Design, synthesis and cytotoxicity screening of new synthesized pyrimidine-5-carbonitrile derivatives showing marked apoptotic effect

A new series of pyrimidine-5-carbonitriles has been designed and synthesized as potent anticancer agents. Pyrimidine-5-carbonitriles 2-6d have been assessed for their cytotoxic activity against hepatocel-lular carcinoma (HepG2) cell line. Results revealed that, N-(2-chlorophenyl) acetamide pyrimidine deriva-tive 5a and pyrimidine acetamide phenylpropanoic acid 6c revealed good cytotoxic activity against HepG2 cells compared with Sorafenib as a reference standard. Compounds 5a and 6c showed potent inhibition of VEGFR-2 with IC50 value 0.067 and 0.44 mu M. Active compounds 5a and 6c elicited pre G1 apoptosis and cell cycle disturbance at G1 phase in a manner similar to Sorafenib. Furthermore, qRT-PCR assay revealed that, 5a and 6c were found to induce apoptosis via elevation of p53, Bax and downregulation of Bcl2. Finally, compounds 5a and 6c were found to upregulate Caspase 3/7 level 1.21-fold higher than SOR as elicited by green flow cytometry analysis. (c) 2022 Elsevier B.V. All rights reserved.

Automated summary

A new series of pyrimidine-5-carbonitriles have been synthesized and evaluated for their cytotoxic activity against HepG2 cells. Compounds 5a and 6c showed good cytotoxic activity and potent inhibition of VEGFR-2. They also induced apoptosis and cell cycle disturbance through modulation of relevant proteins. These findings suggest that these compounds have potential as anticancer agents against hepatocellular carcinoma.