新型血管内皮生长因子受体-2酪氨酸激酶抑制剂的合成

发布时间：2018-11-25 16:51

【摘要】：血管生成(Angiogenesis)是指从已有的血管中发芽生成新血管的过程,肿瘤的生长、侵袭和转移依赖于新生血管的形成。抑制肿瘤介导的血管生成,阻断癌细胞的营养途径,就可以有效抑制癌细胞增殖。血管内皮生长因子(Vascular endothelial growth factor, VEGF)是肿瘤新生血管形成中的关键性促血管生长因子,可在体内诱导血管新生。目前已经得到公认,VEGF对内皮细胞的分化、增殖作用是由血管内皮生长因子受体-2(Vascular endothelial growth factor receptor-2, VEGFR-2)介导的。因此,在抗肿瘤药物研发中,针对VEGFR-2的酪氨酸激酶是一个关键的药物作用靶点,VEGFR-2酪氨酸激酶抑制剂也成为了抗肿瘤药物研究的一个重要方向。本研究的目的是合成各种新型吲哚-苯并咪唑类衍生物,通过筛选获得具有一定活性和自主知识产权的化合物,用于进一步的活性研究。本研究主要进行了以下方面的工作： 1对已设计出的一系列结构新颖、未见报导的新型VEGFR-2酪氨酸激酶抑制剂进行逆合成路线分析,根据反应可行性、路线复杂性、操作安全性等,针对每个化合物的结构设计出尽可能合理可行的合成路线。 2根据设计出的合成路线,对每种化合物进行合成。通过不同的合成路线分别合成了吲哚-3-甲酸、吲哚-3-乙酸、吲哚-3-丙酸、2-吲哚酮-3-丙酸、2-甲基吲哚-3-乙酸和5-甲氧基-2-甲基吲哚-3-乙酸等吲哚酸类化合物。 3合成的这几种吲哚酸再分别与邻苯二胺盐酸盐、4-甲基邻苯二胺和3,4-二氨基苯甲酸乙酯在多聚磷酸的催化下发生脱水环合反应,生成九种目标产物吲哚-苯并咪唑类衍生物。 4由(R)-3-喹核醇经酯交换法和乙酸酐法两种方法合成了(R)-3-乙酸奎宁环基酯,并比较得知,乙酸酐法操作简单、收率高。
[Abstract]:Angiogenesis (Angiogenesis) is the process of sprouting new blood vessels from existing vessels. Tumor growth, invasion and metastasis depend on the formation of neovascularization. Inhibition of tumor-mediated angiogenesis, blocking the nutritional pathway of cancer cells, can effectively inhibit the proliferation of cancer cells. Vascular endothelial growth factor (Vascular endothelial growth factor, VEGF) is a key angiogenic factor in tumor angiogenesis, which can induce angiogenesis in vivo. It has been recognized that the differentiation and proliferation of endothelial cells by VEGF is mediated by vascular endothelial growth factor receptor-2 (Vascular endothelial growth factor receptor-2, VEGFR-2. Therefore, tyrosine kinase targeting VEGFR-2 is a key drug target in the research and development of antitumor drugs. VEGFR-2 tyrosine kinase inhibitor has also become an important research direction of antitumor drugs. The aim of this study was to synthesize various new indole-benzimidazole derivatives and obtain compounds with certain activity and independent intellectual property rights for further study. The main work of this study is as follows: 1 A series of novel VEGFR-2 tyrosine kinase inhibitors that have been designed have been studied by reverse synthesis route analysis, according to the feasibility of the reaction and the complexity of the route, a series of novel VEGFR-2 tyrosine kinase inhibitors have been designed. According to the structure of each compound, the synthetic route is designed as reasonable and feasible as possible. 2 according to the designed synthetic route, each compound is synthesized. Indole-3-formic acid, indole-3-acetic acid, indole-3-propionic acid, 2-indole-3-propionic acid were synthesized by different synthetic routes. 2-methylindole-3-acetic acid and 5-methoxy-2-methyl-indole-3-acetic acid and other indoleic acid compounds. (3) the synthesized indoleic acid reacts with o-phenylenediamine hydrochloride, 4-methyl-o-phenylenediamine, and ethyl 3o 4-diaminobenzoate respectively under the catalysis of polyphosphoric acid. Nine target products of indole-benzimidazole derivatives were obtained. 4 (R) 3-quinine cycloester was synthesized by transesterification method and acetic anhydride method from (R) 3-quinolinol. It was found that the acetic anhydride method was simple and the yield was high.
【学位授予单位】：青岛科技大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5

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