Synthesis and Antitumor Activity Evaluation in Vitro of Novel 5-cyano-6-phenyl-2,4-Disubstituted Pyrimidine Derivatives

Abstract In order to search for new antitumor drugs with high efficiency, a series of novel 5-cyano-6phenyl-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-4phenyl-6-(pyrimidin-2-ylthio) pyrimidin-2-yl) thio) acetamide (15n) showed good anti-tumor proliferation activity against four tested cancer cell lines, with IC50 values of 1.86±0.27μM 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.