1-取代-6-甲氧基-1,2,3,4-四氢喹喔啉类衍生物的设计合成及抗肿瘤活性研究

Design,synthesis and antitumor activities of 1-substituted-6-methoxy-1,2,3,4-tetrahydroquinoxaline derivatives

目的设计合成1-取代-6-甲氧基-1,2,3,4-四氢喹喔啉类衍生物,并进行体外抗肿瘤活性及细胞周期阻滞测试。方法以4-氨基-3-硝基苯酚为原料,经羟基甲基化、氨基苄基保护以及成环反应得到Boc保护的6-甲氧基喹喔啉中间体8,该中间体通过光气偶联反应、脱Boc保护得到目标化合物10a~10i。采用MTT法测试目标化合物对HeLa(宫颈癌细胞)、HT-29(结肠癌细胞)的体外抗增殖活性,采用流式细胞术测试目标化合物10h对HeLa细胞的生长周期阻滞作用。结果与结论设计、合成了9个未见文献报道的目标化合物,其结构均经^(1)H-NMR、^(13)C-NMR、HR-MS谱确证。目标化合物均表现出显著的肿瘤细胞生长抑制活性,其中化合物10h对肿瘤细胞的IC_(50)值达到微摩尔级,优于阳性对照药物阿霉素,同时10h能够使HeLa细胞的生长阻滞在G2/M期,具有进一步开发为新型抗肿瘤药物的潜力。

Quinoxaline represents as an important framework in the development of anticancer agents,which was reported possessing various biological activities such as antidiabetic,anti-HIV and NMDA receptor antagonists.Based on our previous study on the antitumor activities of quinoxaline derivatives,nine novel 1-substituted-6-methoxy-1,2,3,4-tetrahydroquinoxaline derivatives were designed and synthesized in this study,and their antitumor activities were evaluated.The chemical structures of the desired compounds were confirmed by^(1)H-,^(13)C-NMR and HR-MS(ESI)spectra.The in vitro antitumor activities were investigated on human cervical cancer cell(HeLa)and human colon cancer cell(HT-29)through MTT assay.The preliminary results revealed that,in general,all the target compounds showed significant capability in cell growth inhibition against the test cancer cell lines.Among them,compound 10 h exhibited the greatest antitumor activity with the IC50 values of 0.22μmol·L^(-1)(against HeLa cells)and 0.32μmol·L^(-1)(against HT-29 cells),respectively.In addition,10 h could markedly induce the HeLa cells arrested in G2/M(67.6%)under the concentration of 0.40μmol·L^(-1).These results clearly demonstrated that 10 h could act as the lead compound for further evaluation in antitumor activity.