發(fā)布時間：2018-06-25 17:05

  本文選題：VEGFR-2酪氨酸激酶 + 吲哚-3-羧酸　； 參考：《青島科技大學(xué)》2017年碩士論文

【摘要】：隨著人們生活水平的提高,腫瘤的發(fā)生率也日益增長。血管內(nèi)皮生長因子(VEGF)是一種重要的血管誘導(dǎo)因子。研究表明,它能夠和血管內(nèi)皮生長因子受體-2(VEGFR-2)酪氨酸激酶發(fā)生特異性結(jié)合,激活下游信號,從而導(dǎo)致腫瘤的增生。因此,VEGFR-2酪氨酸激酶抑制劑應(yīng)運而生,成為抗腫瘤藥物的研究熱點。吲哚羧酸類化合物是通過從頭設(shè)計和類藥性篩選獲得的潛在VEGFR-2酪氨酸激酶抑制劑,本文重點對其進行了合成和生物活性方面的探索。主要包括以下內(nèi)容:1首先以吲哚為原料合成了5-溴吲哚和5-硝基吲哚,然后以吲哚及其衍生物為原料,與三氟乙酸酐在N,N-二甲基甲酰胺(DMF)中反應(yīng)、水解得到了吲哚-3-甲酸及其衍生物。2以鄰苯二胺及其衍生物為原料,和羥基乙酸作用生成了2-羥甲基苯并咪唑及其衍生物,并和L-乳酸在磷酸作溶劑條件下,經(jīng)親核取代、脫水合環(huán)生成苯并咪唑-2-乙醇及其衍生物。3以苯胺及其衍生物為原料,與硫氰酸銨、液溴反應(yīng)合成了2-氨基苯并噻唑及其衍生物。4以水楊醛及其衍生物為原料,與氯乙酸乙酯經(jīng)酯化,縮合,水解反應(yīng)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-羥甲基苯并咪唑及其衍生物作原料,以N,N-二環(huán)己基碳酰亞胺(DCC)作為脫水劑,4-二甲氨基吡啶(DMAP)為催化劑,經(jīng)酯化反應(yīng)生成了(1H-苯并咪唑-2-基)甲基1H-吲哚-3-羧酸酯類化合物。然后,以2-氨基苯并噻唑和吲哚-3-羧酸及其衍生物為原料,生成了N-(苯并噻唑-2-基)-1H-吲哚-3-酰胺類化合物。最后,以苯并呋喃-2-甲酸和2-羥甲基苯并咪唑為原料,合成了(1H-苯并咪唑-2-基)甲基1H-苯并呋喃-2-甲酸酯類化合物。6測定了所合成目標化合物對VEGFR-2酪氨酸激酶以及5種腫瘤細胞的抑制活性。
[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.
【學(xué)位授予單位】：青島科技大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R914;R96

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