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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/45017
標題: | α-GalCer及其衍生物之合成 Synthesis of α-GalCer and analogs |
作者: | Bing-Ching Wu 吳秉青 |
指導教授: | 翁啟惠(Chi-Huey Wong) |
關鍵字: | α-Galactosyl Ceramide,α-GalCer,CD1d, 醣脂類化合物,自然免疫殺手T細胞, |
出版年 : | 2010 |
學位: | 碩士 |
摘要: | α-Galactosyl Ceramide(簡稱α-GalCer),是日本一家啤酒製造公司於1993年於天然海綿中萃取出來的醣脂類化合物,生物活性實驗證實可以有效在感染癌症的老鼠身上刺激其自然免疫殺手T細胞(Natural Killer T-Cell)增生以對抗癌細胞。但是進入人體臨床實驗時發現,並沒有明顯的療效,因為α-GalCer在與CD1d結合,會藉由T細胞受器刺激NKT細胞,進而釋放Th1與Th2免疫反應的細胞激素,例如Interferon-γ(IFN-γ)或是Interleukin 4(IL-4);造成在提升抗癌細胞免疫力時,也相對提升抑制性的免疫反應,產生抵消作用。
分析α-Galactosyl Ceramide的結構,主要組成分別是galactose、fatty acids以及phytosphingosine,本實驗室運用電腦模擬設計並合成出許多醣類化合物,目前發現在原結構尾端的fatty acids加上芳香族環的結構,不但繼承α-GalCer抗癌活性,同時也提升與CD1d的結合力,選擇性進行Th1免疫反應,提升抗癌免疫力。 本論文嘗試改變醣基上的修飾,在galactose的4號與5號位置進行氟的修飾(Fluorination),使得醣基化作用(Glycosylation)產生較強的醣苷鍵(Glycosyl Bond),再藉由活性測試以探討此類衍生物是否具有專一性的抗癌免疫能力。 α-Galactosyl Ceramide(also called α-GalCer),was originally discovered by the Pharmaceutical Division of the Kirn Brewery Company during a screen for reagents derived from the marine sponge Agelas mauritianus in 1993, and has showed potential antitumor activity. However, in Phase I study, α-GalCer was ineffective in the treatment of tumor. When α-GalCer bound to CD1d, it activated NKT cells to produced T help 1(Th1) and T help 2(Th2) cytokines, such as Interferon-γ (IFN-γ)and Interleukin 4(IL-4). Both cytokines were hindered by each other, and thus gave no benefit. α-GalCer consisted of galactose, fatty acids and phytosphingosine. Our lab tried to synthesize many derivatives by computer modeling and evaluated the biological activities. The results showed synthetic glycolipid analogs which contained an aromatic ring in the acyl tail or sphingosine tail were more effective than α-GalCer in inducing Th1 cytokines. In this thesis, I tried to modify the α-GalCer by fluorination of 5’- and 4’- hydroxyl group of the galactosyl moiety, and strengthen the glycosyl bonds. These analogs may increase the selectivity toward either Th1 or Th2 cytokines responses, and have great anticancer efficacy and other immune-enhancing activities than α-GalCer itself. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/45017 |
全文授權: | 有償授權 |
顯示於系所單位: | 化學系 |
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