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

• A new series of pyrimidine-5-carbonitriles have been designed and synthesized. • Potent VEGFR-2 inhibitory activity correlated cytotoxicity of compound 5a. • Compounds 5a and 6c showed significant cytotoxic activity against HepG2 cells • Compounds 5a and 6c arrested the cell cycle at G2/M phase and induced apoptosis by increasing pre-G1 phase • The pro-apoptotic activity for compounds 5a and 6c were due to up-regulation of p53, Bax and downregulation of Bcl2. 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 hepatocellular carcinoma (HepG2) cell line. Results revealed that, N -(2-chlorophenyl) acetamide pyrimidine derivative 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 IC 50 value 0.067 and 0.44 µM. 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 C aspase 3/7 level 1.21- fold higher than SOR as elicited by green flow cytometry analysis. [ABSTRACT FROM AUTHOR]