本文選題：炭疽　切入點(diǎn)：炭疽致死因子　出處：《廣西醫(yī)科大學(xué)》2017年碩士論文

【摘要】：炭疽是由炭疽芽孢桿菌(Bacillus anthracis)引起的惡性傳染病,是世界上最危險(xiǎn)的三大生化武器之一(其它兩種是天花病毒和沙林)。炭疽桿菌主要通過釋放炭疽毒素使宿主致病,因此炭疽毒素是炭疽感染導(dǎo)致死亡的重要原因。炭疽毒素包括三種毒力因子:保護(hù)性抗原(Protective antigen,PA),致死因子(Lethal factor,LF)和水腫因子(Edema factor,EF)。PA和EF裝配成水腫毒素、PA和LF裝配成致死毒素。其中保護(hù)性抗原不參與毒理作用,它的作用是介導(dǎo)其他兩種毒力因子進(jìn)入細(xì)胞。EF/LF在胞內(nèi)釋放并發(fā)揮酶活性而引起細(xì)胞死亡。針對(duì)這一機(jī)理,有三種可能的治療策略:1)阻斷PA與受體的結(jié)合;2)阻斷毒素的裝配;3)抑制LF和EF的酶活性。迄今為止還沒有能夠抗炭疽毒素中毒的藥物。由于致死因子是炭疽毒素的主要毒力因子。因此,研究炭疽致死因子抑制劑,進(jìn)而開發(fā)抗炭疽致死毒素藥物,是關(guān)乎國家安全穩(wěn)定的迫切需要。在前期研究中,我們根據(jù)炭疽致死因子的結(jié)構(gòu)特征,結(jié)合國際在研的活性化合物,進(jìn)行了致死因子抑制劑的設(shè)計(jì)、合成和活性評(píng)價(jià)工作,建立了從分子、細(xì)胞到動(dòng)物模型的抗炭疽毒素化合物的評(píng)價(jià)方法獲得了在動(dòng)物體內(nèi)具有顯著抗炭疽致死毒素的化合物。在此基礎(chǔ)上,我們分析每個(gè)化合物結(jié)構(gòu)特征,進(jìn)一步設(shè)計(jì)了一系列新結(jié)構(gòu)的目標(biāo)化合物。對(duì)這些目標(biāo)化合物的合成設(shè)計(jì)了五條合成路線,利用這些合成路線共合成了47個(gè)目標(biāo)化合物分子。這些化合物尚未見文獻(xiàn)報(bào)道,其結(jié)構(gòu)都通過了1H-NMR、LC-MS的確證。在目標(biāo)化合物的合成過程中,對(duì)反應(yīng)條件都進(jìn)行了比較詳細(xì)的探索,尤其對(duì)各個(gè)中間體的合成,都找到了適合于本課題的合成方法。利用熒光多肽裂解試驗(yàn)測定目標(biāo)化合物對(duì)LF裂解MAPPKide多肽的抑制活性。結(jié)果表明:對(duì)炭疽致死因子(LF)的抑制活性,百分抑制率大于陽性藥的有Ⅰ-1、Ⅰ-6、Ⅱ-1、Ⅱ-3、Ⅱ-6、Ⅱ-7、Ⅲ-1、Ⅲ-4、Ⅲ-6、Ⅲ-7、Ⅲ-8、Ⅲ-13、Ⅳ-1、Ⅳ-2、Ⅳ-3、Ⅳ-4、Ⅳ-5、Ⅳ-6、Ⅳ-7、Ⅳ-9、Ⅳ-11和Ⅴ-4二十二個(gè)化合物;百分抑制率接近陽性藥的有Ⅲ-3、Ⅲ-5和Ⅲ-12三個(gè)化合物;百分抑制率小于陽性藥的有Ⅰ-2、Ⅰ-3、Ⅰ-4、Ⅰ-5、Ⅰ-7、Ⅱ-2、Ⅱ-4、Ⅱ-5、Ⅱ-8、Ⅱ-9、Ⅱ-10、Ⅱ-11、Ⅲ-2、Ⅲ-9、Ⅲ-10、Ⅲ-11、Ⅳ-8、Ⅳ-10、Ⅳ-12、Ⅴ-1、Ⅴ-2和Ⅴ-3二十二個(gè)化合物。根據(jù)初步活性評(píng)價(jià)實(shí)驗(yàn)結(jié)果,對(duì)每一類目標(biāo)化合物進(jìn)行了構(gòu)效關(guān)系的初步分析,為進(jìn)一步對(duì)這些化合物的結(jié)構(gòu)改造以及活性評(píng)價(jià)奠定了一定的基礎(chǔ)。
[Abstract]:Anthrax is composed of Bacillus anthracis (Bacillus anthracis) caused by infectious diseases, is one of the three chemical weapons the most dangerous in the world (the other two kinds of smallpox and anthrax sarin). Mainly through the release of anthrax toxin to host pathogens, so the anthrax toxin is an important cause of death of anthrax infection. Including anthrax toxin three kinds of virulence factors: protective antigen (Protective, antigen, PA), (Lethal factor, LF lethal factor) and edema factor (Edema factor, EF.PA) and EF assembly PA edema toxin, and LF assembly. The lethal toxin protective antigen is not involved in the toxicity, its role is mediated by the other two kinds of virulence factors into the cells of.EF/LF in intracellular release and activity caused by cell death. According to this mechanism, there are three possible treatment strategies: 1) blocking PA binding to the receptor; 2) blocking toxin suppression assembly; 3) Enzyme activity LF and EF. So far there is no drug resistance to anthrax toxin poisoning. The lethal factor is a major virulence factor of anthrax toxin. Therefore, the research and development of anthrax lethal factor inhibitor, anti anthrax lethal toxin drug, is an urgent need for national security and stability. In our previous study, we according to the structure the characteristics of anthrax lethal factor, combined with the international active compounds in research, design of lethal factor inhibitor, synthesis and activity evaluation, established from molecular, cell to evaluation of anthrax toxin compounds in animal models obtained compounds with significant anti anthrax lethal toxin in the animal. On this basis, we analysis of each compound structure, we design a series of new compounds structure. The synthesis of these compounds has designed five synthesis 璺嚎,鍒╃敤榪欎簺鍚堟垚璺嚎鍏卞悎鎴愪簡47涓洰鏍囧寲鍚堢墿鍒嗗瓙.榪欎簺鍖栧悎鐗╁皻鏈鏂囩尞鎶ラ亾,鍏剁粨鏋勯兘閫氳繃浜，

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