目的 合成吲哚-1,3,4-噁二唑类衍生物,并进行体外抗肿瘤活性研究。方法 以吲哚-3-甲酰肼为起始原料,通过[4+1]环加成反应、水解反应、缩合反应得到目标化合物。采用MTT法测试目标化合物对HeLa、SCG-7901和MDA-MB-231细胞的体外抗肿瘤活性。采用克隆形成实验考察化合物6f对SCG-7901细胞增殖的影响。采用Annexin V-APC/PI双染法检测化合物6f对SCG-7901细胞凋亡和坏死的影响。采用DAPI染色法检测化合物6f对SCG-7901细胞凋亡核染色质形态学的影响。采用DCFH-DA染色法检测化合物6f对SCG-7901细胞中活性氧含量的影响。结果 合成了15个吲哚-1,3,4-噁二唑类衍生物,其结构经¹H-NMR、¹³C-NMR和HR-ESI-MS确证。部分化合物表现出良好的抗肿瘤活性,其中化合物6f对HeLa、SCG-7901和MDA-MB-231 3种肿瘤细胞株均表现出明显的抗增殖作用,且具有一定的选择性。进一步研究表明,化合物6f以浓度相关的方式促进细胞产生活性氧,抑制细胞增殖,诱导细胞凋亡。结论 部分吲哚-1,3,4-噁二唑类衍生物表现出良好的抗肿瘤活性,为该类化合物的进一步抗肿瘤活性研究提供思路。

Objective To synthesize indole-1,3,4-oxadiazole derivatives and investigate antitumor activities in vitro. Methods Taking 1H-indole-3-carbohydrazide as the starting material, the target compounds were obtained through[4+1] cycloaddition reaction, hydrolysis reaction and condensation reaction. Antitumor activity in vitro of target compounds against HeLa, SCG-7901, and MDA-MB-231 cells were evaluated by MTT assay. The effect of compound 6f against the growth of SCG-7901 cells was assessed by colony formation assay, the effect of it on apoptosis and necrosis in SCG-7901 cells was detected using Annexin V-APC/PI double staining method, the effect of it on nuclear chromatin morphological changes of SCG-7901 cells were examined using DAPI staining method, and the effect of it on contents of reactive oxygen species (ROS) in SCG-7901 cells was detected using DCFH-DA staining method. Results Fifteen indole-1,3,4-oxadiazole derivatives were synthesized and their structures were characterized by ¹H-NMR, ¹³C-NMR, and HR-ESI-MS. Some compounds exhibited significant antitumor activity, among which compound 6f exhibited significant anti-proliferative effects against all three tumor cell lines and had certain selectivity. Further research has shown that compound 6f promoted cell production of ROS generation, inhibited cell proliferation, and induced cell apoptosis in a concentration dependent manner. Conclusion Some indole-1,3,4-oxadiazole derivatives have shown good antitumor activity, providing ideas for further research on the anti-tumor activity of these compounds.

R914;R962

国家重大新药创制科技重大专项（2019ZX09735002）；中国医学科学院医学与健康科技创新工程项目（2022-I2M-1-017）