基于结构的细胞周期蛋白依赖性激酶1和2的2-芳基氨基-4-环己基甲基-5-亚硝基-6-氨基嘧啶抑制剂的设计
Structure-based design of 2-arylamino-4-cyclohexylmethyl-5-nitroso-6-aminopyrimidine inhibitors of cyclin-dependent kinases 1 and 2.
作者信息
Sayle Kerry L, Bentley Johanne, Boyle F Thomas, Calvert A Hilary, Cheng Yuzhu, Curtin Nicola J, Endicott Jane A, Golding Bernard T, Hardcastle Ian R, Jewsbury Philip, Mesguiche Veronique, Newell David R, Noble Martin E M, Parsons Rachel J, Pratt David J, Wang Lan Z, Griffin Roger J
机构信息
Northern Institute for Cancer Research, School of Natural Sciences-Chemistry, Bedson Building, University of Newcastle, Newcastle Upon Tyne NE1 7RU, UK.
出版信息
Bioorg Med Chem Lett. 2003 Sep 15;13(18):3079-82. doi: 10.1016/s0960-894x(03)00651-6.
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.
合成了一系列带有2-芳基氨基取代基的O(4)-环己基甲基-5-亚硝基-6-氨基嘧啶，并对其CDK1和CDK2抑制活性进行了评估。与对O(6)-环己基甲基嘌呤的类似研究一致，在4'-位带有磺酰胺或羧酰胺基团的2-芳基氨基嘧啶是强效抑制剂，对CDK2的IC(50)值分别为1.1±0.3和34±8 nM。4'-羧酰胺衍生物与磷酸化Thr160 CDK2/细胞周期蛋白A复合物的晶体结构证实了抑制剂预期的结合模式，并揭示了羧酰胺官能团与天冬氨酸残基之间的额外相互作用。
Zotero 插件