本文選題：酪氨酸激酶 + 血管內(nèi)皮生長因子受體-2��； 參考：《青島科技大學(xué)》2017年碩士論文

【摘要】：隨著食品安全、環(huán)境污染問題的日益突出,惡性腫瘤的發(fā)病率正逐年升高,成為危害人類健康的重大殺手。酪氨酸激酶作為人體內(nèi)最大的激酶體系,在調(diào)控細(xì)胞生長、增殖和凋亡的過程中具有極其重要的作用。血管內(nèi)皮生長因子(VEGF)與血管新生密切相關(guān),研究表明阻斷VEGF與血管內(nèi)皮生長因子受體-2(VEGFR-2)酪氨酸激酶的相互作用可抑制腫瘤細(xì)胞的增殖。本文主要對運(yùn)用計(jì)算機(jī)輔助藥物設(shè)計(jì)(CADD)方法設(shè)計(jì)出的吲哚醇類化合物進(jìn)行合成與活性的探索。研究的內(nèi)容主要包括以下幾方面:1.以取代吲哚為原料,經(jīng)威爾斯邁爾-哈克反應(yīng)生成取代吲哚-3-甲醛,然后在NaOH/DMSO體系中,通過與溴代試劑作用得到N-取代吲哚-3-甲醛,最后經(jīng)NaBH4還原得到吲哚-3-甲醇類衍生物。2.以取代鄰苯二胺為原料,在酸性條件與氯乙酸下進(jìn)行合環(huán)反應(yīng)得到2-氯甲基苯并咪唑類衍生物,同時(shí)也對2-溴甲基苯并咪唑類化合物的合成進(jìn)行了探索。3.以5-取代吲哚-3-甲醛為原料,與鹽酸羥胺反應(yīng)生成5-取代吲哚-3-甲醛肟,進(jìn)而在Pd/C催化劑的存在下,與甲酸銨反應(yīng)生成5-取代-3-氨甲基吲哚。4.經(jīng)過大量的實(shí)驗(yàn)探索后,最終選擇在丙酮為溶劑,碳酸鉀為縛酸劑的條件下,吲哚-3-甲醇類衍生物與2-鹵甲基苯并咪唑類衍生物進(jìn)行反應(yīng)生成醚鍵連接的吲哚-苯并咪唑類目標(biāo)化合物,并分別測試了部分目標(biāo)化合物對VEGFR-2酪氨酸激酶和4種腫瘤細(xì)胞的抑制活性。
[Abstract]:With the food safety and environmental pollution, the incidence of malignant tumors is increasing year by year and has become a major killer of human health. Tyrosine kinase, as the largest kinase system in human body, plays an important role in regulating cell growth, proliferation and apoptosis. Vascular endothelial growth factor (VEGF) is closely related to angiogenesis. It has been shown that blocking the interaction of VEGF with vascular endothelial growth factor receptor (VEGFR-2) tyrosine kinase can inhibit the proliferation of tumor cells. In this paper, the synthesis and activity of indole alcohols designed by computer aided drug design (CADDD) were studied. The main contents of the study include the following aspects: 1. Substituted indole-3-formaldehyde was synthesized from substituted indole by Welmayer-Huck reaction. Then in NaOH/DMSO system, N- substituted indole -3-formaldehyde was synthesized by brominating reagent. Finally, indole -3-methanol derivative. 2 was obtained by NaBH4 reduction. 2-chloromethyl benzimidazole derivatives were synthesized from substituted o-benzenediamine by cyclization under acidic conditions with chloroacetic acid. The synthesis of 2-bromomethyl benzimidazole compounds was also studied. In the presence of Pd/C catalyst, 5-substituted indole -3-formaldehyde was synthesized by reacting with hydroxylamine hydrochloride to produce 5-substituted -3-aminomethyl indole. 4. In the presence of Pd/C catalyst, 5-substituted -3-aminomethyl indole. 4 was obtained by reaction with ammonium formate. After a lot of experiments, we choose acetone as solvent and potassium carbonate as acid binding agent. Indole-3-methanol derivatives reacted with 2-halomethyl benzimidazole derivatives to form indole-benzimidazole bound target compounds. The inhibitory activities of some target compounds on VEGFR-2 tyrosine kinase and four kinds of tumor cells were tested.
【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

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本文編號：1812469