Design And Synthesis Of A Kind Of New Cyclin Dependent Kinases 4 And 6 Inhibitors And Biological Activity Evaluation

Previous studies have shown that the CDK4/6-Rb-E2 F pathway is disrupted in 90% of cancers.Abnormal changes of this pathway speeded up the process of cell cycle G1 phase,which speeds up tumor cell proliferation to survive.Therefore,the study of a new type of CDK4/6 inhibitor has become an effective strategy for the treatment of cancer.Lilly molecular LY2835219(Abemaciclib)is a new type of CDK4/6 inhibitor,which has good activity to breast cancer,but the bad selectivity greatly limits the development and utilization.In the light of the weakness of compound LY2835219 selective sent four areas to decorate,can retain the form hydrogen bonding with Lys43 residues imidazole structure,can form hydrogen bonds with Val101 residues of pyrimidine structure,can form hydrogen bonds with His100 residues of pyridine structure,can be generated with Lys of CDK1/2/3/5 electronic repulsion of piperazine ring.First will of benzene and isopropyl on imidazole and methyl links up and modify build into different fat ring,at the same time of pyridine,pyridine and piperazine ring to replace the design of substituents 23 compounds were synthesized.A simple and reasonable synthetic route was designed by the reverse synthetic method,and the problems encountered in the chemical experiment were solved.Eighteen target compounds were synthesized after 7 steps.After 8 steps,2 target compounds were synthesized and 3 target compounds were synthesized after 9 steps.Most of the intermediates and target compounds have been the 1 h NMR and ESI-MS confirmed that the enzyme for the synthesis of the target compounds and the activity of cells,and Herg test and rat pharmacokinetic experiment.The results showed that the compound 10 d had not only good activity and pharmacokinetic data,but also the selectivity of CDK1 was nearly 50 times that of LY2835219.So compound 10 d is a promising candidate for clinical compounds.