- 學位論文
設計程式化一鍋化合成法應用於聚乙醯基乳糖胺與其衍生物之合成
Design of the Programmable One-Pot Synthesis for Poly-LacNAc Derivatives
摘要
醣類，以各式各樣的形式存在於生物體中並在其中扮演著許多關鍵的角色。醣類包含單醣、雙醣、寡糖以及多醣類。而本論文將聚焦於 ”聚乙醯基乳糖胺 (poly-LacNAc)”。 聚乙醯基乳糖胺屬於多醣類，其組成單體為乙醯基乳糖胺 (N-acetyllactosamine)。乙醯基乳糖胺其基本結構為半乳糖 (galactose)經由β-(1, 4)醣苷鍵與乙醯基葡萄糖胺 (GlcNAc)連結。經研究發現附帶有聚乙醯基乳糖胺之醣綴合物 (glycoconjugate)是一種常見的醣鏈抗原 (glycan epitope)，尤其是經過唾液酸化 (sialylated)或者岩藻糖化 (fucosylated)修飾的聚乙醯基乳糖胺醣綴合物，其在生物體中具有重要且顯著的功能。 為了更加詳細地了解聚乙醯基乳糖胺在生物體中所扮演的重要角色，科學家們藉由化學方法或是化學酵素合成法以致力於製備對稱與非對稱等具有多樣性的N型醣鏈 (N-glycans)，其中某些N型醣鏈的支鏈上更連結著不同長度的聚乙醯基乳糖胺。然而，在這些現行的合成方法中仍存在著諸多的挑戰，特別是非對稱性的N型醣鏈 (asymmetric N-glycans)。 本論文中，我們將設計新的合成策略以有效率的合成直鏈型聚乙醯基乳糖胺與其衍生物並期許促進製備非對稱性的N型醣鏈之效率。此合成策略是結合”程式化一鍋化合成法 (programmable one-pot synthesis)”與”酵素合成法”。 在程式化一鍋化合成法之中，我們採用N-乙醯基葡萄糖胺-β-(1, 3)-半乳糖為基底之構築體 (building block)，並有效率的合成出直鏈型聚乙醯基乳糖胺與其衍生物。經過完整的去保護過程後，我們藉由半乳糖轉移酶 (galactosyl transferase) 與 α-(2, 3)-唾液酸轉移酶 (sialyltransferase)順利地直鏈型聚乙醯基乳糖胺其末端裝配上半乳糖與唾液酸。由於此直鏈型聚乙醯基乳糖胺衍生物之還原端具備有易拆卸的p-methoxyphenyl保護基團，可以輕易的將此衍生物轉換成醣予體 (glycosyl donor)以利於執行醣基化 (glycosylation) 並應用於非對稱性的N型醣鏈之合成。
並列摘要
Poly-N-acetyllactosamines (poly-LacNAc), containing the repeating unit of N-acetyllactosamine (LacNAc, Gal β-1, 4-GlcNAc), are a general glycan epitope of glycoconjugates and after sialylated or fucosylated to exhibit significant biological functions. To explore the biological significance of poly-LacNAc, scientists have made efforts in preparing bi-, tri- , tetra- and multi-antennary N-glycans linked with different numbers of LacNAc units via chemical or chemoenzymatic approaches. However, current methods have not met the challenge of producing asymmetric N-glycans with poly-LacNAc extension for further glycosylation. In this study, we have developed a new strategy to address this issue using a combined programmable one-pot synthesis and enzymatic strategy based on glycosyltransferases to prepare linear poly-LacNAc and derivatives. The programmable one-pot synthesis is carried out with the use of building blocks that have the “GlcNAc-β-(1, 3)-Gal skeleton” and the concept of O-2/O-5 cooperative effect. The LacNAc repeats can be deprotected and further glycosylated enzymatically, as illustrated by the galactosyl transferase and α-(2, 3)-sialyltransferase reaction to add galactose and sialic acid sequentially. In addition, the synthetic LacNAc derivatives contain a temporary protecting group, p-methoxyphenyl group (OPMP), on the anomeric position that can be easily removed and converted into a glycosyl donor such as glycosyl fluoride for the subsequent synthesis of asymmetric N-glycans.
參考文獻
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