4-alkoxy-2,6-diaminopyrimidine derivatives: Inhibitors of cyclin dependent kinases 1 and 2
4-alkoxy-2,6-diaminopyrimidine derivatives: Inhibitors of cyclin dependent kinases 1 and 2
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DOI：
10.1016/s0960-894x(02)00884-3
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发表时间：
2003-01-20
影响因子：
2.7
通讯作者：
Hardcastle, IR
中科院分区：
文献类型：
--
作者：
Mesguiche, V;Parsons, RJ;Hardcastle, IR
细胞周期蛋白依赖性激酶（cdk）抑制剂NU 6027，4-环己基甲氧基-5-亚硝基-嘧啶-2，6-二胺（对cdk 1/细胞周期蛋白B1的IC 50 = 2.9 +/- 0.1 μ M，对cdk 2/细胞周期蛋白A3的IC 50 = 2.2 +/- 0.6 μ M），被用作设计一系列4-烷氧基-2，6-二氨基-5-亚硝基嘧啶衍生物的基础。本文报道了21个化合物作为细胞周期蛋白依赖性激酶1和2的潜在抑制剂的合成和评价，并探讨了与NU 6027有关的构效关系。在O-4-位上的简单烷氧基或环烷氧基是容许的，4-（2-甲基丁氧基）-衍生物（对cdk 1/cyclinB 1的IC 50 = 12 +/- 2 μ M和cdk 2/cyclinA 3 = 13 +/- 4 μ M）保留了显著的活性。在N-6位置的取代是不容许的。用酮、肟和缩氨基脲基团取代5-亚硝基取代基基本上消除了活性。然而，带有电子等排的5-甲酰基的衍生物，2，6-二氨基-4-环己基甲氧基-嘧啶-5-甲醛，显示出适度的活性（对cdk 1/细胞周期蛋白B1的IC 50 = 35 +/- 3 μ M，cdk 2/细胞周期蛋白A3的IC 50 =43 +/- 3 μ M）。与cdk 2结合的5-甲酰基化合物的X-射线晶体结构已被确定为2.3埃分辨率。从NU 6027与cdk 2结合的结构推导出的分子内氢键在具有相应甲酰基化合物的结构中不明显。因此，母体化合物，4-环己基甲氧基-5-亚硝基嘧啶-2，6-二胺（NU 6027），仍然是未来的结构活性研究的最佳基础，在这个系列中的细胞周期蛋白依赖性激酶抑制剂。(C)2002爱思唯尔科技有限公司。保留所有权利。
The cyclin dependent kinase (cdk) inhibitor NU6027, 4-cyclohexylmethoxy-5-nitroso-pyrimidine-2,6-diamine (IC50 vs cdk1/cyclinB1 = 2.9 +/- 0.1 muM and IC50 vs cdk2/cyclinA3 = 2.2 +/- 0.6 muM), was used as the basis for the design of a series of 4-alkoxy-2,6-diamino-5-nitrosopyrimidine derivatives. The synthesis and evaluation of 21 compounds as potential inhibitors of cyclin-dependent kinases 1 and 2 is described and the structure-activity relationships relating to NU6027 have been probed. Simple alkoxy- or cycloalkoxy-groups at the O-4-position were tolerated, with the 4-(2-methylbutoxy)-derivative (IC50 vs cdk1/cyclinB1 = 12 +/- 2 muM and cdk2/cyclinA3 = 13 +/- 4 muM) retaining significant activity. Substitutions at the N-6 position were not tolerated. Replacement of the 5-nitroso substituent with ketone, oxime and semicarbazone groups essentially abolished activity. However, the derivative bearing an isosteric 5-formyl group, 2,6-diamino-4-cyclohexylmethoxy-pyrimidine-5-carbaldehyde, showed modest activity (IC50 vs cdk1/cyclinB1 = 35 +/- 3 muM and cdk2/cyclinA3=43 +/- 3 muM). The X-ray crystal structure of the 5-formyl compound bound to cdk2 has been determined to 2.3 Angstrom resolution. The intramolecular H-bond deduced from the structure with NU6027 bound to cdk2 is not evident in the structure with the corresponding formyl compound. Thus the parent compound, 4-cyclohexylmethoxy-5-nitrosopyrimidine-2,6-diamine (NU6027), remains the optimal basis for future structure-activity studies for cyclin-dependent kinase inhibitors in this series. (C) 2002 Elsevier Science Ltd. All rights reserved.