O6-Substituted Guanine Deriv. 35

• 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: O6-Substituted Guanine Deriv. 35
• 英文别名: 6-[(3-methoxyphenyl)methoxy]-7H-purin-2-amine
• 化学式: C₁₃H₁₃N₅O₂
• 分子量: 271.279
• InChiKey: VMADRKOVJJNYIX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  20
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  98.9
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  sodium 3-methoxyphenylmethoxide 、 1-(2-amino-9H-purin-6-yl)-4-aza-1-azoniabicyclo[2.2.2]octane chloride 以 二甲基亚砜 为溶剂， 以72%的产率得到O6-Substituted Guanine Deriv. 35
  参考文献：
  名称：

  Probing the ATP Ribose-Binding Domain of Cyclin-Dependent Kinases 1 and 2 with O⁶-Substituted Guanine Derivatives

  摘要：

  O-6-Substituted guanines are adenosine 5'-triphosphate (ATP) competitive inhibitors of CDK1/cyclin B I and CDK2/cyclin A, the O-6 substituent occupying the kinase ribose binding site. Fifty-eight O-6-substituted guanines were prepared to probe the ribose pocket, and the structures of four representative compounds bound to monomeric CDK2 were determined by X-ray crystallography. Optimum binding occurs with a moderately sized aliphatic 06 substituent that packs tightly against the hydrophobic patch presented by the glycine loop, centered on Val18, an interaction promoted by the conformational restraints imposed in a cyclohexylmethyl or cyclohexenylmethyl ring. Structure-based design generated (R)-(2-amino-9H-purin-6-yloxymethyl)pyrrolidin-2-one (56), which reproduces the reported hydrogen bonds formed between ATP and Asp86 and Gln131 but failed to improve inhibitory potency. Thus, the parent compound O-6-cyclohexylmethylguanine (NU2058, 25) is the preferred starting point for exploring other areas of the kinase active site.

  DOI：

  10.1021/jm020056z

文献信息

• Probing the ATP Ribose-Binding Domain of Cyclin-Dependent Kinases 1 and 2 with <i>O</i>⁶-Substituted Guanine Derivatives
  作者：Ashleigh E. Gibson、Christine E. Arris、Johanne Bentley、F. Thomas Boyle、Nicola J. Curtin、Thomas G. Davies、Jane A. Endicott、Bernard T. Golding、Sharon Grant、Roger J. Griffin、Philip Jewsbury、Louise N. Johnson、Veronique Mesguiche、David R. Newell、Martin E. M. Noble、Julie A. Tucker、Hayley J. Whitfield

  DOI：10.1021/jm020056z

  日期：2002.8.1

  O-6-Substituted guanines are adenosine 5'-triphosphate (ATP) competitive inhibitors of CDK1/cyclin B I and CDK2/cyclin A, the O-6 substituent occupying the kinase ribose binding site. Fifty-eight O-6-substituted guanines were prepared to probe the ribose pocket, and the structures of four representative compounds bound to monomeric CDK2 were determined by X-ray crystallography. Optimum binding occurs with a moderately sized aliphatic 06 substituent that packs tightly against the hydrophobic patch presented by the glycine loop, centered on Val18, an interaction promoted by the conformational restraints imposed in a cyclohexylmethyl or cyclohexenylmethyl ring. Structure-based design generated (R)-(2-amino-9H-purin-6-yloxymethyl)pyrrolidin-2-one (56), which reproduces the reported hydrogen bonds formed between ATP and Asp86 and Gln131 but failed to improve inhibitory potency. Thus, the parent compound O-6-cyclohexylmethylguanine (NU2058, 25) is the preferred starting point for exploring other areas of the kinase active site.