酪氨酸蛋白激酶抑制剂的设计、合成和筛选

发布时间：2018-03-07 10:08

本文选题：酪氨酸蛋白激酶　切入点：Abl　出处：《吉林大学》2014年硕士论文　论文类型：学位论文

【摘要】：酪氨酸蛋白激酶（Protein tyrosine kinases，PTKs）是一类能催化多种底物蛋白质酪氨酸残基磷酸化的酶，它可以催化ATP上的γ-磷酸转移到很多重要蛋白酪氨酸残基上，使其残基磷酸化，以此引起肿瘤细胞的生长。酪氨酸蛋白激酶在细胞内的信号转导通路上占据非常重要的位置，细胞体内生长、分化、死亡等一系列的生理过程都由它调节，其也与肿瘤细胞的增殖、分化、迁移和凋亡有重要联系，通过阻断酪氨酸激酶的方法可以破坏肿瘤细胞的信号传递，最终达到抗肿瘤的目的。在临床上采用传统的化学疗法治疗肿瘤选择性不强，副作用大。随着肿瘤发病机制的逐渐阐明，作用于特定分子靶点的新型抗肿瘤药物的研究越来越受到重视，尤其是以酪氨酸蛋白激酶为靶点的小分子抑制剂的研究成为国际上抗肿瘤药物的研究热点，具有广阔前景。很多酪氨酸蛋白激酶和肿瘤关系密切，临床研究表明PTKs的过表达或者是表达下降都可能对患肿瘤的人群有评价预后价值，以酪氨酸蛋白激酶为靶点的靶向药物可以针对特定的靶点，不仅对于肿瘤治疗效果好，对于正常细胞毒副作用也比传统化疗药物小的多。本文采用酪氨酸蛋白激酶为靶点，设计合成酪氨酸蛋白激酶的小分子抑制剂。选取达沙替尼作为先导化合物，对其结构进行改造，设计一系列Abl、Src双靶点酪氨酸蛋白激酶抑制剂，以期能找到治疗慢性粒细胞性白血病活性最好的药物以及抗肿瘤效果更佳，选择性更强，更为广谱的药物。选取对Abl和Src具有双重抑制作用的达沙替尼来进行骨架跃迁，为了避开专利保护，本文对达沙替尼母核上所含的硫原子用硒原子进行电子等排体替换，因此确定了将2-甲基-5-羰基-1，3-硒唑作为母核结构。通过查阅文献，参考达沙替尼的部分合成路线，设计和改进目标化合物的合成路线。本文共设计了30个目标化合物并最终通过9步反应合成了其中的20个，其结构均经ESI-MS和1H-NMR确证。本文将这20个化合物对Abl、Src两种激酶的抑制作用进行了筛选，结果表明，在10μM浓度下，大部分化合物对Abl激酶、Src激酶均有抑制作用，其中12个化合物对Abl、Src激酶的抑制率大于70%，在对这12个化合物进行复筛后发现，，其中有6个化合物的活性与阳性对照药相近，其中化合物1活性比阳性药活性高。本文为高活性的Abl、Src双靶点酪氨酸蛋白激酶抑制剂的发现和酪氨酸蛋白激酶抑制剂的进一步研究提供了依据。
[Abstract]:Tyrosine protein protein tyrosine kineses (PTKs) is a kind of enzyme that can catalyze the phosphorylation of tyrosine residues in many substrates. It can catalyze the transfer of 纬 -phosphoric acid from ATP to many important protein tyrosine residues and make its residues phosphorylated. Tyrosine protein kinase plays a very important role in the signal transduction pathway, and a series of physiological processes, such as cell growth, differentiation, death and so on, are regulated by tyrosine protein kinase. It is also associated with proliferation, differentiation, migration and apoptosis of tumor cells. Blocking tyrosine kinase can destroy the signal transduction of tumor cells and ultimately achieve the purpose of anti-tumor. The traditional chemotherapeutic therapy is less selective and has great side effects in clinic. With the gradual elucidation of the pathogenesis of tumor, more and more attention has been paid to the study of new antitumor drugs acting on specific molecular targets. In particular, the study of small molecular inhibitors targeting tyrosine protein kinases has become a hot topic in the field of antitumor drugs and has broad prospects. Many tyrosine protein kinases are closely related to tumors. Clinical studies have shown that overexpression or decreased expression of PTKs may have prognostic value for tumor patients. Tyrosine protein kinase targeting drugs can be targeted at specific targets, not only for tumor treatment effect. Toxicity and side effects to normal cells are also much smaller than traditional chemotherapeutic drugs. In this paper, a small molecular inhibitor of tyrosine protein kinase was designed and synthesized by using tyrosine protein kinase as target. A series of double target tyrosine protein kinase inhibitors were designed in order to find the best drugs for the treatment of chronic myeloid leukemia and the more effective, selective and broad-spectrum drugs for the treatment of chronic myeloid leukemia. In order to avoid patent protection, the sulfur atoms in the mother nucleus of dasatinib were replaced with selenium atoms by electron emission, in order to avoid patent protection, dasatinib, which has double inhibitory effect on Abl and Src, was selected for skeleton transition. Therefore, the structure of 2-methyl-5-carbonyl-1-3-selenazole was determined. The synthesis route of the target compound was designed and improved by referring to the partial synthesis route of dasatinib. In this paper, 30 target compounds were designed and 20 of them were synthesized by 9 steps reaction. Their structures were confirmed by ESI-MS and 1H-NMR. In this paper, the inhibitory effects of these 20 compounds on two kinds of Abl kinase were screened. The results showed that at 10 渭 M concentration, most of the compounds had inhibitory effects on Abl kinase and SRC kinase. The inhibitory rate of 12 compounds on Abln Src kinase was greater than 70. After screening the 12 compounds, it was found that the activity of 6 of them was similar to that of the positive control drug. The activity of compound 1 is higher than that of the positive drug, which provides a basis for the discovery of high activity Abln Src double target tyrosine protein kinase inhibitor and the further study of tyrosine protein kinase inhibitor.
【学位授予单位】：吉林大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914

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