細胞表面硫酸乙醯肝素寡醣的合成研究:與纖維細胞成長因子一型結合的雙醣體及與單純疱疹病毒一型gD蛋白作用的八醣體

Synthesis of Cell Surface Heparan Sulfate FGF 1-Binding Disaccharides and HSV-1 gD-Binding Octasaccharide

胡育朋

指導教授 ： 洪上程 ； 林俊成

國立清華大學/理學院/化學系/博士(2010年)

摘要

本論文主要論述細胞表面硫酸乙醯肝素寡醣的合成研究，以纖維細胞成長因子一型和單純疱疹病毒一型的gD蛋白為作用目標，進而合成十二種硫酸乙醯肝素的雙醣分子和一種與gD蛋白作用的八醣分子。
第一章主要在介紹細胞表面的醣共軛分子，並說明肝素及硫酸乙醯肝素的結構及生物活性；第二章將有關於與FGF結合、分子庫合成、及與單純疱疹病毒作用之硫酸乙醯肝素八醣體的合成相關文獻，加以回顧探討；第三章則敘述十二種硫酸乙醯肝素雙醣分子的反合成分析。
第四章為合成十二種硫酸乙醯肝素雙醣分子的部份，使用一鍋化醣鏈結反應進行雙醣骨架的製備，其後經數步官能基轉換，可得到共同中間體213及215，再以此二個中間體做為基礎，經由變換去保護及官能基轉換反應的順序，即可獲得十二個硫酸乙醯肝素雙醣分子。
第五章主要介紹本實驗室先前對與gD蛋白作用的八醣分子之合成工作，並提出本論文的工作目標及目標分子的反合成分析；第六章是探討與gD蛋白作用的八醣骨架之合成研究，經過變換鏈結組合單元的順序及醣予體離去基的種類，建立合成方法的基礎。
第七章描述以三醣醣予體330、三醣醣受體299及N,N-雙乙醯基的醣予體334三個片段組合成八醣骨架332的過程，最後經去保護及官能基轉換反應，可成功合成硫酸乙醯肝素八醣體276。
在第八章中，統整了第四章、第六章及第七章的合成工作。第九章則提供了合成工作的詳細實驗步驟及化合物的物理性質

關鍵字

硫酸乙醯肝素 ； 纖維細胞成長因子 ； 單純疱疹病毒 ； 醣鏈結

並列摘要

This dissertation describes the synthesis of twelve heparin sulfate disaccharides that binds with FGF-1 and the octasaccharide that binds to HSV-1 gD protein.
Chapter 1 introduces the cell surface glycoconjugates and explains the biological function of heparin/heparan sulfate. The literature reports about the synthesis of heparan sulfates that bind with FGF-1 and an uncompleted preparation of heparan sulfate octasaccharide that binds with HSV-1 gD protein are summarized in Chapter 2. Chapter 3 describes the retro-synthetic plan of the twelve heparan sulfate disaccharides.
Chapter 4 describes the synthesis of twelve heparin sulfate disaccharides that binds with FGF-1. The fully protected disaccharide skeleton was prepared by one-pot glycosylation procedure. The common disaccharide intermediates 213 and 215 were accessed through functional group transformations to form the disaccharide skeleton. With the disaccharide 213 and 215 in hand, the final twelve heparan sulfate disaccharides were synthesized by the subsequent deprotection and sulfonation strategies.
Chapter 5 initially introduces the previous work of HSV-1 gD protein binding octasaccharide which was carried out in our research group, followed by the retrosynthesis of our target molecule 276. Chapter 6 describes the construction of heparan sulfate octasaccharide skeleton. The synthetic method was established via changing the sequence of fragment assembly and the leaving group of glycosyl donor.
Chapter 7 relates with the synthesis of octasaccharide 276. The octasaccharide skeleton 332 was prepared by assembling glycosyl donor 330, glycosyl acceptor 299 and N,N-diacetyl glycosyl donor 334. Finally, the expected HS target molecule 276, was smoothly obtained from 332 via a series of functional group transformations.
The conclusion of our synthetic work is summarized in Chapter 8. A total synthesis of FGF-1 binding twelve heparin sulfate disaccharides and the octasaccharide that binds to HSV-1 gD protein are carried out in an efficient manner. Chapter 9 provides the detailed experimental procedure and physical data of the compounds synthesized herein.

並列關鍵字

Heparan Sulfate ； FGF 1 ； HSV-1 ； gD

參考文獻

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