新型磺胺三氮唑衍生物的设计、合成及抗肿瘤活性评价

发布时间：2018-02-19 22:26

本文关键词： 磺胺 1 2 3-三氮唑合成抗肿瘤 IC_(50) 构效关系　出处：《郑州大学》2017年硕士论文　论文类型：学位论文

【摘要】：磺胺类化合物是一类结构相对简单,生物活性比较广泛,且安全性相对较高的小分子化合物。磺胺类化合物已被报道出具有抗炎、抗病毒、抗肿瘤等活性,并被广泛应用于医药行业。近年来随着点击化学在抗肿瘤研究领域中的应用,1,2,3-三氮唑活性片段常被作为Linker基团连接于其他活性片段中,并快速合成大量新颖的具有抗肿瘤活性的化合物。基于以上研究,为寻求高效、低毒的抗肿瘤化合物,本文将磺胺结构作为母核与1,2,3-三氮唑拼接,在1,2,3-三氮唑的C-4位引入抗肿瘤活性基团,设计、合成了六个系列的磺胺类衍生物,并对其抗肿瘤活性进行了测试及构效关系分析。具体研究工作如下:通过重氮化反应、亲核取代、点击化学等有机反应,合成磺胺-1,2,3-三氮唑-氨基二硫代甲酸酯、磺胺-1,2,3-三氮唑-磺胺、磺胺-1,2,3-三氮唑-硫代杂环、磺胺-1,2,3-三氮唑-芳酰胺、磺胺-1,2,3-三氮唑-苯并氮杂环、磺胺-1,2,3-三氮唑-香豆素六个系列46个衍生物,并经过1H NMR、13C NMR、质谱等进行了结构确认,且均为未被报道的新的化合物。选用胃癌细胞株MGC-803、食管癌细胞株EC-109、前列腺癌细胞株PC-3三种细胞株对目标化合物进行了体外抗肿瘤活性的评价及构效关系分析,并对构效关系进行总结。结果表明,大部分化合物对一种或多种癌细胞株表现出良好的抗肿瘤活性,磺胺-1,2,3-三氮唑-氨基二硫代甲酸酯衍生物对PC-3细胞株具有选择抑制作用,磺胺-1,2,3-三氮唑-磺胺、磺胺-1,2,3-硫代杂环、磺胺-1,2,3-三氮唑-香豆素列则对MGC-803细胞株表现出明显的抑制作用,磺胺-1,2,3-三氮唑-芳酰化合物、磺胺-1,2,3-三氮唑-苯并氮杂环衍生物表现为广谱抗肿瘤活性。其中化合物1G对PC-3细胞株的活性测试值IC50为2.35μM,2C、3G、6C对MGC-803细胞株的活性测试值IC50分别达0.696μM、0.866μM、0.710μM。综上研究工作,共合成磺胺-1,2,3-三氮唑衍生物46个,合成方法简单,化合物新颖。体外抗肿瘤活性最好的化合物2C、3G、6C值得进一步研究,并且可作为先导化合物,为以后的结构修饰和抗肿瘤机制研究提供方向。
[Abstract]:Sulfonamides are small molecular compounds with relatively simple structure, wide biological activity and relatively high safety. Sulfonamides have been reported to have anti-inflammatory, anti-viral and anti-tumor activities. It has been widely used in pharmaceutical industry. In recent years, with the application of click-chemistry in the field of antitumor research, the active fragment of triazole is often linked to other active fragments as a Linker group. A large number of novel antitumor compounds were synthesized rapidly. Based on the above studies, in order to search for high efficiency and low toxicity antitumor compounds, the sulfanilamide structure was used as the mother nucleus to splice with 1: 2, 2, 3-triazolium, in order to search for the high efficiency and low toxicity of antitumor compounds. Six series of sulfanilamide derivatives were designed and synthesized by introducing antitumor active group at C-4 position of 1H 2N 3- triazole. The antitumor activity of sulfanilamide derivatives was tested and the structure-activity relationship was analyzed. The specific research work is as follows: diazotization, diazotization, diazotization, diazotization, diazotization, diazotization, diazotization, Nucleophilic substitution, click-chemical reactions, etc., to synthesize sulfanilamide, sulfadiazolium, sulfadiazole-triazole-sulfonamide, sulfanilamide, sulfadiazole-triazole-thioazole-aromide, sulfamethylamine, sulfadiazole-triazole-triazole-aromide, The structures of 46 derivatives of six series of sulfamethoxazole-3-triazole-benzoazo-heterocyclic, sulfamethylamine, triazole-3-coumarin, were confirmed by 1H NMR-13C NMR-MS, etc. The three cell lines of gastric cancer cell line MGC-803, esophageal carcinoma cell line EC-109 and prostate cancer cell line PC-3 were used to evaluate the antitumor activity and structure-activity relationship of the target compounds in vitro. The results showed that most of the compounds showed good antitumor activity on one or more cancer cell lines, and sulfonamide-1-triazole-3-triazole-aminodithiocarbamate derivatives had selective inhibitory effects on PC-3 cell lines. Sulfamethoxazole-sulfadiazole-sulfadiazolamide, sulfamethoxazole-3-thioheterocycline, sulfamethoxazole-coumarin showed significant inhibitory effects on MGC-803 cell lines, and sulfamethylamine 1-triazole-3-triazole-aromalanyl compounds, The activity test value of compound 1G on PC-3 cell line was 2.35 渭 M ~ 2C ~ 3G ~ + ~ 6C, IC50 was 0.696 渭 M ~ (0.866) 渭 M ~ (0.710) 渭 m ~ (-1), respectively, which showed broad-spectrum antitumor activity of sulfamethoxazole-3-triazole-benzo-azo heterocyclic derivative. The results showed that the activity of compound 1G to MGC-803 cell line was 0.696 渭 M ~ (0.866) 渭 M ~ (0.710) 渭 M, respectively. A total of 46 derivatives of sulfamethylamine 2o 2o 3 triazole were synthesized. The synthetic method is simple and the compounds are novel. The antitumor activity of 2Cn3Gf6C in vitro is worthy of further study, and it can be used as a leading compound. It provides a direction for the study of structural modification and anti-tumor mechanism in the future.
【学位授予单位】：郑州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914;R96

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