3-(2-amino-6-(cyclohexylmethoxy)-9H-purin-8-yl)-2-methylbenzamide | 1520101-58-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 3-(2-amino-6-(cyclohexylmethoxy)-9H-purin-8-yl)-2-methylbenzamide
• 英文别名: 3-[2-amino-6-(cyclohexylmethoxy)-7H-purin-8-yl]-2-methylbenzamide
• CAS: 1520101-58-9
• 化学式: C₂₀H₂₄N₆O₂
• 分子量: 380.45
• InChiKey: NUODIKTWVQSQRP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  133
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  3-溴-2-甲基苯甲酸 在 吡啶 、 4-二甲氨基吡啶 、 1,1'-双(二苯基膦)二茂铁 、 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) 、 potassium acetate 、 caesium carbonate 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 为溶剂， 反应 126.25h， 生成 3-(2-amino-6-(cyclohexylmethoxy)-9H-purin-8-yl)-2-methylbenzamide
  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

文献信息

• 8-Substituted <i>O</i>⁶-Cyclohexylmethylguanine CDK2 Inhibitors: Using Structure-Based Inhibitor Design to Optimize an Alternative Binding Mode
  作者：Benoit Carbain、David J. Paterson、Elizabeth Anscombe、Allyson J. Campbell、Celine Cano、Aude Echalier、Jane A. Endicott、Bernard T. Golding、Karen Haggerty、Ian R. Hardcastle、Philip J. Jewsbury、David R. Newell、Martin E. M. Noble、Celine Roche、Lan Z. Wang、Roger J. Griffin

  DOI：10.1021/jm401555v

  日期：2014.1.9

  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.