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

• Published in: Journal of molecular structure 2022-07, Vol.1259, p.132749, Article 132749
• Main Authors: Zaki, Islam, Masoud, Reham E., Hamoud, Mohamed M.S., Ali, Ola A. Abu, Abualnaja, Matokah, Fayad, Eman, Almaaty, Ali H. Abu, Elnaghia, Lamis K.
• Format: Article
• Language: English
• Subjects: Anticancer; Bax; Bcl2; Cell cycle analysis; p53, Caspase 3/7; Pyrimidine; VEGFR-2
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2022.132749

•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 IC50 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 Caspase 3/7 level 1.21- fold higher than SOR as elicited by green flow cytometry analysis.