Design, Synthesis, and Evaluation of Antitumor Activity of Novel Pyrimidine Derivatives Containing Acrylamide and a Cyano Group

Abstract

Objective: Based on the observed in vitro antitumor activity, the conformational influence of various substituents at the 2-position of the pyrimidine ring was systematically investigated to develop more effective antitumor pyrimidine analogs. Methods: A series of novel pyrimidine derivatives containing acrylamide and cyano groups were designed and synthesized. Their antiproliferative activities against four human tumor cell lines (MDA-MB-231, MGC-803, PC-3, and A549) were evaluated using the MTT assay. Additionally, colony formation, migration, cell cycle distribution, and apoptosis assays were performed to elucidate the antitumor mechanisms of compound (XVIIIg). Results and Discussion: Compound (XVIIIg) exhibited the strongest inhibitory activity against PC-3 cells, with an IC₅₀ value of 1.50 ± 0.29 μM. Cellular assays confirmed that (XVIIIg) significantly suppressed PC-3 cell proliferation and migration, induced G₀/G₁ cell cycle arrest, and promoted apoptosis. Structural modifications at the 2-position of the pyrimidine ring had a pronounced effect on in vitro antitumor activity. The 4-fluorophenyl (4-F-C₆H₄) substituent in compound (XVIIIg) contributed to its superior inhibitory effect, suggesting its potential as a lead compound. Conclusions: Among the 21 synthesized compounds, (XVIIIg) demonstrated the most potent antiproliferative and antimigratory activity, along with dose-dependent apoptosis induction in PC-3 cells. These results highlight its promise as a candidate for further development of novel antitumor agents.