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

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

  • Medchemcomm. 2015 Mar 1;6(3):444-454. doi: 10.1039/C4MD00412D.
Jiadi Gao 1,  Cheng Fang 1,  Zhiyan Xiao 1,  Li Huang 2,  Chin-Ho Chen 2,  Li-Ting Wang 3,  Kuo-Hsiung Lee 4
Affiliations

Affiliations

  • 1 Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 2 Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
  • 3 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599-7568, USA.
  • 4 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599-7568, USA ; Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan.
PMID: 25914804 DOI: 10.1039/C4MD00412D
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 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.

Keywords

5-fluoro-N2; N4-diphenylpyrimidine-2, 4-diamines; anti-HIV-1; cyclin-dependent kinases; cytotoxicity; pharmacophore.

Figures