發(fā)布時(shí)間：2018-07-03 13:20

  本文選題：乙醛脫氫酶1 + 姜黃素　； 參考：《廣東工業(yè)大學(xué)》2014年碩士論文

【摘要】：乙醛脫氫酶1(Aldehyde dehydrogenasel, ALDH1)是一種可降解細(xì)胞內(nèi)有毒醛從而維持細(xì)胞內(nèi)環(huán)境穩(wěn)定的醛氧化酶,主要分布在細(xì)胞質(zhì)中,少數(shù)分布在線粒體中,在輔酶Ⅰ的參與下可以將體內(nèi)的視黃醛和脂肪醛等氧化成相應(yīng)的酸。近年研究報(bào)道發(fā)現(xiàn),ALDH1對(duì)腫瘤干細(xì)胞的分離、鑒定、診斷、治療,以及腫瘤預(yù)后及腫瘤細(xì)胞耐藥性等具有重要的作用。姜黃素是一種來(lái)源于中藥姜黃的主要有效成分,大量文獻(xiàn)表明,姜黃素具有抗氧化、抗炎、抗病毒、抗菌、抗癌、治療老年癡呆、降血脂等多種功效。本實(shí)驗(yàn)課題組前期研究并報(bào)道了姜黃素及其姜黃素類似物對(duì)具有高表達(dá)ALDH1的腫瘤細(xì)胞PC-3、H1299和HT-29有良好的抑制活性。 本文以姜黃素及其類似物為基礎(chǔ),研究了其對(duì)乙醛脫氫酶1的抑制作用,并同時(shí)測(cè)試了抗腫瘤活性。主要包括以下方面： (1)對(duì)姜黃素及姜黃素類似物進(jìn)行了ALDH1的抑制作用篩選,結(jié)果表明：化合物6的抑制濃度IC50達(dá)到3.41μmol/L,與陽(yáng)性對(duì)照物二硫侖(IC502.91μmol/L)的抑制活性相近,但比姜黃素(IC5036.9μmol/L)的活性高10倍。 (2)基于姜黃素類似物對(duì)ALDH1的抑制活性測(cè)試數(shù)據(jù),通過(guò)計(jì)算機(jī)輔助設(shè)計(jì)的CoMFA和CoMSIA方法,建立了3D-QSAR模型。模型值如下：q2分別為0.597和0.56,最佳組分?jǐn)?shù)為8和6,非交叉驗(yàn)證相關(guān)系數(shù)r2為0.998和0.987；所建立的模型具有穩(wěn)定性和較好的預(yù)測(cè)性。從3D-QSAR模型中可知,以母體戊二烯酮結(jié)構(gòu)的化合物,當(dāng)增加兩端苯環(huán)的氫鍵受體和吸電子取代基,以及增加戊二烯酮母體結(jié)構(gòu)的氫鍵供體及增大體積結(jié)構(gòu)時(shí),化合物對(duì)ALDH1的抑制活性增強(qiáng)。通過(guò)3D-QSAR結(jié)果,設(shè)計(jì)并合成了20個(gè)新型的姜黃素類似物,所有化合物的結(jié)構(gòu)均通過(guò)質(zhì)譜、核磁碳譜及核磁氫譜等手段進(jìn)行表征,確定了所合成的化合物均是目標(biāo)產(chǎn)物。 (3)應(yīng)用MTT染色法測(cè)試姜黃素類似物對(duì)人肺癌H1299細(xì)胞,結(jié)腸癌HT-29細(xì)胞和人前列腺癌PC-3細(xì)胞的抗癌活性。半數(shù)抑制濃度IC50值表示：化合物a2,a4,b2,b4,b7,c4等具有顯著的的強(qiáng)抗腫瘤活性,體外抗腫瘤活性比姜黃素強(qiáng)10-90倍,有進(jìn)一步開(kāi)展應(yīng)用研究的價(jià)值。
[Abstract]:Acetaldehyde dehydrogenase (1 (Aldehyde dehydrogenasel, ALDH1) is a kind of aldehyde oxidase that can degrade toxic aldehyde in cells and maintain the stability of intracellular environment. It mainly distributes in cytoplasm and a few in mitochondria. Coenzyme I can oxidize retinoic aldehyde and aliphatic aldehyde to corresponding acids. In recent years, ALDH1 has been found to play an important role in the isolation, identification, diagnosis, treatment, prognosis and drug resistance of tumor cells. Curcumin is one of the main active components of curcumin, which is a kind of traditional Chinese medicine. A large number of literatures show that curcumin has many functions such as antioxidation, anti-inflammation, anti-virus, anti-bacterial, anti-cancer, treating senile dementia, lowering blood lipid and so on. The previous study of curcumin and its curcumin analogues showed that curcumin and curcumin analogues had good inhibitory activity on tumor cells PC-3H1299 and HT-29, which had high expression of ALDH1. Based on curcumin and its analogues, the inhibitory effect of curcumin on acetaldehyde