Design, Synthesis And Anti-tumor Activity Of Novel CDK2Inhibitors

Cancer is a multifactorial disease and cause significant mortalicy in the world. Cyclin dependent kinases are the key targets for antitumor drug discovery, many candidate compounds have enter the clinical trials. Among the members of CDKs family, CDK2plays an important role in cell cycle regulation, and over-expressed in many cancer cell lines. Consequently, the inhibition of CDK2by small molecule inhibitors can be a promising strategy in cancer therapty.According to the co-crystal of R-roscovitine and CDK2, the nitrogen atom at position-3of purine scaffold has interaction with the binding site of CDK2kinase, so according to the principle of drug design, the N atom of position-3can be replaced by C atom and NO2group was introduced to keep the similar electronic character with the purine scaffold. What’s more, the NO2group was also reduced to NH2to investigate the influence of different substituent on activity. Meanwhile, the further modification were made by changing the substituent at position-2,6,9of the lead compound. Twenty-two target compounds including two structure types were prepared. And the anti-proliferative evaluation result indicated that most compounds with NO2group exhibit comparable to more potent activity than lead compound. And the compounds with NH2group showed less potent activity than lead compound. The compounds with NO2group were selected to test the CDK2inhibitory activity; the results indicated that some compounds exhibited more potent activity than lead compound with the IC50value of nanomolar. Thus, these compounds might be potent leads for developing CDK2 inhibitors.In our previous study we discover a series of6-azaindole derivatives with moderate CDKs inhibitory activity, while these compounds exhibited potent activity against multiple cancer cell lines with the IC50value of nanomolar, base on the structure similarity between6-azaindazole and purine, we designed and prepared fourteen6-azaindazole derivatives. The anti-proliferative activity evaluation result show that most compounds exhibit comparable anti-proliferative activity to lead compound but the CDK2inhibitory activity were weaker than lead compound.In order to increase the structure dicersity and discover CDK2inhbitors with novel scaffold, we design and synthesis seventeen7-azadioxoindoline derivatives. But the anti-proliferative activity result showed that almost all compounds are without activity. Designing CDK2inhibitors with novel scaffold still need to be explored.