新型蛋白酪氨酸激酶抑制剂的设计与合成

发布时间：2018-02-01 02:34

本文关键词： 蛋白酪氨酸激酶抑制剂定量构效关系分子对接 2-吲哚酮苯并咪唑　出处：《青岛科技大学》2013年硕士论文　论文类型：学位论文

【摘要】：蛋白酪氨酸激酶(Protein tyrosine kinase, PTK)是一类催化ATP上γ-磷酸转移到蛋白酪氨酸残基上的激酶,能催化多种底物蛋白酪氨酸残基磷酸化,在细胞生长、增殖、分化中具有重要作用。蛋白酪氨酸激酶是多种肿瘤最常见的生长因子受体,抑制其活性可破坏肿瘤细胞的信号传导,抑制肿瘤细胞增殖和新生血管形成,而对正常细胞的影响较小,这与传统的化学治疗药物相比是很大的优势,因此,蛋白酪氨酸激酶是当今肿瘤化学治疗的热门靶点,其抑制剂是抗肿瘤研究的重要方向。本研究的目的是设计和合成新型的蛋白酪氨酸激酶抑制剂,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。本文主要进行了以下方面的工作 1运用定量构效关系(QSAR)勺方法研究了2-吲哚酮类血管内皮生长因子受体-2(VEGFR-2)蛋白酪氨酸激酶抑制剂的定量构效关系,以定量构效关系研究的结构为指导,结合已有的苯并咪唑类蛋白酪氨酸激酶抑制剂的构效关系研究结果,设计出了一系列结构新颖、未见报导的新型VEGFR-2蛋白酪氨酸激酶抑制剂,组建成虚拟化合物库。 2将新型VEGFR-2蛋白酪氨酸激酶抑制剂分子用分子对接软件DOCK6.0与人的VEGFR-2蛋白酪氨酸激酶进行分子对接研究。通过对接能量大小的比较,筛选出活性较高的10个小分子,分析了抑制剂分子与受体的结合位点的情况。 3以取代苯胺为原料,经成肟、合环成靛红、水合肼还原等反应合成了一系列2-吲哚酮衍生物,优化了合成条件,积累了合成此类蛋白酪氨酸激酶抑制剂药物的相关经验。 4以取代苯胺为原料,经酰基化保护氨基、硝化、还原、和乙醇酸反应、氧化等反应合成了一系列苯并咪唑-2-甲醛衍生物,探索了合成苯并咪唑醛衍生物的合成条件,为下面的合成工作提供了有效的借鉴。
[Abstract]:Protein tyrosine kinase protein tyrosine kinase (PTK) is a kind of kinase that catalyzes the transfer of 纬 -phosphoric acid from ATP to the protein tyrosine residue. It can catalyze the phosphorylation of tyrosine residues in many substrates and play an important role in cell growth proliferation and differentiation. Protein tyrosine kinase is the most common growth factor receptor in many kinds of tumors. Inhibition of its activity can destroy the signal transduction of tumor cells, inhibit tumor cell proliferation and angiogenesis, but have little effect on normal cells, which is a great advantage over traditional chemotherapeutic drugs. Protein tyrosine kinase (PKK) is a hot target of tumor chemotherapeutic therapy, and its inhibitor is an important direction of anti-tumor research. The aim of this study was to design and synthesize novel protein tyrosine kinase inhibitors and obtain compounds with certain activity and independent intellectual property rights by screening. The main work of this paper is as follows 1 the quantitative structure-activity relationship of 2-indole ketone receptor-2 VEGFR-2 protein tyrosine kinase inhibitor was studied by quantitative structure-activity relationship (QSAR). A series of novel structures were designed under the guidance of the structure of quantitative structure-activity relationship (QSAR) and the results of the existing studies of benzimidazole protein tyrosine kinase inhibitors. A novel inhibitor of VEGFR-2 protein tyrosine kinase has been constructed into a virtual compound library. (2) the molecular docking of novel VEGFR-2 protein tyrosine kinase inhibitor (DOCK6.0) with human VEGFR-2 protein tyrosine kinase was studied by means of docking energy. A comparison of size. Ten small molecules with high activity were screened and the binding sites of inhibitor molecules to receptors were analyzed. 3 A series of 2-indoleone derivatives were synthesized from substituted aniline by oxime, cyclization into indirubin and reduction of hydrazine hydrate. The synthesis conditions were optimized. Accumulated experience in the synthesis of such protein tyrosine kinase inhibitors. A series of benzimidazole-2-formaldehyde derivatives were synthesized from substituted aniline by acylation of protected amino groups, nitration, reduction, reaction with glycolic acid and oxidation. The synthetic conditions of benzimidazolaldehyde derivatives were explored, which provided an effective reference for the following synthesis work.
【学位授予单位】：青岛科技大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R914.5

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