Design, Synthesis And SAR Study Of Nitrogen-contained Chalcone Derivatives As CDK1 Inhibitors

Cancer remains a worldwide concern for human health.Since most clinical drugs exhibit considerable toxicity and inefficacy,it is of vital importance to develop novel anticancer drug with improved potency and reduced toxicity.Cyclin-dependent kinasel (CDK1) is a major target of anticancer drugs.With a number of structurally diverse CDK1 small molecular inhibitors entering clinical studies in recent years,great interest has been attached to the research and development of CDK1 small-molecule inhibitors for cancer therapy.Based on the literatures,pharmacophore model of CDK1 inhibitors was built and 3D structure of homology models of CDK1 was constructed.The establishment of pharmacophore and 3D structure of CDK1 provides important information on the interaction patterns between ligands and receptors,thus being useful for further design and compound evaluation.Guided by previous work of our group and taking nitrogen-containing chalcone as the lead compound,three new nitrogen-containing chalcone derivatives were designed based on the principles of analog:(1) D-series of chalcones were designed through changing the length of side chain;(2) U-series of methyl chalcones,and L-series of pyrazole compounds were obtained by modifying the chalcone skeleton.A virtual compound library was constructed and compounds were selected based on virtual screening using the pharmacophore model and CDK1-based molecular docking.29 new chalcone derivatives were synthesized.In vitro antitumor activity of 29 new compounds showed that most chalcone derivatives have potent antitumor activity against all tested cell lines,so did pyrazole compounds(except for MCF-7 cell line),while methyl chalcones exhibit relatively weak inhibitory activity.24 compounds were chosen for further in vitro biological tests against CDK1/CyclinB.It showed that most pyrazole compounds bear potent inhibitory activity at the concentration of 10μM(inhibition rate＞50%).Potent CDK1/CyclinB inhibitory activity were observed for half of the D-series of chalcone derivatives,while methyl chalcones have modest activity.Based on the experimental results of CDK1 inhibitory activity and in vitro antitumor activity,it was revealed that of the three types of compounds,part of D-series of chalcones and L-series of pyrazole compounds have potent CDK1 inhibitory activity and in vitro antitumor activity,thus might be potent leads for developing CDK1 inhibitors for anticancer research.The above research provides a reliable experimental and theoretical basis for further design and research of potent anticancer drugs.