本文選題：蛋白酪氨酸激酶抑制劑　切入點(diǎn)：L029衍生物　出處：《安徽醫(yī)科大學(xué)》2017年碩士論文

【摘要】：本文工作分為兩部分:第一部分是新型蛋白酪氨酸激酶抑制劑的設(shè)計(jì)合成研究。蛋白酪氨酸激酶(PTK)與腫瘤信號(hào)傳導(dǎo)關(guān)系密切,已被作為抗腫瘤藥物的靶點(diǎn)。c-Met作為小分子抑制劑與受體肝細(xì)胞生長(zhǎng)因子(HGF)結(jié)合激活酪氨酸激酶,誘導(dǎo)細(xì)胞發(fā)生一系列生物學(xué)效應(yīng)。HGF的特異性膜受體是原癌基因c-Met的表達(dá)產(chǎn)物。在多種腫瘤組織中發(fā)現(xiàn)HGF/c-Met信號(hào)通路異�；罨�,這種異常活化參與并調(diào)控這些腫瘤的發(fā)生、發(fā)展或轉(zhuǎn)移,阻斷HGF/c-Met信號(hào)途徑可有效抑制腫瘤細(xì)胞生長(zhǎng)、侵襲和轉(zhuǎn)移。SU5416是HGF的高效抑制劑,其能阻斷HGF誘導(dǎo)的Hep G2肝癌細(xì)胞侵襲和轉(zhuǎn)移。本課題組前期對(duì)SU5416進(jìn)行結(jié)構(gòu)改造研究,從一系列化合物中發(fā)現(xiàn)了對(duì)c-Met酪氨酸激酶抑制活性佳且成藥性好的新化合物L(fēng)029。本文針對(duì)L029溶解性差等不足,通過還原在其活潑H等位點(diǎn)接入側(cè)鏈3-二甲基氨基-1-丙烷、乙酸甲酯、丙酸甲酯等基團(tuán),設(shè)計(jì)合成了一系列L029衍生物。對(duì)目標(biāo)化合物進(jìn)行酪氨酸激酶活性初步篩選發(fā)現(xiàn),在100mM的濃度下,化合物TM03、TM04、TM08、TM10、TM15、TM11K(TM11的鉀鹽)具有比較明顯的抑制活性,其中TM11K對(duì)PTK的抑制作用強(qiáng)于L029;在1m M濃度下,化合物TM03、TM04、TM08、TM10、TM15、TM11Na也具有比較明顯的抑制活性。第二部分是新型抗輻射分子DBIBB合成路線優(yōu)化及其鹵代衍生物的合成。LPA_2是一類G蛋白偶聯(lián)受體,該受體的非脂類激動(dòng)劑具有治療急性放射病的作用。DBIBB作為一類特異性LPA_2激動(dòng)劑具有降低急性放射性骨髓損傷和胃腸損傷的作用,這兩個(gè)系統(tǒng)是高劑量放射暴露最敏感的器官。本文合成了DBIBB,并對(duì)其原合成路線進(jìn)行了優(yōu)化,縮短了反應(yīng)的加熱時(shí)間,避免了濃硫酸的使用,提高了產(chǎn)率,新的合成路線未見文獻(xiàn)報(bào)道。為其規(guī)模化生產(chǎn)奠定了基礎(chǔ)。文獻(xiàn)報(bào)道DBIBB氟代衍生物及氯代衍生物活性遠(yuǎn)高于DBIBB,本文對(duì)此二者的合成方法進(jìn)行改進(jìn),有望實(shí)現(xiàn)放大制備,為后期開展此類新型抗輻射分子的進(jìn)一步研究奠定了基礎(chǔ)。綜上所述,本文以L029為先導(dǎo)化合物設(shè)計(jì)合成了12個(gè)新化合物,并篩選出幾個(gè)酪氨酸激酶抑制活性良好的化合物,為此類化合物進(jìn)一步結(jié)構(gòu)優(yōu)化提供了重要參考。同時(shí),制備了DBIBB及其氟代、氯代衍生物,并對(duì)三者的合成路線進(jìn)行了改進(jìn),為進(jìn)一步開展新型抗輻射分子的研究奠定了基礎(chǔ)。
[Abstract]:This paper is divided into two parts: the first part is the design and synthesis of novel protein tyrosine kinase inhibitors. C-Met has been used as a target of anti-tumor drugs to activate tyrosine kinase by binding to the receptor hepatocyte growth factor (HGF) as a small molecule inhibitor. A series of biological effects were induced. The specific membrane receptor of HGF was the expression product of proto-oncogene c-Met. Abnormal activation of HGF/c-Met signaling pathway was found in various tumor tissues, and this abnormal activation was involved in and regulated the occurrence of these tumors. Development or metastasis, blocking HGF/c-Met signaling pathway can effectively inhibit the growth of tumor cells. Invasion and metastasis. SU5416 is an efficient inhibitor of HGF, which can block the invasion and metastasis of Hep G2 hepatoma cells induced by HGF. A new compound L029, which has good inhibitory activity to c-Met tyrosine kinase and good drug properties, was found from a series of compounds. In this paper, due to the poor solubility of L029, 3-Dimethylamino-1-propane was inserted into the side chain of L029 at its active H sites. A series of L029 derivatives were designed and synthesized with methyl acetate and methyl propionate groups. Tyrosine kinase activity of the target compound was preliminarily screened. It was found that the potassium salt of TM03N, TM04, TM08, TM010, TM15 and TM11KN TM11 had obvious inhibitory activity at the concentration of 100mM. The inhibitory effect of TM11K on PTK was stronger than that on L029. The second part is the optimization of synthesis route of new anti-radiation molecule DBIBB and the synthesis of halogenated derivatives. The non-lipid agonist of the receptor has the effect of treating acute radiation sickness. As a specific LPA_2 agonist, DBIBB can reduce acute radiation-induced bone marrow injury and gastrointestinal injury. These two systems are the most sensitive organs for high dose radiation exposure. DBIBB was synthesized, and its original synthesis route was optimized to shorten the heating time of the reaction, avoid the use of concentrated sulfuric acid, and increase the yield. The new synthesis route has not been reported in literature, which lays a foundation for its large-scale production. It is reported in the literature that the activity of DBIBB fluorinated derivatives and chlorinated derivatives is much higher than that of DBB. In this paper, 12 new compounds were designed and synthesized with L029 as the lead compound, and several compounds with good inhibitory activity of tyrosine kinase were screened out. At the same time, DBIBB and its fluorinated and chlorinated derivatives were prepared, and their synthesis routes were improved, which laid a foundation for the further study of new radiation-resistant molecules.
【學(xué)位授予單位】：安徽醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R914;R96

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