Design, synthesis, and biological evaluation of 2,6,7-substituted pyrrolo[2,3-d]pyrimidines as cyclin dependent kinase inhibitor in pancreatic cancer cells

Abstract

Pancreatic cancer is a highly malignant tumor, and more effective treatment is urgently needed to lengthen the life of patients. In this paper a class of new 2,6,7-substituted pyrrolo[2,3-d]pyrimidine derivatives of CDK 4/6 inhibitor ribociclib (1) was designed and synthesized to investigate their effect on the proliferation of pancreatic cancer cells. The structure–activity relationship (SAR) of synthetic compounds was analyzed based on both their in vitro anti-proliferative activity and the CDK4 inhibitory activity. A series of 6-anilinocarbonyl-substituted pyrrolo[2,3-d]pyrimidine derivatives (25, 41–48) showed the significantly increased potency against two proliferating cancer cell lines (MIA PaCa-2 and BxPC-3) in MTT assay though their CDK4 inhibitory activity were lower in a varying range compared to 1. The most potent compound 41 was identified as a highly selective and potent CDK 4/6 inhibitor in the human kinases profiling assay, it also exhibited the favorable in vitro pharmacokinetic properties for further in vivo evaluation. Meanwhile, 41 exhibited the potential as a combination partner with mTOR inhibitor to treat pancreatic cancer. Alternatively, introducing of sulfonamide fragment into C2-substituent of pyrrolo[2,3-d]pyrimidine provided the clue for future optimization to afford new CDK9 inhibitors.