含苯甲醚结构的2,4,5,6-四取代嘧啶衍生物的合成及抗增殖活性研究

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

为了寻找高效的新型抗肿瘤药物,设计并合成了一系列含苯甲醚结构的2,4,5,6-四取代嘧啶衍生物,并采用噻唑蓝(MTT)法测定了目标化合物对PC-3(人前列腺癌细胞)、MGC-803(人胃癌细胞)、MCF-7(人乳腺癌细胞)、HGC-27(人未分化胃癌细胞)四种人肿瘤细胞的抗增殖活性.结果显示部分化合物表现出中度至强效的抗增殖活性,其中5-乙基6-((4-甲氧基苯基)硫代)-N4-(3,4,5-三甲氧基苯基)嘧啶-2,4-二胺(14t)对HGC-27细胞具有最好的抗增殖活性,IC_(50)值为(0.98±0.12)μmol•L^(-1),抗增殖活性明显优于阳性对照5-氟尿嘧啶.进一步抗肿瘤机制研究表明,化合物14t可以显著抑制HGC-27细胞的克隆形成和迁移,诱导细胞凋亡.同时化合物14t可以下调抗凋亡蛋白Bcl-2的表达,上调促凋亡蛋白Bax和P53的表达.

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)-N4-(3,4,5-trimethoxyphenyl)pyrimidine-2,4-diamine(14t)showed the best antiproliferative activity on HGC-27 cells,with IC_(50) value of(0.98±0.12)μmol•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.