目的 合成吲哚-1,3,4-噁二唑類衍生物,并進(jìn)行體外抗腫瘤活性研究。方法 以吲哚-3-甲酰肼為起始原料,通過(guò)[4+1]環(huán)加成反應(yīng)、水解反應(yīng)、縮合反應(yīng)得到目標(biāo)化合物。采用MTT法測(cè)試目標(biāo)化合物對(duì)HeLa、SCG-7901和MDA-MB-231細(xì)胞的體外抗腫瘤活性。采用克隆形成實(shí)驗(yàn)考察化合物6f對(duì)SCG-7901細(xì)胞增殖的影響。采用Annexin V-APC/PI雙染法檢測(cè)化合物6f對(duì)SCG-7901細(xì)胞凋亡和壞死的影響。采用DAPI染色法檢測(cè)化合物6f對(duì)SCG-7901細(xì)胞凋亡核染色質(zhì)形態(tài)學(xué)的影響。采用DCFH-DA染色法檢測(cè)化合物6f對(duì)SCG-7901細(xì)胞中活性氧含量的影響。結(jié)果 合成了15個(gè)吲哚-1,3,4-噁二唑類衍生物,其結(jié)構(gòu)經(jīng)¹H-NMR、¹³C-NMR和HR-ESI-MS確證。部分化合物表現(xiàn)出良好的抗腫瘤活性,其中化合物6f對(duì)HeLa、SCG-7901和MDA-MB-231 3種腫瘤細(xì)胞株均表現(xiàn)出明顯的抗增殖作用,且具有一定的選擇性。進(jìn)一步研究表明,化合物6f以濃度相關(guān)的方式促進(jìn)細(xì)胞產(chǎn)生活性氧,抑制細(xì)胞增殖,誘導(dǎo)細(xì)胞凋亡。結(jié)論 部分吲哚-1,3,4-噁二唑類衍生物表現(xiàn)出良好的抗腫瘤活性,為該類化合物的進(jìn)一步抗腫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

國(guó)家重大新藥創(chuàng)制科技重大專項(xiàng)（2019ZX09735002）；中國(guó)醫(yī)學(xué)科學(xué)院醫(yī)學(xué)與健康科技創(chuàng)新工程項(xiàng)目（2022-I2M-1-017）