dehydrogenase 1 was studied and its antitumor activity was also tested. The results showed that the inhibitory concentration of compound 6 was 3.41 渭 mol / L, which was similar to that of the positive control, IC502.91 渭 mol / L, and the inhibitory activity of IC502.91 渭 mol / L was similar to that of IC502.91 渭 mol / L, the inhibitory activity of compound 6 was similar to that of IC502.91 渭 mol / L, the inhibitory activity of compound 6 was similar to that of IC502.91 渭 mol / L. However, the activity of curcumin (IC5036.9 渭 mol / L) was 10 times higher than that of curcumin (IC5036.9 渭 mol / L). (2) based on the inhibitory activity of curcumin analogue to ALDH1, a 3D-QSAR model was established by using the method of CoMFA and CoMSIA. The values of the model are as follows: Q2 is 0.597 and 0.56, the optimum fraction is 8 and 6, and the correlation coefficient R2 is 0.998 and 0.987 respectively. The model is stable and predictable. From the 3D-QSAR model, it can be seen that when the hydrogen bond receptor and electron absorbent substituent of the benzene ring at both ends are added, and the hydrogen bond donor and volume structure of the pentadienone matrix are increased, the structure of the compound with the parent pentadienone is increased. The inhibitory activity of the compound on ALDH1 was enhanced. Twenty new curcumin analogues were designed and synthesized by 3D-QSAR. The structures of all the compounds were characterized by mass spectrometry, nuclear magnetic carbon spectrum and nuclear magnetic hydrogen spectrum. (3) the anticancer activity of curcumin analogue against human lung cancer H1299 cell line, colon cancer HT-29 cell line and human prostate cancer PC-3 cell line was determined by MTT staining. The IC50 value of IC50 indicated that the compounds a2xa4, b4nb2, b4, B4, B7, c4, and so on, had strong antitumor activity, and the antitumor activity in vitro was 10-90 times higher than that of curcumin, so it was valuable to further study the application.
【學(xué)位授予單位】：廣東工業(yè)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R914;R96

【參考文獻(xiàn)】

相關(guān)期刊論文 前4條

1 張南文;劉洋;許建華;陳崇宏;;姜黃素衍生物FM0817體外抗腫瘤活性研究[J];海峽藥學(xué);2009年05期

2 萬(wàn)琪;王飛;陳亞麗;鄭艾;;乙醛脫氫酶1與腫瘤干細(xì)胞相關(guān)性研究[J];華西醫(yī)學(xué);2011年03期

3 吳裕丹,陳燕,何明生;The Influence of Curcumin on the Cell Cycle of HL-60 Cells and Contrast Study[J];Journal of Tongji Medical University;2000年02期

4 ;Effects of TNF-α and curcumin on the expression of VEGF in Raji and U937 cells and on angiogenesis in ECV304 cells[J];Chinese Medical Journal;2005年24期

相關(guān)碩士學(xué)位論文 前1條

1 符W，

本文編號(hào)：2093790