Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 68, Issue -, Pages 1-9Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2013.07.003
Keywords
Cyclin-dependent kinases; CDK2; Cell cycle profile; Structure-activity relationship; Molecular docking
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Funding
- Science & Technology Agency of Jiangsu Province [BY2012136]
- Science & Technology Bureau of Lianyuangang City of Jiangsu Province [CXY1213, CXY1222]
- PCSIRT [IRT1020]
- Universities Natural Science research project of Anhui Province [KJ2013B088]
- opening foundation of the Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, China [2011GDGP0105]
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It was discovered that a number of cyclin dependent kinase inhibitors containing the pyrazole core structure exhibited high inhibitory potency against broad-range CDKs and corresponding anti-proliferative activities. This information guided us to design and synthesize a series of 1,3-diphenyl-N-(phenylcarbamothioyl)-1H-pyrazole-4-carboxamide derivatives (5a-10d), and evaluate their biological activities as CDKs inhibitors. Among all the synthesized compounds, compound 10b inhibited CDK2 with an IC50 value of 25 nM, counteracting tumor cell proliferation of three cancer cell lines (H460, MCF-7, A549) in the micromolar range (from 0.75 mu M to 4.21 mu M), In addition, flow cytometry indicated that compound 10b could induce cycle G(0)/G(1) phase arrest in A549 cells with a dose dependent. Taken together, compound 10b could be selected for further preclinical evaluation. (C) 2013 Elsevier Masson SAS. All rights reserved.
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