姜黄素类似物设计、合成及其对乙醛脱氢酶1的抑制与抗肿瘤活性的研究

发布时间：2018-07-03 13:20

本文选题：乙醛脱氢酶1 + 姜黄素　；参考：《广东工业大学》2014年硕士论文

【摘要】：乙醛脱氢酶1(Aldehyde dehydrogenasel, ALDH1)是一种可降解细胞内有毒醛从而维持细胞内环境稳定的醛氧化酶,主要分布在细胞质中,少数分布在线粒体中,在辅酶Ⅰ的参与下可以将体内的视黄醛和脂肪醛等氧化成相应的酸。近年研究报道发现,ALDH1对肿瘤干细胞的分离、鉴定、诊断、治疗,以及肿瘤预后及肿瘤细胞耐药性等具有重要的作用。姜黄素是一种来源于中药姜黄的主要有效成分,大量文献表明,姜黄素具有抗氧化、抗炎、抗病毒、抗菌、抗癌、治疗老年痴呆、降血脂等多种功效。本实验课题组前期研究并报道了姜黄素及其姜黄素类似物对具有高表达ALDH1的肿瘤细胞PC-3、H1299和HT-29有良好的抑制活性。本文以姜黄素及其类似物为基础,研究了其对乙醛脱氢酶1的抑制作用,并同时测试了抗肿瘤活性。主要包括以下方面： (1)对姜黄素及姜黄素类似物进行了ALDH1的抑制作用筛选,结果表明：化合物6的抑制浓度IC50达到3.41μmol/L,与阳性对照物二硫仑(IC502.91μmol/L)的抑制活性相近,但比姜黄素(IC5036.9μmol/L)的活性高10倍。 (2)基于姜黄素类似物对ALDH1的抑制活性测试数据,通过计算机辅助设计的CoMFA和CoMSIA方法,建立了3D-QSAR模型。模型值如下：q2分别为0.597和0.56,最佳组分数为8和6,非交叉验证相关系数r2为0.998和0.987；所建立的模型具有稳定性和较好的预测性。从3D-QSAR模型中可知,以母体戊二烯酮结构的化合物,当增加两端苯环的氢键受体和吸电子取代基,以及增加戊二烯酮母体结构的氢键供体及增大体积结构时,化合物对ALDH1的抑制活性增强。通过3D-QSAR结果,设计并合成了20个新型的姜黄素类似物,所有化合物的结构均通过质谱、核磁碳谱及核磁氢谱等手段进行表征,确定了所合成的化合物均是目标产物。 (3)应用MTT染色法测试姜黄素类似物对人肺癌H1299细胞,结肠癌HT-29细胞和人前列腺癌PC-3细胞的抗癌活性。半数抑制浓度IC50值表示：化合物a2,a4,b2,b4,b7,c4等具有显著的的强抗肿瘤活性,体外抗肿瘤活性比姜黄素强10-90倍,有进一步开展应用研究的价值。
[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.
【学位授予单位】：广东工业大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914;R96

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