Synthesis, biological evaluation and molecular docking studies of pyrazole derivatives coupling with a thiourea moiety as novel CDKs inhibitors

• DOI: 10.1016/j.ejmech.2013.07.003
• Publication Date: 2013-07-18T22:37:18Z
• Authors: Jian Sun; Xian-Hai Lv; Han-Yue Qiu; Yan-Ting Wang; Qian-Ru Du; Dong-Dong Li; Yong-Hua Yang; Hai-Liang Zhu
• Keywords: 0301 basic medicine; 0303 health sciences; Molecular Structure; Thiourea; Antineoplastic Agents; Cyclin-Dependent Kinases; 3. Good health; Enzyme Activation; Molecular Docking Simulation; Inhibitory Concentration 50; 03 medical and health sciences; Cell Line, Tumor; Humans; Pyrazoles; Protein Kinase Inhibitors; Cell Proliferation

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 μM to 4.21 μM), In addition, flow cytometry indicated that compound 10b could induce cycle G0/G1 phase arrest in A549 cells with a dose dependent. Taken together, compound 10b could be selected for further preclinical evaluation.