開發新方法合成細胞表面肝素八醣分子

Development of New Methods for the Synthesis of Heparan Sulfate Octasaccharides on the Cell Surface

柯彥均(Yen-Chun Ko)

指導教授 ： 洪上程 ； 廖文峯

國立清華大學/理學院/化學系/博士(2014年)

摘要

醣共軛分子存在於細胞表面，細胞間的訊息傳遞、基質的轉換和許多生理反應皆與其有關。醣共軛分子包含許多以不同雙醣重複單元所組成的葡胺聚醣分子，硫酸乙醯肝素(heparan sulfate, HS）即為其中的一種，其結構為D式葡萄胺醣以α式1→4 鏈結到醣酸的雙醣重複單元。但硫酸乙醯肝素不易從自然界中取得，因此若需要較大量的醣體供研究之用，勢必需要靠化學方法來合成，而經由合成所得到的醣體也可確認其純度、結構與所需之長度。 本論文主要嘗試開發新的方法合成建構醣體骨架的單醣單元，以及細胞表面硫酸乙醯肝素寡醣分子庫的合成研究，首先進行單醣體的製備，再以醣鏈結反應得到不同雙醣體，之後以[2+2]、[4+4]方式建構八醣體骨架，再選擇其一合成八個硫酸乙醯肝素八醣體。 第一章主要介紹細胞表面的醣共軛分子，並說明肝素、硫酸乙醯肝素的結構特性及生物活性；第二章則是回顧近年來醣化學家在合成硫酸乙醯肝素寡醣分子的相關文獻。 第三章說明合成目標八醣體分子的策略，與逆合成分析；第四章則敘述一鍋化合成單醣醣予體以及八醣體骨架所需之單醣建構單元合成方法；第五章則以取得的單醣建構單元進行雙醣體、四醣體、八醣體骨架的建構。第六章為八醣目標分子的合成，經幾步官能基轉換，製備出八種硫酸乙醯肝素八醣體。 在第七章中，統整了第三章、第四章、第五章的合成工作。最後第八章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 ； 醣共軛分子 ； 選擇性一鍋化保護 ； 葡胺聚醣

並列摘要

Heparan sulfate, which is a ubiquitous glycosaminoglycan on the cell surface, is comprised of alternating 1→4-linked D-glucosamine and uronic acid backbone. The highly heterogenous linear chain is decorated with a complex pattern of sulfation that has been associated with many important physiological mechanisms. Because of the difficulty in acquiring heparan sulfate carrying defined structures from nature, chemical synthesis acted as the main source of these important compounds for biological evaluation. Chemical syntheses allow the potential preparation of heparin sulfate oligosaccharides of different lengths and sulfation patterns with good purity.

This dissertation describes an attractive method for the synthesis of eight heparan sulfate octasaccharides and provides an opportunity to prepare more octasaccharides of different structures. Herein, eight fully protected and linker-attached octasaccharide skeletons bearing different sets of residues were assembled in a modular and combinatorial manner. A representative octasaccharide was then subjected to divergent transformations to afford eight final compounds having the heparin sulfate structure and functionalizations. In Chapter 1, the cell-surface glycoconjugates and the biological functions of heparan sulfate are introduced. The recent advances in the synthesis of heparan sulfate oligosaccharides are reviewed in Chapter 2. Chapter 3 explains the retrosynthetic plan in attaining the octasaccharides. In Chapter 4, the preparation of monosaccharide building blocks and a new one-pot strategy in acquiring them are described. The synthesis of the disaccharide, tetrasaccharide and octasaccharide skeletons are laid out in Chapter 5 and the transformations toward the eight final heparin sulfate-based octasaccharides are specified in Chapter 6. Chapter 7 states the conclusions for the present synthetic work. Finally, the detailed experimental procedures and physical data of the compounds synthesized herein are provided in Chapter 8.

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