Design, Synthesis And Biological Evaluation Of Ammo-pyrimidine/4-cyano-6-azaindole Derivatives

Nowadays, cancer has surpassed the cardiovascular diseases in motality. The traditional anti-cancer agents applied clinically suffer from shortcomings, including poor efficacy, high toxicity and advance of multidrug resistance. Thereby, the exploration of novel anti-cancer drugs that conquer these limitations has emerged to be a focus in the field of drug research and development. CDKs (cyclin dependent kinases) play a vital role in regulating the cell cycle. Inhibition of the overexpressed CDKs of tumor cells to block tumor cell proliferation effectively has become a potential cancer therapy.According to literature survey, clinical candidate PHA848125 was choosed as a lead compound. We retained amino-pyrimidine structure which formed two hydrogen bonds with the hinge region Leu83 amino acid. Based on bioisosterism, triazole ring and imidazole ring were used to replace pyrazole ring of lead compound respectively. The introduction of different substituents on imidazole ring formed interactions with the hydrophobic pocket. Two series bearing 33 compounds were designed, synthesized and confirmed by 1H NMR and MS. After testing them for CDK2/Cyclin A inhibitory activities,5 compounds (A-5* A-11、B-12、B-15、B-19) displayed potent inhibitory activities with IC50 range from 0.22 uM to 1.42μM. Furthermore, the 5 compounds were tested for their in vitro cytotoxic activities. Compound A-11 displayed moderate activities against HL60 and A549 with IC50 of 21.05μM and 21.53 μM respectively.In addition, our previous efforts to discover novel CDK inhibitors led to the identification of a series of 6-azaindole deviratives with poor structural sbabilities. To address this issue,8 compounds containing 4-cyano-6-azaindole skeletion were designed, synthesized and comfirmed by 1H NMR and MS. CDK2/Cyclin A inhibitory assay revealed that these compounds demonstrated weak activities at lμg/mL. Further in vitro cytotoxic evaluation against human colcnic carcinoma cell line (HCT116) showed that compound C-4 and C-7 displayed potent activities with IC50 of 2.7μM and 4.0μM respectively.