吲哚羧酸衍生物的合成及活性测定

发布时间：2018-06-25 17:05

本文选题：VEGFR-2酪氨酸激酶 + 吲哚-3-羧酸　；参考：《青岛科技大学》2017年硕士论文

【摘要】：随着人们生活水平的提高,肿瘤的发生率也日益增长。血管内皮生长因子(VEGF)是一种重要的血管诱导因子。研究表明,它能够和血管内皮生长因子受体-2(VEGFR-2)酪氨酸激酶发生特异性结合,激活下游信号,从而导致肿瘤的增生。因此,VEGFR-2酪氨酸激酶抑制剂应运而生,成为抗肿瘤药物的研究热点。吲哚羧酸类化合物是通过从头设计和类药性筛选获得的潜在VEGFR-2酪氨酸激酶抑制剂,本文重点对其进行了合成和生物活性方面的探索。主要包括以下内容:1首先以吲哚为原料合成了5-溴吲哚和5-硝基吲哚,然后以吲哚及其衍生物为原料,与三氟乙酸酐在N,N-二甲基甲酰胺(DMF)中反应、水解得到了吲哚-3-甲酸及其衍生物。2以邻苯二胺及其衍生物为原料,和羟基乙酸作用生成了2-羟甲基苯并咪唑及其衍生物,并和L-乳酸在磷酸作溶剂条件下,经亲核取代、脱水合环生成苯并咪唑-2-乙醇及其衍生物。3以苯胺及其衍生物为原料,与硫氰酸铵、液溴反应合成了2-氨基苯并噻唑及其衍生物。4以水杨醛及其衍生物为原料,与氯乙酸乙酯经酯化,缩合,水解反应生成苯并呋喃-2-羧酸及其衍生物。5首先,以吲哚-3-羧酸及其衍生物、2-羟甲基苯并咪唑及其衍生物作原料,以N,N-二环己基碳酰亚胺(DCC)作为脱水剂,4-二甲氨基吡啶(DMAP)为催化剂,经酯化反应生成了(1H-苯并咪唑-2-基)甲基1H-吲哚-3-羧酸酯类化合物。然后,以2-氨基苯并噻唑和吲哚-3-羧酸及其衍生物为原料,生成了N-(苯并噻唑-2-基)-1H-吲哚-3-酰胺类化合物。最后,以苯并呋喃-2-甲酸和2-羟甲基苯并咪唑为原料,合成了(1H-苯并咪唑-2-基)甲基1H-苯并呋喃-2-甲酸酯类化合物。6测定了所合成目标化合物对VEGFR-2酪氨酸激酶以及5种肿瘤细胞的抑制活性。
[Abstract]:With the improvement of people's living standard, the incidence of tumor is increasing day by day. Vascular endothelial growth factor (VEGF) is an important angiogenic factor. It can specifically bind to vascular endothelial growth factor receptor -2 (VEGFR-2) tyrosine kinase, activate downstream signal, and lead to tumor proliferation. Therefore, VEGFR-2 tyrosine kinase inhibitor emerges as the times require, and becomes the research hotspot of anti-tumor drugs. Indole carboxylic acid compounds are potential VEGFR-2 tyrosine kinase inhibitors obtained by ab initio design and drug-like screening. The main contents are as follows: firstly, 5-bromoindole and 5-nitroindole were synthesized from indole, and then reacted with trifluoroacetic anhydride in N-dimethylformamide (DMF) from indole and its derivatives. The indole-3-formic acid and its derivative .2 were synthesized from o-phenylenediamine and its derivatives and reacted with glycolic acid to produce 2-hydroxymethyl benzimidazole and its derivatives, which were substituted by nucleophilic acid with L-lactic acid in phosphoric acid. Synthesis of benzimidazole-2-ethanol and its derivatives from aniline and its derivatives by reaction of aniline and its derivatives with ammonium thiocyanate, 2-aminobenzothiazole and its derivatives were synthesized from salicylaldehyde and its derivatives. After esterification, condensation and hydrolysis of ethyl chloroacetate, benzofuran -2-carboxylic acid and its derivatives were synthesized. Firstly, indole-3-carboxylic acid and its derivative, 2-hydroxymethyl benzimidazole, were used as raw materials. (1H-benzimidazole-2-yl) methyl 1H-indole-3-carboxylic acid esters were synthesized by esterification of N- (N-dicyclohexyl) carboimide (DCC) as dehydrator, 4-dimethylaminopyridine (DMAP). Then, N- (benzothiazole-2-yl) -1H-indole-3-amide was synthesized from 2-aminobenzothiazole, indole -3-carboxylic acid and its derivatives. Finally, benzofuran -2-formic acid and 2-hydroxymethyl benzimidazole were used as raw materials, (1H-benzimidazole-2-yl) methyl 1H-benzofuran-2-formate ester compound .6 was synthesized to determine the inhibitory activity of the target compounds against VEGFR-2 tyrosine kinase and five kinds of tumor cells.
【学位授予单位】：青岛科技大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914;R96

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