Synthesis and in vitro antitumor activity evaluation of novel 5-cyano-6-phenyl-2,4-disubstituted-pyrimidine derivatives

In order to search for new antitumor drugs with high efficiency, a series of novel 5-cyano-6-phenyl-2,4-disubstituted pyrimidine derivatives were designed, synthesized, and evaluated for antiproliferative activity against four human cancer cell lines (MGC-803, PC-3, A549, and H1975) using MTT assay in vitro. Among them, compound N-(3-chloro-4-fluorophenyl)-2-((5-cyano-4-phenyl-6-(pyrimidin-2-ylthio)pyrimidin-2-yl)thio)acetamide ( 15n ) showed good anti-tumor proliferation activity against four tested cancer cell lines, with IC 50 values of 1.86 ± 0.27 μM to PC-3 cell. The antitumor activity was significantly better than that of the positive control 5-Fluorouracil. Further mechanism studies showed that compound ( 15n ) inhibited the clonal formation and migration of PC-3 cells in a concentration dependent manner, and induced PC-3 cell cycle arrest in G0/G1 phase, thereby inhibiting the proliferation of PC-3 cells. At the same time, compound ( 15n ) induced PC-3 cell apoptosis in a concentration dependent and time-dependent manner. When the concentration of compound ( 15n ) is 4 μM, the proportion of apoptotic cells was 66.13%. And compound ( 15n ) promoted the accumulation of reactive oxygen species in PC-3 cells in a concentration-dependent manner. Graphical abstract