本文選題：酪氨酸蛋白激酶　切入點(diǎn)：Abl　出處：《吉林大學(xué)》2014年碩士論文　論文類型：學(xué)位論文

【摘要】：酪氨酸蛋白激酶（Protein tyrosine kinases，PTKs）是一類能催化多種底物蛋白質(zhì)酪氨酸殘基磷酸化的酶，它可以催化ATP上的γ-磷酸轉(zhuǎn)移到很多重要蛋白酪氨酸殘基上，使其殘基磷酸化，以此引起腫瘤細(xì)胞的生長(zhǎng)。酪氨酸蛋白激酶在細(xì)胞內(nèi)的信號(hào)轉(zhuǎn)導(dǎo)通路上占據(jù)非常重要的位置，細(xì)胞體內(nèi)生長(zhǎng)、分化、死亡等一系列的生理過程都由它調(diào)節(jié)，其也與腫瘤細(xì)胞的增殖、分化、遷移和凋亡有重要聯(lián)系，通過阻斷酪氨酸激酶的方法可以破壞腫瘤細(xì)胞的信號(hào)傳遞，最終達(dá)到抗腫瘤的目的。 在臨床上采用傳統(tǒng)的化學(xué)療法治療腫瘤選擇性不強(qiáng)，副作用大。隨著腫瘤發(fā)病機(jī)制的逐漸闡明，作用于特定分子靶點(diǎn)的新型抗腫瘤藥物的研究越來越受到重視，尤其是以酪氨酸蛋白激酶為靶點(diǎn)的小分子抑制劑的研究成為國(guó)際上抗腫瘤藥物的研究熱點(diǎn)，具有廣闊前景。很多酪氨酸蛋白激酶和腫瘤關(guān)系密切，臨床研究表明PTKs的過表達(dá)或者是表達(dá)下降都可能對(duì)患腫瘤的人群有評(píng)價(jià)預(yù)后價(jià)值，以酪氨酸蛋白激酶為靶點(diǎn)的靶向藥物可以針對(duì)特定的靶點(diǎn)，不僅對(duì)于腫瘤治療效果好，對(duì)于正常細(xì)胞毒副作用也比傳統(tǒng)化療藥物小的多。 本文采用酪氨酸蛋白激酶為靶點(diǎn)，設(shè)計(jì)合成酪氨酸蛋白激酶的小分子抑制劑。選取達(dá)沙替尼作為先導(dǎo)化合物，對(duì)其結(jié)構(gòu)進(jìn)行改造，設(shè)計(jì)一系列Abl、Src雙靶點(diǎn)酪氨酸蛋白激酶抑制劑，以期能找到治療慢性粒細(xì)胞性白血病活性最好的藥物以及抗腫瘤效果更佳，選擇性更強(qiáng)，更為廣譜的藥物。 選取對(duì)Abl和Src具有雙重抑制作用的達(dá)沙替尼來進(jìn)行骨架躍遷，為了避開專利保護(hù)，本文對(duì)達(dá)沙替尼母核上所含的硫原子用硒原子進(jìn)行電子等排體替換，因此確定了將2-甲基-5-羰基-1，3-硒唑作為母核結(jié)構(gòu)。 通過查閱文獻(xiàn)，參考達(dá)沙替尼的部分合成路線，設(shè)計(jì)和改進(jìn)目標(biāo)化合物的合成路線。本文共設(shè)計(jì)了30個(gè)目標(biāo)化合物并最終通過9步反應(yīng)合成了其中的20個(gè)，其結(jié)構(gòu)均經(jīng)ESI-MS和1H-NMR確證。 本文將這20個(gè)化合物對(duì)Abl、Src兩種激酶的抑制作用進(jìn)行了篩選，結(jié)果表明，在10μM濃度下，大部分化合物對(duì)Abl激酶、Src激酶均有抑制作用，其中12個(gè)化合物對(duì)Abl、Src激酶的抑制率大于70%，在對(duì)這12個(gè)化合物進(jìn)行復(fù)篩后發(fā)現(xiàn)，，其中有6個(gè)化合物的活性與陽性對(duì)照藥相近，其中化合物1活性比陽性藥活性高。本文為高活性的Abl、Src雙靶點(diǎn)酪氨酸蛋白激酶抑制劑的發(fā)現(xiàn)和酪氨酸蛋白激酶抑制劑的進(jìn)一步研究提供了依據(jù)。
[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 緯 -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.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R914

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