摘要/Abstract
设计、合成了一系列含吡啶基的新型3-硫醚-4-吲哚亚氨基-4H-1,2,4-三唑衍生物17a~17r. 采用噻唑蓝(MTT)法对目标化合物在人类四种癌细胞A549、PC-3、HepG2、K562和大鼠正常肾细胞NRK-52E进行抗增殖活性评价. 结果显示部分化合物表现出一定的抗增殖活性, 其中乙基(E)-2-((4-(((2-氯-1-乙基-1H-吲哚-3-基)亚甲基)氨基)-5-(吡啶-4-基)-4H-1,2,4-三唑-3-基)硫代)乙酸酯(17k)对PC-3表现出较好的抗增殖活性, IC50值为9.90 μmol/L, 且对NRK-52E的细胞增殖毒性低于对照药5-氟尿嘧啶. 同时, 采用细胞迁移试验、4,6-二脒基-2-苯基吲哚(DAPI)染色、线粒体膜电位分析以及细胞凋亡、周期分析, 进一步研究了化合物 17k的作用机制, 证明化合物17k能够有效抑制肿瘤细胞的迁移, 诱发细胞凋亡, 还可以浓度依赖性方式将人前列腺癌细胞PC-3的细胞周期阻滞在G2期. 此外, 还探究了目标化合物对水稻白叶枯病菌(Xanthomonas oryzae pv. Oryzae, Xoo)的抑制活性, 初步抗菌活性结果显示: 化合物17b、17e和17h在50和100 μg/mL时, 对水稻白叶枯病菌表现出一定的抑制活性, 优于对照药叶枯唑(BMT)和噻菌铜(TDC).
关键词: 1,2,4-三唑, 吲哚, 抗肿瘤活性, 杀菌活性
A series of novel 3-thioether-4-indolimino-4H-1,2,4-triazole derivatives bearing pyridyl moiety (17a~17r) have been designed, synthesized and evaluated for antiproliferative activities against four human cancer cells A549, PC-3, HepG2 and K562, and normal rat kidney cells NRK-52E using methyl thiazolyl tetrazolium (MTT) assay. The results showed that some compounds exhibited moderate antiproliferative activities against four cancer cells. Among these derivatives, ethyl (E)-2-((4-(((2-chloro-1-ethyl-1H-indol-3-yl)methylene)amino)-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)thio)acetate (17k) showed the most potent antiproliferative activity against PC-3 cells with IC50value of 9.90 μmol/L, and the toxicities of compound 17k to NRK-52E cells were significantly lower than the positive control 5-fluorouracil. Meanwhile, the cell migration assay, 4,6-diamidino-2-phenylindole (DAPI) staining, mitochondrial membrane potential analysis, cell apoptosis and cell cycle analysis were carried out to further studied the mechanism of compound 17k, which demonstrated that compound 17k can effectively inhibit tumor cell migration and significantly induce cell apoptosis, arrest PC-3 cells in the G2 stage in a dose-dependent manner. In addition, the antibacterial tests of target compounds against Xanthomonas oryzae pv. oryzae (Xoo) were also explored. The preliminary antibacterial activity results showed that compounds 17b, 17e and 17h displayed a noteworthy inhibition rate against Xoo compared to standard drugs bismerthiazol (BMT) and thiodiazole copper (TDC) at 50 and 100 μg/mL.
Key words: 1,2,4-triazole, indole, antiproliferative activity, bactericidal activity
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