Discovery of novel 5-fluoro-N2,N4-diphenylpyrimidine-2,4-diamines as potent inhibitors against CDK2 and CDK9
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 a 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.
Jiadi Gao Cheng Fang Zhiyan Xiao Li Huang Chin-Ho Chen Li-Ting Wang Kuo-Hsiung Lee
Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation,Institute of Materi Department of Surgery,Duke University Medical Center,Durham,NC 27710,USA Natural Products Research Laboratories,UNC Eshelman School of Pharmacy,University of North Carolina, Natural Products Research Laboratories,UNC Eshelman School of Pharmacy,University of North Carolina,
国内会议
大连
英文
339-349
2016-09-24（万方平台首次上网日期，不代表论文的发表时间）