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研究生： 梁健夫
Liang, Chien-Fu
論文名稱： 合成專有α位向硫-醣苷鍵之唾液酸寡醣體
Synthesis of Oligosialic Acids via Exclusive α S-Glycosidic Bond Fromation
指導教授： 林俊成
Lin, Chun-Cheng
口試委員:
學位類別： 博士
Doctor
系所名稱： 理學院 - 化學系
Department of Chemistry
論文出版年： 2009
畢業學年度： 97
語文別： 英文
論文頁數： 176
中文關鍵詞： 醣生物學 、醣水解酶 、唾液酸寡糖抗原 、異丁基雙硫鍵 、α(2→9)唾液酸寡糖 、α(2→8)/ α(2→9)唾液酸三醣體 、碳水化合物結合疫苗
外文關鍵詞： glycobiology, glycosyl hydrolases, oligosialic acid antigens, tert-butyl disulfide bond, α(2→9)oligosialic acids, α(2→8)/ α(2→9)trisialic acid, carbohydrate conjugate vaccine
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    • Abstract

    There are three linear polysialic acids identified in nature, α(2→9), α(2→8) and α(2→8)/α(2→9) alternative Neu5Ac units. Recent studies in glycobiology indicate that α(2→8) and/or α(2→9) di/oligosialic acids play important roles in the biological events that occur on the cell surface. However, these sugars are very labile under mild acidic or basic conditions and are susceptible to be degraded by glycosyl hydrolases. So, S-linked glycosides have been proposed to enhance the stability of the glycosidic linkage towards hydrolysis by either chemical or enzymatic means.
    The objectives of this thesis are development of convenient strategy for the synthesis of thio-oligosialic acid antigens. A new approach to the synthesis of S-linked α(2→9) oligosialic acids is developed using an asymmetric tert-butyl disulfide linkage as thiol protecting group. Compared with conventional thio-sialosides, these asymmetric disulfide sialosides can tolerate the functional group transformation conditions without resulting undesired elimination and racemization of the anomeric center. Furthermore, these sialosides can be efficiently deprotected to afford thiol nucleophile at α anomeric position without flipping the anomeric stereochemistry. By this strategy, we have successfully synthesized the α(2→9) di-, tetra-, hexa-, octa-oligosialic acids.
    In addition, the synthesis of S-linked □□2→8) and α(2→8)/α(2→9) trisialic acids by S-alkylation were developed. The methods involve chemo- and stereo-selective alkylation of C2-thiolated sialosides as nucleophile with the C8-iodide activated sialoside as electrophile. Additionally, we developed an efficient migration method to transform the C7 acetyl group of sialoside to the C9 position under mild basic conditions. The acetyl group migrated sialoside was subsequently used to synthesize C8 iodide by dichlorodimethylsilane with sodium iodide. By this strategy, the synthesis of S-linked □□2→8) and α(2→8)/α(2→9) trisialic acids were achieved.
    Owing to the successfully synthesized of S-α(2→9) oligosialic acids, conjugation of synthetic thio-antigens with carrier protein (KLH) was also investigated to the vaccine development. We used a novel and efficient method for synthetic carbohydrate conjugate vaccine preparation by attachment of an MHSu (6-maleimidohexanoic acid active ester) to the S-α(2→9) oligosialic acids, and then conjugated with thiolated KLH. Furthermore, we have used Ellman’s reagent to assay the amount of S-linked sialosides on KLH. These methods may be generally applicable for synthetic oligosaccharides.

    摘 要
    自然界存在之聚唾液酸醣苷鍵形式主要有三種，α(2→8)與α(2→9)醣鍵結形式，以及α(2→8)/ α(2→9)醣鍵結交錯出現形式。最近在醣生物學研究上指出，出現在細胞表面的α(2→8)和α(2→9) 醣鍵形式的雙醣及寡醣在生物方面上扮演重要的角色。然而這些醣類在溫和的酸性或鹼性條件下是不穩定的，而且容易被醣水解酶影響而水解。因此，硫鍵結之醣苷分子已經被提出用來增強被化學或酵素水解之醣苷鍵結的穩定度。
    本論文的目標是發展便利的策略來合成硫鍵結之唾液酸寡糖抗原。我們發展了一個不對稱的異丁基雙硫鍵來當作變旋異位性(anomeric)硫原子的保護基，並利用此新方法來合成硫鍵結α(2→9)唾液酸寡糖。比較一般傳統在唾液酸變旋異位性硫原子的保護基，我們所使用的不對稱異丁基雙硫鍵保護基能夠承受在官能基轉換過程中而不會產生不飽和鍵的脫去產物。此外，不對稱異丁基雙硫鍵保護基可以有效率的去保護而在變旋異位中心產生具有硫醇的親核試劑，並且不會造成變旋異位中心的變旋異構化。我們實驗室藉由這個方法已經成功合成了4-,6-,8-硫鍵結α(2→9)唾液酸寡糖。
    除此之外，藉由硫親核反應來發展合成硫鍵結之α(2→8)以及α(2→8)/α(2→9)三醣體，這些方法包含利用C2-硫基化之唾液酸醣苷分子當做親核試劑以及C8-碘基化之唾液酸醣苷分子當做活性化之親電試劑，來進行化學及立體選擇性之烷基化反應。此外，我們也發展了一個有效的轉移方法，在溫和的鹼性條件下將唾液酸醣苷分子七號位置的乙醯基官能基轉換至九號位置上。接著利用二氯二甲基矽烷和碘化鈉的條件下將乙醯基轉移之唾液酸醣苷分子在八號位置上進行碘基化反應。藉由這些方法，我們已經合成了硫鍵結α(2→8)唾液酸三醣體以及α(2→8)/ α(2→9)唾液酸三醣體。
    由於已經成功合成了硫鍵結之α(2→9)唾液酸寡醣體，將合成的硫代抗原和載體蛋白(KLH)進行結合也在疫苗發展上被研究。藉由MHSu(6-maleimidohexanoic acid active ester)裝配在硫鍵結之α(2→9)唾液酸寡醣體，接著與硫基化之載體蛋白(KLH)進行結合，我們利用此新穎與有效的方法來製備碳水化合物結合疫苗。另外，我們也使用Ellmans試劑去定量有多少硫鍵結之α(2→9)唾液酸醣苷分子在載體蛋白(KLH)上面。這些方法可以普遍適用在合成的寡糖上面。

