Synthesis, Biological Evaluation And Molecular Docking Studies Of Pyrazole Derivatives Coupling With A Thiourea Moiety As Novel CDKs Inhibitors

Cell cycle is an important part of cell life activities, the disorder of cell cycle regulation is closely related to carcinogenesis. The study found that a variety of CDKs are in a state of disorder in many tumor tissues, probably due to the high expression of CDK, Cyclin gene or CDK inhibitors inactivation caused. Thus, selective inhibition of CDKs activity in tumor cells may be able to control its proliferation. In the foregoing studying, we have introduced the pyrazole derivatives having excellent anticancer activity. Besides, given the remarkable pharmacological activities (antibacterial, antifungal, tumor necrosis and antiangiogenic) of thiourea derivatives. We attempted to design a series of compounds which contains pyrazole and thiourea simultaneously, and presumably these compounds have good antitumor activity. Docking simulations were performed using the X-ray crystallographic structure of the CDK2 in complex with an inhibitor to explore the binding modes of these compounds at the active site.Twenty novel pyrazole derivatives were synthesized and characterized by 1H NMR,13C-NMR and elemental analysis (6a-10d). Besides, Compounds 7a were provided with single crystal X-ray structural analysis. Due to there is no detail activity reported about these 20 compounds, all those compounds then were tested on three tumor cell lines A549, H460 and MCF-7 in vitro and most of the compounds exhibited low toxicity and excellent antitumor activity. 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 in the micromolar range (0.75?M for A549 cell), 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.