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標題: | 以具備親水性取代基之帕拉米弗衍生物克服流感病毒的抗藥性問題 Peramivir Analogues Bearing Hydrophilic Substituents to Overcome Influenza Viral Resistance |
作者: | Din-Chi Chiu 邱鼎棋 |
指導教授: | 方俊民(Jim-Min Fang) |
關鍵字: | 流行性感冒,神經胺酸?抑制劑,突變流感病毒,抗藥性, Influenza,neuraminidase inhibitor,mutant influenza virus,drug resistance, |
出版年 : | 2017 |
學位: | 碩士 |
摘要: | 流行性感冒至今仍為一嚴重的公眾議題,並持續影響大眾衛生及健康。虧得眾多化學家之諸多貢獻,現今已有瑞樂沙、克流感及帕拉米弗等以不同投藥方式使用的神經胺酸酶抑制劑,且已成為針對流感最主要亦最有效的藥物。但由於這類藥物的抗藥性問題已經浮出檯面並日漸頻繁,嚴重影響了神經胺酸酶抑制劑的療效,也點出了研發新型流感藥物的急迫性。所以,以這些抑制劑與突變病毒株之神經胺酸酶的共結晶為基礎,我們設計出一系列具備親水性側鏈之帕拉米弗衍生物,企圖克服目前已發現因突變而引起的抗藥性問題。在合成方面,我們利用異抗壞血酸來製備1,3-偶集體氧化腈,而引入親水側鏈上的手性中心,並且開發出一個進行1,3-偶極環加成反應的新方法來製備關鍵中間物異噁唑,以建構帕拉米弗衍生物之主架構。其與傳統方法相較,需要較少之1,3-偶極體氧化腈且能有較高的立體選擇性。經大刀闊斧地延伸分子架構後,我們成功合成了四個帶有親水性側鏈的帕拉米弗衍生物。除了合成路徑開發的成功,我們所製備的衍生物皆具有不錯的抑制活性,且用於對抗突變病毒株時,也可觀測到抗藥性大幅緩解,此研究結果可啟發我們產出更優良的神經胺酸酶抑制劑。 So far, influenza remains to be a major problem and impact public health greatly. Thanks to many efforts of chemists, a number of neuraminidase inhibitors such us zanamivir, oseltamivir and peramivir have been developed and have become most widely used drugs in clinical treatments of influenza infections by different administrations. However, certain resistance has been observed and becoming common, thus leading to suppression of drug efficacies. The emergence of drug resistance reminds the urgency of discovering novel inhibitors. Based on the results acquired from the cocrystal of inhibitors in mutant NA, we designed peramivir derivatives bearing various hydrophilic side chains in order to conquer problems of drug resistance. In the phase of synthesis, we employed D-(–)-isoascorbic acid to prepare nitrile oxide 1,3-dipole and introduce the chirality of hydrophilic side chain. In addition, a pioneering method with complete consumption of the dipolariphile was developed by using reduced amount of nitrile oxide 1,3-dipole to conduct the cycloaddition reaction for syntheses of isoxazolines, which are key intermediates to establish the scaffold of peramivir analogs, with enhanced stereoselectivity. After extensive derivatizations, we successfully synthesized four peramivir analogues carrying hydrophilic side chains. Aside from discovery of an alternative synthetic route, our synthetic candidate compounds demonstrated fairly good biological activity and alleviated drug resistance. These results may inspire us to produce better inhibitors. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/76581 |
DOI: | 10.6342/NTU201701070 |
全文授權: | 未授權 |
顯示於系所單位: | 化學系 |
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