    Content Abstract.........................................................................................................................i Acknowledgement……………………………………………………………………v Abbreviations..............................................................................................................vii List of Figures...............................................................................................................x List of Tables...............................................................................................................xv Content.......................................................................................................................xvi Chapter 1: Introduction……………………………………………………………..1 1.1 Carbohydrates……………………………………………………………………1 1.2 Sialic acids……………………………………………………………………….3 1.2.1 Chemical structure of sialic acids…………………………………………….3 1.2.2 Biological function of the sialic acid…………………………………………5 1.2.3 Enzymatic and chemical synthesis of the sialic acid…………………………7 1.2.3.1 Enzymatic syntheses………………………………………………………7 1.2.3.2 chemical syntheses………………………………………………………...9 1.2.4 Synthesis of oligosialic acid…………………………………………………11 1.2.4.1 Introduction of polysialic acid……………………………………………11 1.2.4.2 Synthesis of α(2-9) linkage oligosialic acid……………………………...14 1.2.5 Objectives……………………………………………………………………18 Chapter 2: Synthesis of Thio-α (2→9) Oligosialic Acids………………………….20 2.1 Introduction……………………………………………………………………..20 2.2 Synthesis of S-α(2→9) octasialic acid………………………………………….24 2.2.1 Synthesis of S-linked α(2→9) octasialic acid……………………………….27 2.2.1.1 Synthesis of S-2-(trimethylsilyl)ethyl sulfide thiol-protecting sialosides..28 2.2.1.2 Synthesis of S-Triphenylmethyl thioether thiol-protecting sialosides…....32 2.2.1.3 Synthesis of unsymmetrical S-ethyl disulfide thiol-protecting sialosides..35 2.2.1.4 Synthesis of unsymmetrical S-tert-butyl disulfide thiol-protecting sialosides…………………………………………………………………38 2.2.1.5 Conclusion……………………………………………………………….47 2.3 Experimental data………………………………………………………………48 Chapter 3: Synthesis of S-linked α(2→8) and α(2→8)/ α(2→9) Trisialic Acids via S-alkylation……………………………………………………………...82 3.1 Introduction……………………………………………………………………..82 3.2 Synthesis of S-linked α(2→8) trisialic acid…………………………………….90 3.2.1 Synthesis of S-linked α(2→8) and α(2→8)/ α(2→9) Trisialic Acids……….92 3.2.2 Conclusion………………………………………………………………….101 3.3 Experimental data……………………………………………………………...101 Chapter 4: Synthesis Protein Conjugated S-Linked Di-, Tetra- and Hexa-Sialic Acids as Immunogens………………………………………………..111 4.1 Introduction……………………………………………………………………111 4.2 Conjugation of S-linked α(2→9) di-, tetra- and hexa-sialic acids with KLH…116 4.2.1 Conjugation of S-linked oligosialic acids with carrier protein……………..118 4.2.1.1 Synthesis of maleimido-functionalized S-linked sialic acids…………...119 4.2.1.2 Preparation of keyhole limpet hemocyanin (KLH) conjugated S-linked sialic acids………………………………………………………………123 4.2.1.3 Conjugation of the S-linked di/oligosialosides with thiolated KLH by 1,4-addition……………………………………………………………125 4.2.1.4 Determination of the S-linked di/oligosialoside content on antigen-KLH conjugate………………………………………………………………..126 4.2.1.5 Conclusion………………………………………………………………129 4.3 Experimental data……………………………………………………………...130 Reference…………………………………………………………………………...140 Publications………………………………………………………………………...153 Appendix…………………………………………………………………………...154

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