紫草宁噻吩羧酸酯及吲哚羧酸的制备及抗肿瘤活性研究

发布时间：2018-04-22 20:44

本文选题：抗肿瘤 + 紫草宁杂环羧酸衍生物　；参考：《南京大学》2014年硕士论文

【摘要】：紫草(Lithospermum erythrorhizon)为我国传统中草药,其主要活性组分为紫草萘醌类化合物,具有杀菌抗炎、抗肿瘤、抗病毒、保肝和免疫调节等作用。近年来,紫草宁作为一种天然提取抗肿瘤组分,受到众多学者的青睐。因此,以其为先导物,获得抗肿瘤活性高、溶解性好、细胞毒性低的衍生物进行活性研究,已成为其研究新方向。噻吩和吲哚等杂环广泛存在于临床药物中(如：度洛西汀、头孢噻吩、布新洛尔,佐米曲普坦等),我们将杂环羧酸(包括噻吩羧酸和吲哚羧酸)引入到紫草宁中,获得13种紫草宁衍生物并进行活性验证。后续实验表明S3(紫草宁-吲哚-3-丙酸酯)和S8(紫草宁-噻吩-3-乙酸酯)对正常细胞HFF(人包皮成纤维细胞)几乎无毒副作用,而对A875(人黑色素瘤细胞)、HeLa(人宫颈癌细胞)、HepG2(人肝癌细胞)活性显著。其中S3、S8对A875及HeLa细胞抑制活性尤为明显。微管蛋白解聚实验表明系列分子对微管蛋白抑制活性显著。分子对接结果显示S3可通过阳离子-π键与微管蛋白的秋水仙素活性位点有效结合,S8则是与该活性位点以多重氢键相互作用,S8作用力明显高于S3,该结果与两者的抗肿瘤活性结果一致,证明紫草宁杂环羧酸衍生物作用于微管蛋白而最终达到抑制肿瘤细胞增殖的作用。细胞凋亡和细胞周期实验也证明S3能有效地促进人宫颈癌细胞HeLa凋亡,并呈现出浓度依赖性。由此可见,本课题所获紫草宁衍生物是一类高效低毒活性分子,S3和S8呈现出了显著的微管蛋白抑制活性,具有深入研究意义。
[Abstract]:Lithospermum erythrorhizon (Lithospermum erythrorhizon), a traditional Chinese herbal medicine, is mainly composed of naphthoquinone compounds, which have bactericidal, anti-inflammatory, anti-tumor, anti-virus, hepatoprotective and immunomodulatory effects. In recent years, Shikonin, as a natural antitumor component, has been favored by many scholars. Therefore, it has become a new research direction to obtain derivatives with high antitumor activity, good solubility and low cytotoxicity. Heterocycles such as thiophene and indole are widely found in clinical drugs (such as doxetine, cefothiophene, buxilol, zomitriptan, etc.). Heterocyclic carboxylic acids (including thiophene carboxylic acid and indole-carboxylic acid) are introduced into Zyranin. 13 kinds of shikonin derivatives were obtained and their activity was verified. The follow-up experiments showed that S3 (Shikonin-indole-3- propionate) and S8 (Shikonin-thiophene-3-acetate) had almost no side effects on HFF (human prepuce fibroblasts) in normal cells. The activity of A875 (human melanoma cell line) HeLa (human cervical cancer cell line HepG2) was significant. The inhibitory activity of S3 + S8 on A875 and HeLa cells was especially obvious. Tubulin depolymerization test showed that a series of molecules had remarkable inhibitory activity against tubulin. The results of molecular docking show that S3 can effectively bind to the colchicine active site of tubulin via cationic-蟺 bond. The interaction force of S8 with the active site is significantly higher than that of S3. The results of tumor activity were consistent. It was proved that the heterocyclic carboxylic acid derivatives of Shikonin could inhibit the proliferation of tumor cells by acting on tubulin. Apoptosis and cell cycle experiments also showed that S3 could effectively promote apoptosis of human cervical cancer cell line HeLa in a concentration-dependent manner. It can be seen that the Shikonin derivatives obtained in this paper are a class of highly effective and low toxic active molecules, S _ 3 and S _ 8, showing significant inhibitory activity of tubulin, which is of great significance for further study.
【学位授予单位】：南京大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914

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