6-(cyclohexylmethoxy)-2-N-(4-methoxyphenyl)-5-nitrosopyrimidine-2,4-diamine

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 6-(cyclohexylmethoxy)-2-N-(4-methoxyphenyl)-5-nitrosopyrimidine-2,4-diamine
• 化学式: C₁₈H₂₃N₅O₃
• 分子量: 357.412
• InChiKey: WWJLGEMPECUYJI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  26
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  112
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  6-amino-2-butylsulfonyl-4-cyclohexylmethoxypyrimidine 在 溶剂黄146 、 三氟乙酸 、 sodium nitrite 作用下， 以 2,2,2-三氟乙醇 为溶剂， 生成 6-(cyclohexylmethoxy)-2-N-(4-methoxyphenyl)-5-nitrosopyrimidine-2,4-diamine
  参考文献：
  名称：

  Structure-Based design of 2-Arylamino-4-cyclohexylmethyl-5-nitroso-6-aminopyrimidine inhibitors of cyclin-Dependent kinases 1 and 2

  摘要：

  A series of O(4)-cyclohexylmethyl-5-nitroso-6-aminopyrimidines bearing 2-arylamino substituents was synthesised and evaluated for CDK1 and CDK2 inhibitory activity. Consistent with analogous studies with O(6)-cyclohexylmethylpurines, 2-arylaminopyrimidines with a sulfonamide or carboxamide group at the 4'-position were potent inhibitors, with IC(50) values against CDK2 of 1.1+/-0.3 and 34+/-8 nM, respectively. The crystal structure of the 4'-carboxamide derivative, in complex with phospho-Thr160 CDK2/cyclin A, confirmed the expected binding mode of the inhibitor, and revealed an additional interaction between the carboxamide function and an aspartate residue.

  DOI：

  10.1016/s0960-894x(03)00651-6

文献信息

• Structure-based design of 2-arylamino-4-cyclohexylmethoxy-5-nitroso-6-aminopyrimidine inhibitors of cyclin-dependent kinase 2
  作者：Francesco Marchetti、Kerry L. Sayle、Johanne Bentley、William Clegg、Nicola J. Curtin、Jane A. Endicott、Bernard T. Golding、Roger J. Griffin、Karen Haggerty、Ross W. Harrington、Veronique Mesguiche、David R. Newell、Martin E. M. Noble、Rachel J. Parsons、David J. Pratt、Lan Z. Wang、Ian R. Hardcastle

  DOI：10.1039/b703241b

  日期：——

  An efficient synthesis of 2-substituted O4-cyclohexylmethyl-5-nitroso-6-aminopyrimidines from 6-amino-2-mercaptopyrimidin-4-ol has been developed and used to prepare a range of derivatives for evaluation as inhibitors of cyclin-dependent kinase 2 (CDK2). The structure–activity relationships (SARs) are similar to those observed for the corresponding O6-cyclohexylmethoxypurine series with the 2-arylsulfonamide and 2-arylcarboxamide derivatives showing excellent potency. Two compounds, 4-(6-amino-4-cyclohexylmethoxy-5-nitrosopyrimidin-2-ylamino)-N-(2-hydroxyethyl)benzenesulfonamide (7q) and 4-(6-amino-4-cyclohexylmethoxy-5-nitrosopyrimidin-2-ylamino)-N-(2,3-dihydroxypropyl)benzenesulfonamide (7s), were the most potent with IC50 values of 0.7 ± 0.1 and 0.8 ± 0.0 nM against CDK2, respectively. The SARs determined in this study are discussed with reference to the crystal structure of 4-(6-amino-4-cyclohexylmethoxy-5-nitrosopyrimidin-2-ylamino)-N-(2,3-dihydroxypropyl)benzenesulfonamide (7j) bound to phosphorylated CDK2/cyclin A.

  我们开发了一种从 6-氨基-2-巯基嘧啶-4-醇高效合成 2-取代 O4-环己基甲基-5-亚硝基-6-氨基嘧啶的方法，并将其用于制备一系列衍生物，以评估其作为细胞周期蛋白依赖性激酶 2（CDK2）抑制剂的效果。其结构-活性关系（SAR）与相应的 O6-环己基甲氧基嘌呤系列相似，其中 2-芳基磺酰胺和 2-芳基甲酰胺衍生物显示出卓越的效力。其中 4-(6-氨基-4-环己基甲氧基-5-亚硝基嘧啶-2-基氨基)-N-(2-羟乙基)苯磺酰胺（7q）和 4-(6-氨基-4-环己基甲氧基-5-亚硝基嘧啶-2-基氨基)-N-(2,3-二羟基丙基)苯磺酰胺（7s）这两种化合物的药效最强，IC50 值分别为 0.对 CDK2 的 IC50 值分别为 0.7 ± 0.1 和 0.8 ± 0.0 nM。本研究中确定的 SARs 参照了与磷酸化 CDK2/cyclin A 结合的 4-(6-氨基-4-环己基甲氧基-5-亚硝基嘧啶-2-基氨基)-N-(2,3-二羟基丙基)苯磺酰胺（7j）的晶体结构进行了讨论。