【作者】 张成；

【导师】 高欣钦；

【作者基本信息】 大连理工大学 ， 应用化学， 2009， 硕士

【摘要】 胆固醇酯转移蛋白(CETP)是一种血浆糖蛋白,它的主要作用是调节中性类脂类化合物在血液脂蛋白中的转移。中性类脂一般有较差水溶性,如甘油三酸酯(TG),自由胆固醇(FC)和胆固醇酯(CE)等,它们在血液中不能自由循环。它们要包裹在具有两亲结构的大的脂蛋白中进行转移。如高密度脂蛋白(HDL)和低密度脂蛋白(LDL),它们的功能是分别从周围组织转移胆固醇至肝脏和转移胆固醇至周围组织。而CETP负责调节这种转移,它有利于胆固醇酯从高密度脂蛋白转移至低密度脂蛋白,同时甘油三酸酯从低密度脂蛋白转移至高密度脂蛋白。因此人们认为CETP抑制剂可以提高血浆中高密度脂蛋白胆固醇(HDLc)水平,降低低密度脂蛋白胆固醇(LDLc)水平,从而为心血管疾病提供了一种潜在的治疗方法。本文依据已有对含硫CETP抑制剂的合成及药性研究,合成了一系列含硫类苯并含氮杂环的CETP抑制剂:3-[1-(2-乙基丁基)环己甲酰胺基]-2-喹啉硫酚(化合物1-7)、3-[1-(2-乙基丁基)环己甲酰胺基]-4-喹啉硫酚(化合物2-7)和S-[2-[1-(2-乙基丁基)甲酰胺基]-1-异喹啉基]硫代异丁酸酯(化合物3-9),并测试了化合物1-7、2-7的抑制活性,另外还改进了苄基保护路线,不仅有效解决了合成过程中存在很大异味的问题,而且缩短了反应时间,提高了反应收率。更多还原

【Abstract】 Cholesteryl ester transfer protein(CETP) is a plasma glycoprotein which can mediate the transfer of neutral lipids in the blood among various lipoproteins.Neutral lipids can’t circulate freely in plasma for their poor water solubility,such as triglycerides(TG),free cholesterol (FC) and cholesteryl esters(CE).As a result,they packed together and transported in larger lipoprotein particles that have amphipathic lipids and proteins as surface components. High-density lipoproteins(HDL) and low-density lipoproteins(LDL) help move cholesterol from and to the periphery respectively.This process is regulated by CETP which facilitates the transfer of CE from HDL to LDL with a balanced exchange of TG.Therefore,CETP inhibitor could be expected to raise plasma HDL cholesterol(HDLc) levels,lower LDL cholesterol(LDLc) levels,and provide a potential therapeutic benefit for patient with heart artery disease.A series of thio-based benzaza-heterocyclic CETP inhibitors were synthesized in this paper:3-[1-(2-ethylbutyl)cyclohexamido]-2-mercapto quinoline(compound 1-7),3-(1-(2-ethylbutyl)cyclohexamido)-4-mercapto quinoline(compound 2-7) and S-(2-(1-(2-ethylbutyl) cyclohexamido)-1-isoquinolyl) isobutanethioate(compound 3-9),and their activity as CETP inhibitors was evaluated.What’s more,a novel environment friendly synthesis route by which the mercapto group could be protected was reported and optimized.By this route,the problem that there was great off odor in the experimentation was solved perfectly while the reaction time was shorted and the yields was elevated.更多还原