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標題: | 合成簡化QS-21與其結構之岩藻糖同質物作為免疫佐劑的研究 Synthesis of the Truncated QS-21 and its Fucose-Congener as Vaccine Adjuvants |
作者: | 蔡盈盈 Yin-Yin Tsai |
指導教授: | 梁碧惠 |
關鍵字: | QS-21,GPI-0100,佐劑,三?,皂皮酸,刺囊酸,岩藻糖,阿拉伯糖,醣化作用, QS-21,GPI-0100,adjuvants,triterpene,quillaic acid,echinocystic acid,fucose,arabinose,glycosylation, |
出版年 : | 2018 |
學位: | 碩士 |
摘要: | 佐劑是添加到疫苗中以修飾針對抗原的免疫反應的藥劑,自從1920年代早期開始被使用。其中,QS-21是一種從皂皮樹(Quillaja saponaria)樹皮分離出來的天然物,是最有潛力的新穎佐劑之一,FDA自2016年通過QS-21使用在皰疹的疫苗,最近許多最近的臨床試驗,如癌症、瘧疾疫苗也使用QS-21作為佐劑。
盡管QS-21具有發展潛力,但是QS-21的缺點為:於皂皮樹中的含量低、全合成步驟冗長、結構不穩定性、具毒性。而學者接著研究出GPI-0100,為一種從皂皮樹萃取物所發展的半合成混合物,具有毒性更低和更穩定等優點,因此很快受到關注。然而,植物混合物成分複雜,因此有多種不同的機轉,生產亦難控制。 本論文中完成了兩個GPI-0100的簡化之衍生物的合成,結構簡化的部分包括三萜的28號位的四醣減為三醣,且在三萜3號位所接的糖由三個減至一個。除此之外,針對結構活性的探討則包括以阿拉伯糖(L-arabinose)取代了岩藻糖(D-fucose)作為結構同質物;此外,鑒於刺囊酸(echinocystic acid)的可用性及低價,我們亦嘗試用刺囊酸(echinocystic acid)替代了皂皮酸(quillaic acid)作為三萜核心合成簡化之GPI-0100類似物。 我們以[1+1+3]之聚合型策略,首先將三醣皆用醯基保護,其再與葡萄醣醛酸鍵結的三萜C-28號位進行醣化作用,此關鍵步驟中,我們使用三氯醯亞胺酸酯(trichloroacetaimidate)為離去基和二氯甲烷為溶劑之三醣提供者,得到45%-56% β位向醣化的最佳結果。在後續的氫化反應時三乙基矽烷基團保護基易離去,因此以質譜儀監測反應,並不單獨純化反應中間體。最後在葡萄醣醛酸6號位接十二烷胺之醯胺鍵,再去除其上的保護基後純化,得到最終產物53-54。是以保護後的單醣及刺囊酸或皂皮酸作為起始物,歷經八步化學反應之總產率為1-2%。 Adjuvants are agents added to vaccines to modify the immunological response to an antigen, which has been used since 1920s. The natural product, QS-21, which is separated from the bark of Quillaja saponaria tree, is one of the most potential adjuvants with favorable humoral responses, which was approved by FDA in 2016 in combination with an anti-herpes vaccine and currently it was used in many recent clinical trials, such as cancers, malaria. Despite its promise, QS-21 has suffered from its scarcity, tedious total synthetic steps, instability in stock solution, and also its toxicity. The semi-synthetic mixture from the extraction of Quillaja saponaria, GPI-0100, soon gains attention, and has several advantages including less toxic and more stable. However, its function and mechanism were not validated, and as a botanical mixture, it should be disassembled. In this study, two compounds of simplified GPI-0100 structures were synthesized. Truncation of GPI-0100 included a branched trisaccharide at triterpene C-28 position and a simplified glucuronic acid at C-3 position. For the structural activity relationship study, a fucose of branched trisaccharide was replaced by an arabinose and quillaic acid was replaced by echinocystic acid, because of its availability and lower price. A concise, [1+1+3] convergent pathway to synthesize these compounds was developed. The hydroxyl groups of trisaccharide were all protected by acyl group and then coupled with the triterpene bearing a C-3 glucuronic acid at C-28 position. In this critical step, use of CH2Cl2 as solvent and trichloroacetaimidate bearing trisaccharide donor for glycosylation, β-glycosylation yields were in the range of 45-56%. The sequential hydrogenation was suffered from the random removal of triethylsilyl groups, which were detected by mass spectroscopy. Amide bond formation of glucuronic acid with 1-dodecylamine and final product deprotection, purification afforded the final products 53-54 with the overall yield of 1-2% in an eight-step process by fully protected sugar donors and echinocystic acid or quillaic acid as starting materials. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78987 |
DOI: | 10.6342/NTU201803343 |
全文授權: | 未授權 |
電子全文公開日期: | 2028-08-15 |
顯示於系所單位: | 藥學系 |
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