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Issue 3, 2015
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Discovery of novel 5-fluoro-N2,N4-diphenylpyrimidine-2,4-diamines as potent inhibitors against CDK2 and CDK9

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Abstract

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.

Graphical abstract: Discovery of novel 5-fluoro-N2,N4-diphenylpyrimidine-2,4-diamines as potent inhibitors against CDK2 and CDK9

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Article information


Submitted
15 Sep 2014
Accepted
27 Nov 2014
First published
28 Nov 2014

Med. Chem. Commun., 2015,6, 444-454
Article type
Concise Article

Discovery of novel 5-fluoro-N2,N4-diphenylpyrimidine-2,4-diamines as potent inhibitors against CDK2 and CDK9

J. Gao, C. Fang, Z. Xiao, L. Huang, C. Chen, L. Wang and K. Lee, Med. Chem. Commun., 2015, 6, 444
DOI: 10.1039/C4MD00412D

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