initially with increasing size of the alkyl substituent. Structural analysis showed that C-8 substitution is poorly tolerated, and to avoid unacceptable steric interactions, these compounds adopt novel binding modes. Thus, 2-amino-6-cyclohexylmethoxy-8-isopropyl-9H-purine adopts a "reverse" binding mode where the purine backbone has flipped 180 degrees. This provided a novel lead chemotype from which we have designed more potent CDK2 inhibitors using, in the first instance, quantum mechanical energy calculations. Introduction of an ortho-tolyl or ortho-chlorophenyl group at the purine C-8 position restored the potency of these "reverse" binding mode inhibitors to that of the parent 2-amino-6-cyclohexylmethoxy-9H-purine. By contrast, the corresponding 8-(2-methyl-3-sulfamoylphenyl)-purine derivative exhibited submicromolar CDK2-inhibitory activity by virtue of engineered additional interactions with Asp86 and Lys89 in the reversed binding mode, as confirmed by X-ray crystallography.

  DOI：

  10.1021/jm401555v