https://scholars.lib.ntu.edu.tw/handle/123456789/178734
標題: | 醣胜肽之合成:用碘促進醛醣醯胺化反應 Synthesis of Glycopeptides by Amidation of Aldoses with Peptides Using Iodine as the Oxidizing Agent |
作者: | 劉珈男 Liu, Jia-Nan |
關鍵字: | 氧化性合成醯胺法;醣胜肽碘;oxidative amidation;glycoepeptide;iodine | 公開日期: | 2008 | 摘要: | 醣分子在許多生物反應過程中扮演重要的角色,以及具有修飾蛋白質特性之功能。醣結合體已經成為研究生物反應過程,及治療與診斷疾病之重要工具。為了合成醣蛋白,文獻中報導許多有關醣分子與蛋白質連結的方法,然而,這些方法主要是將醣分子或蛋白質修飾適當的官能基後,再進行共價鍵結得到醣蛋白。由於修飾過程中,需要進行許多保護、鍵結及去保護之步驟,造成總產率低且耗時的缺點。近年來,還原胺化法被廣泛地使用,並可一步化將未保護、未修飾醣分子進行鍵結,但是反應過程及條件仍具有許多缺 點。 為了尋找可替代及改善連結之方法,我們實驗室開發新的連接方法,利用碘促進醛醣氧化並與胺類化合物形成醯胺鍵。我們藉由氧化性合成醯胺法,將醛醣與代表性α-胺基酯及胜肽進行鍵結,其結果顯示此方法在醣分子之還原端與胺基反應具有良好的化學選擇性,同時在此反應條件下,α-胺基酯在α碳上無消旋化發生,且醣苷鍵亦無斷裂。根據實驗結果,我們認為氧化性合成醯胺法最可能經由醣內酯中間體以生成醣醯化合物。另外,一鍋兩步化的加料順序,對於醛醣與胺基酯鍵結十分重要。我們也順利藉由氧化性合成醯胺法,將雙醣與聚離胺酸(poly-L-lysine)、牛血清白蛋白(bovine serum albumin)鍵結。 氧化性合成醯胺法提供一個新的、快速的路徑,可直接對於未保護、未修飾之醣分子與胜肽胺基進行醣胜肽之合成。未來可利用氧化醯胺法,將由生物體液中分離或酵素切下之寡醣體,以一步化與載體蛋白鍵結,以製備出醣疫苗,亦可進一步生產抗寡醣體之抗體,作為治療及診斷疾病之工具。另外,也可以應用於胜肽藥物傳導上,氧化性合成醯胺法可提供快速篩選平台,挑選出合適醣分子連接胜肽藥物,使得藥物之生物可用性增加,如增加藥物半衰期、穿透血腦屏障等能力。 Carbohydrates play key roles in many biological processes and modulate the intrinsic properties of proteins. Glycoconjugates have become essential tools for investigation of many biological processes, and created new opportunities for the development of therapeutic and diagnostic strategies. In order to prepare glycoproteins, several conjugation methods have been developed for attaching carbohydrates to proteins. These methods lead to activated carbohydrate derivatives with a suitable functional group to be covalently linked to proteins. Some processes may be time-consuming and result in low overall yield because of many protection, coupling and deprotection steps. Though reductive amination is an extensive method for direct conjugation of unprotected and unmodified carbohydrate molecules, the process is sluggish. To find an improved conjugation method, our laboratory has developed a novel way to conjugate aldoses by amide-linkage with amine compounds via oxidative amidation using iodine as the appropriate oxidizing agent. In this thesis, the results of aldose amidation with representative α-amino esters and peptides are reported. The reaction occurred by condensation at the reducing end of carbohydrate molecules with amino group of the substrates. No racemerization at the α-carbon of α-amino esters, or cleavage of glycosidic bonds occurred under the reaction conditions. The desired product, aldonamide, was formed by nucleophilic attack of amine to the glyconolactone. The one-pot two-step process was convenient for aldose amidation with amino esters. Direct conjugation of disaccharide with poly-L-lysine and bovine serum albumin were also successfully carried out via oxidative amidation. The oxidative amidation may provide a new and rapid approach for direct synthesis of glycopeptides of unprotected and unmodified oligosaccharides by linkage with the amino groups of peptides. This method can be further applied to the preparation of carbohydrate-based vaccines and to increase bioavailability of peptide drugs. |
URI: | http://ntur.lib.ntu.edu.tw//handle/246246/187431 |
顯示於: | 化學系 |
檔案 | 描述 | 大小 | 格式 | |
---|---|---|---|---|
ntu-97-R95223010-1.pdf | 23.32 kB | Adobe PDF | 檢視/開啟 |
在 IR 系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。