本文選題：抗腫瘤 + 紫草寧雜環(huán)羧酸衍生物�。� 參考：《南京大學(xué)》2014年碩士論文

【摘要】：紫草(Lithospermum erythrorhizon)為我國(guó)傳統(tǒng)中草藥,其主要活性組分為紫草萘醌類化合物,具有殺菌抗炎、抗腫瘤、抗病毒、保肝和免疫調(diào)節(jié)等作用。近年來(lái),紫草寧作為一種天然提取抗腫瘤組分,受到眾多學(xué)者的青睞。因此,以其為先導(dǎo)物,獲得抗腫瘤活性高、溶解性好、細(xì)胞毒性低的衍生物進(jìn)行活性研究,已成為其研究新方向。噻吩和吲哚等雜環(huán)廣泛存在于臨床藥物中(如：度洛西汀、頭孢噻吩、布新洛爾,佐米曲普坦等),我們將雜環(huán)羧酸(包括噻吩羧酸和吲哚羧酸)引入到紫草寧中,獲得13種紫草寧衍生物并進(jìn)行活性驗(yàn)證。后續(xù)實(shí)驗(yàn)表明S3(紫草寧-吲哚-3-丙酸酯)和S8(紫草寧-噻吩-3-乙酸酯)對(duì)正常細(xì)胞HFF(人包皮成纖維細(xì)胞)幾乎無(wú)毒副作用,而對(duì)A875(人黑色素瘤細(xì)胞)、HeLa(人宮頸癌細(xì)胞)、HepG2(人肝癌細(xì)胞)活性顯著。其中S3、S8對(duì)A875及HeLa細(xì)胞抑制活性尤為明顯。微管蛋白解聚實(shí)驗(yàn)表明系列分子對(duì)微管蛋白抑制活性顯著。分子對(duì)接結(jié)果顯示S3可通過(guò)陽(yáng)離子-π鍵與微管蛋白的秋水仙素活性位點(diǎn)有效結(jié)合,S8則是與該活性位點(diǎn)以多重氫鍵相互作用,S8作用力明顯高于S3,該結(jié)果與兩者的抗腫瘤活性結(jié)果一致,證明紫草寧雜環(huán)羧酸衍生物作用于微管蛋白而最終達(dá)到抑制腫瘤細(xì)胞增殖的作用。細(xì)胞凋亡和細(xì)胞周期實(shí)驗(yàn)也證明S3能有效地促進(jìn)人宮頸癌細(xì)胞HeLa凋亡,并呈現(xiàn)出濃度依賴性。由此可見(jiàn),本課題所獲紫草寧衍生物是一類高效低毒活性分子,S3和S8呈現(xiàn)出了顯著的微管蛋白抑制活性,具有深入研究意義。
[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.
【學(xué)位授予單位】：南京大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R914

【共引文獻(xiàn)】

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本文編號(hào)：1788874