Synthesis and Antiproliferative Activity of 2,4,5,6-Tetrasubstituted Pyrimidine Derivatives Containing Anisole

In order to find efficient new anti-tumor drugs, a series of 2,4,5,6-tetrasubstituted pyrimidine derivatives containing anisole structure were designed, synthesized and evaluated for antiproliferative activity against four human cancer cell lines of PC-3, MGC-803, MCF-7 and HGC-27 using methyl thiazolyl tetrazolium (MTT) assay. Most of compounds displayed moderate to excellent antiproliferative activity against the four human tumor cell lines, among which the compound 5-ethyl-6((4-methoxyphenyl)thio)-N-4-(3,4,5-trimethoxyphenyl)pyrimidine-2,4-diamine (14t) showed the best antiproliferative activity on HGC-27 cells, with IC50 value of (0.98 +/- 0.12) mu mol.L-1, the antiproliferative activity is significantly better than that of the positive control 5-fluorouracil. Further research on anti-tumor mechanism showed that compound 14t could significantly inhibit the colony formation and migration of HGC-27 cells and induce apoptosis. At the same time, compound 14t can down-regulate the expression of anti-apoptotic protein Bcl-2 and up-regulate the expression of pro-apoptotic proteins Bax and P53.