摘要/Abstract

为了寻找高效的新型抗肿瘤药物, 设计合成了一系列2,4,6-取代嘧啶衍生物, 并使用噻唑蓝(MTT)法对4种人的肿瘤细胞人结肠癌细胞(SW-620)、人前列腺癌细胞(PC-3)、人非小细胞肺癌细胞(A549)和人胃癌细胞(MGC-803)进行了体外抗肿瘤活性研究. 其中化合物 N-((4-乙基苯基)氨基甲酰基)-2-((4-(对甲苯基氨基)-6-(三氟甲基)嘧啶-2-基)硫代)乙酰胺(5i), 2-((4-((4-乙氧基苯基)氨基)-6-(三氟甲基)嘧啶-2-基)硫基)- N-((4-乙基苯基)氨基甲酰基)乙酰胺(5o)和 N-((4-乙基苯基)氨基甲酰基)-2-((4-((4-甲氧基苯基)氨基)-6-(三氟甲基)嘧啶-2-基)硫代)乙酰胺(5r)对4种测试的癌细胞系显示出高的抗肿瘤增殖活性, 特别是化合物5r具有最高的抑制活性, 对SW-620的IC₅₀值最低, 为1.46 μmol/L. 进一步机制研究表明, 化合物5r诱导SW-620凋亡, 使细胞周期阻滞在S期. 分子对接揭示了化合物5r可以很好地结合表皮生长因子受体(EGFR)的活性位点, 被认为是一种有前途的化合物, 可用于进一步研究开发新的抗癌药物.
关键词: 嘧啶衍生物, 合成, 抗肿瘤活性, 细胞周期, 凋亡
With the expectation to find out novel and effective anti-tumor agents, a series of novel 2,4,6-substituted pyrimidine derivatives were synthesized and evaluated for their anti-tumor activity against four human cancer cells [SW-620 (human colon cancer cells), PC-3 (human prostate cancer cells), A549 (Human non-small cell lung cancer cells), MGC-803 (human gastric cancer cells)] using methyl thiazolyl tetrazolium (MTT) assay. Among tested compounds, N-((4-ethylphenyl)- carbamoyl)-2-((4-( p-tolylamino)-6-(trifluoromethyl)pyrimidin-2-yl)thio)acetamide (5i), 2-((4-((4-ethoxyphenyl)amino)-6-(tri- fluoromethyl)pyrimidin-2-yl)thio)- N-((4-ethylphenyl)carbamoyl)acetamide (5o) and N-((4-ethylphenyl)carbamoyl)-2-((4-((4- methoxyphenyl)amino)-6-(trifluoromethyl)pyrimidin-2-yl)thio)acetamide (5r) displayed strong antiproliferative activity on 4 tested cancer cell lines. In particular, compound5r has the highest inhibitive activity, and possessed the lowest IC₅₀ value of 1.46 μmol/L towards SW-620 cells. Further mechanism research shows that compound5rinduces SW-620 apoptosis, arrests cell cycle at S phase. Molecular docking reveals that5r can bind well to the active site of epidermal growth factor receptor (EG-FR), and may be considered as a promising compound amenable for further investigation for the development of new anticancer agents.
Key words: pyrimidine derivative, synthesis, antitumor activity, cell cycle, apoptosis


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