Design, Synthesis And Antitumor Activity Of6-azaindole/Indazole Derivatives As Cell Cycle Related Kinase Inhibitors

Tumorigenesis is a multistep process. As promising therapeutic targets, key regulators of cell growth and proliferation play an important role in anticancer drug development. Based on the core function of cyclin dependent kinases1(CDK1) in cell cycle regulation together with its irreplaceability by other CDKs and its selective inhibition activity targeting tumor-cells, inhibiting the over-expressed CDK1in tumors can be a rather effective therapeutic strategy that has significant advantages in improving selectivity and reducing drug toxicity.Based on our previous studies and the structural features of CDK1small-molecule inhibitors that have recently been progressed into (pre-)clinical trails, purine derivatives R-roscovitine and SCH727965were selected as leading compounds to construct a series of novel purine analogues guided by binding modes of reported CDK1, basic principles of drug design, together with the utilization of CADD method. Through further design by changing the substituent of its6position that targeting ATP ribose-binding pocket and modifying the2position subsituent that inserted into the hydrophobic region,13novel6-azaindole derivatives (series YJY-A) were synthesized. All compounds were tested for their in vitro cytotoxic activities against four human tumor cell lines, the result of which revealed that most compounds showed excellent activities against all test cell lines (IC50from0.00024to3.95μM). Furthermore, in vitro biological tests against CDK1/CyclinB showed that the majority also bear potent inhibitory activity at a concentration of10μM (inhibition rate95.8%～100%. Thus, these compounds might be potent leads for developing CDK1inhibitors in anticancer research. It also provides a reliable experimental and theoretical basis for further research of potent anticancer drugs.Besides, antitumor drugs are now developing from the traditional non-selective single cytotoxicity agents towards either new effective ones with multi-anticancer targets or combination application with several selective ones. Considering the extremely significant role that cdc7plays in cell cycle regulation through a synergistic effect with CDKs by finally firing the replication origins, together with its selective inhibition targeting tumor-cells, pharmacophore combination, rational drug design principle and CADD strategy were utilized to design and synthesize22novel amino heterocyclic CDK1/Cdc7dual-target inhibitors (series YJY-B and YJY-C). Unfortunately, apart from some amino-pyrazole derivatives that showed moderate activity, the potency of other compounds were not obvious. Further optimization and biological evaluation for these compounds are currently under investigation.