Journal
MEDCHEMCOMM
Volume 6, Issue 3, Pages 444-454Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c4md00412d
Keywords
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Funding
- National Natural Science Foundation of China [81172985, 81261120391]
- NIH from the National Cancer Institute [CA177584]
- National Institute of Allergy and Infectious Disease [AI 033066]
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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-N-2, N-4-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.
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