合成帶有負電荷的乙醯乳醣胺衍生物以探討與半乳糖凝集素親合性之研究

生物系統中，能與醣體結合的蛋白稱之為凝集素(lectins)，其中半乳醣凝集素(galectins)被證實在許多生物活性以及許多疾病上扮演相當重要的角色，其醣辨識區(carbohydrate recognition domain, CRD)主要辨識為具有b-半乳糖苷(b-galactoside)的醣體，如N-乙醯基乳醣胺(N-acetyllacosamine)、乳醣(lactose)等。本實驗室先前針對具有硫酸化的N-乙醯基乳醣胺以及其衍生物進行結合能力試驗發現，其結合能力相對於N-乙醯基乳醣胺有顯著的提升；此外，在文獻中提到，經由半乳醣凝集素與醣體之間的結構分析，發現半乳醣凝集素在醣辨識區中有某些特定位置附近具有帶有正電荷的胺基酸殘基：組胺酸(histidine)和精胺酸(arginine)，提供了一些電荷的交互作用。本論文的主題為合成在C6或C6’位置具有羧酸根基團的N-乙醯基乳醣胺以及其衍生物，以用來探討帶有不同的負電荷基團的醣體與半乳醣凝集素結合能力的差異，合成此類化合物涉及有機醣化學合成中：(1) 具有交錯保護基的醣予體及醣受體的設計及合成；(2) 醣苷鍵的建立；(3) 一級醇的氧化；在合成策略上，採取醣基化後氧化，將氧化反應於合成末期進行，設計具有交錯保護基特性的醣予體及醣受體，且運用鄰近基效應(neighboring group participation)在醣予體C2位置修飾酯基以建立b-醣苷鍵，最後則在醣基化反應後透過保護基的操作再進行氧化；此外，在還原端接上帶有疊氮官能基的橋接分子，以利往後進行生物活性的測試，得到目標產物。

關鍵字

醣予體；醣受體；醣基化反應；氧化

並列摘要

Galectins are a family of b-galactoside-binding protein to share a high sequence similarity in their carbohydrate recognition domains. They play an important role in numerous biological activities and have been attributed to several diseases. We previously prepared sulfated Gal-b1,3/1,4-GlcNAc disaccharides where the sulfate is attached to O6 of GlcNAc, O6 or O3 of Gal. Some of these saccharides were found to have enhanced affinity with galectins-1, -3, and -8, as compared to the non-sulfated disaccharides. To study how the negative charge contributes to the binding affinity with galectins, carboxylate-containing analogues are thus designed and synthesized in this thesis, i.e. the O6- or O6’-hydroxymethyl group of Gal-b1,3/1,4-GlcNAc are oxidized to produce carboxylic acid. The synthesis contains several key reaction steps, including protecting group manipulation, glycosylation, and the aforementioned oxidation. In order to maintain good reactivity of glycosyl donors and acceptors, we performed oxidation of the O6- or O6’-hydroxymethyl group after constructing the desired b1,3/1,4 linkages. Additionally, several orthogonally protecting groups were introduced for the purpose of site-specific glycosylation and oxidation. The saccharide products will be examined by our previously developed carbohydrate array, in company with the sulfated and non-sulfated analogues.

並列關鍵字

glycosyl donor ； glycosyl acceptor ； glycosylation ； oxidation

參考文獻

1. Varki, A.; Cummings, R. D.; Esko, J. D.; Freeze, H. H.; Hart, G. W.; Etzler, M. E. Essentials of Glycobiology 2nd; Cold Spring Harbor Laboratory: Plainviwe, NY 2009.