Discovery of novel 5-fluoro-N(2),N(4)-diphenylpyrimidine-2,4-diamines as potent inhibitors against CDK2 and CDK9.
Discovery of novel 5-fluoro-N(2),N(4)-diphenylpyrimidine-2,4-diamines as potent inhibitors against CDK2 and CDK9.
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DOI：
10.1039/c4md00412d
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发表时间：
2015-03-01
期刊：
影响因子：
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通讯作者：
Lee KH
中科院分区：
文献类型：
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作者：
Gao J;Fang C;Xiao Z;Huang L;Chen CH;Wang LT;Lee KH
基于一系列已知的细胞周期蛋白依赖性激酶9（CDK 9）抑制剂的三维定量构效关系（3D-QSAR）药效团和一个从Flavopiridol（FVP）-CDK 9复合结构中提取的复合药效团，设计并合成了30个新的5-氟-N2，N4-二苯基嘧啶-2，4-二胺衍生物。用磺酰罗丹明B（SR B）测定法对四种肿瘤细胞系进行的初步试验鉴定了一系列具有较低微摩尔或亚微摩尔水平GI 50值的有效化合物。大多数高细胞毒性化合物对CDK 2/细胞周期蛋白E1和CDK 9/细胞周期蛋白T1都表现出有效的抑制活性。值得注意的是，对这两种酶的抑制作用通常与这些化合物的细胞毒性密切相关。在抗HIV-1试验中，还观察到选定化合物的明显抑制作用。化合物6d和9 g的对接研究为进一步的结构优化提供了有益的线索。
Based on a 3D-QSAR pharmacophore derived from a diverse set of known cyclin-dependent kinase 9 (CDK9) inhibitors and a composite pharmacophore extracted from the complex structure of flavopiridol (FVP)-CDK9, thirty novel 5-fluoro-N2,N4-diphenylpyrimidine-2,4-diamine derivatives were designed and synthesized. Initial tests against four tumor cell lines with the sulforhodamine B (SRB) assay identified a series of potent compounds with GI50 values at lower micromolar or submicromolar level. Most of the highly cytotoxic compounds exhibited potent inhibitory activities against both CDK2/cyclin E1 and CDK9/cyclin T1. Notably, inhibitions against the two enzymes were generally correlated well with the cytotoxicity of these compounds. Appreciable inhibition was also observed for selected compounds in the anti-HIV-1 assay. Docking studies on compounds 6d and 9g provided conducive clues to further structural optimization.