吲哚醇类新型酪氨酸激酶抑制剂的合成

发布时间：2018-04-27 21:46

本文选题：酪氨酸激酶 + 血管内皮生长因子受体-2　；参考：《青岛科技大学》2017年硕士论文

【摘要】：随着食品安全、环境污染问题的日益突出,恶性肿瘤的发病率正逐年升高,成为危害人类健康的重大杀手。酪氨酸激酶作为人体内最大的激酶体系,在调控细胞生长、增殖和凋亡的过程中具有极其重要的作用。血管内皮生长因子(VEGF)与血管新生密切相关,研究表明阻断VEGF与血管内皮生长因子受体-2(VEGFR-2)酪氨酸激酶的相互作用可抑制肿瘤细胞的增殖。本文主要对运用计算机辅助药物设计(CADD)方法设计出的吲哚醇类化合物进行合成与活性的探索。研究的内容主要包括以下几方面:1.以取代吲哚为原料,经威尔斯迈尔-哈克反应生成取代吲哚-3-甲醛,然后在NaOH/DMSO体系中,通过与溴代试剂作用得到N-取代吲哚-3-甲醛,最后经NaBH4还原得到吲哚-3-甲醇类衍生物。2.以取代邻苯二胺为原料,在酸性条件与氯乙酸下进行合环反应得到2-氯甲基苯并咪唑类衍生物,同时也对2-溴甲基苯并咪唑类化合物的合成进行了探索。3.以5-取代吲哚-3-甲醛为原料,与盐酸羟胺反应生成5-取代吲哚-3-甲醛肟,进而在Pd/C催化剂的存在下,与甲酸铵反应生成5-取代-3-氨甲基吲哚。4.经过大量的实验探索后,最终选择在丙酮为溶剂,碳酸钾为缚酸剂的条件下,吲哚-3-甲醇类衍生物与2-卤甲基苯并咪唑类衍生物进行反应生成醚键连接的吲哚-苯并咪唑类目标化合物,并分别测试了部分目标化合物对VEGFR-2酪氨酸激酶和4种肿瘤细胞的抑制活性。
[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.
【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

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