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標題: | 利用exo-Glycal化學合成含限制構形α-半乳糖神經醯胺
類似物並且探討其對於自然殺手T細胞之生物活性 Synthesis of Conformationally Constrained α-Galactosylceramide Analogues by exo-Glycal Chemistry and Evaluation of Biological Activity on Natural Killer T Cells |
作者: | Ching-Lun Liao 廖敬倫 |
指導教授: | 林俊宏(Chun-Hung Lin) |
關鍵字: | α-半乳糖神經醯胺,自然殺手T細胞,限制構形, α-Galactosylceramide,Natural Killer T Cells,Conformationally Constrained, |
出版年 : | 2007 |
學位: | 碩士 |
摘要: | 自然殺手T (NKT) 細胞是會同時表現T細胞受器及自然殺手細胞標記的一種T淋巴細胞。NKT細胞藉由非典型主要組織相容複合體 (MHC) I分子:CD1d 辨識醣脂質抗原。目前已知人類或是老鼠CD1d所呈獻的醣脂質之中,α-半乳糖苷神經醯胺 (α-GalCer) 具有最強的免疫刺激活性。α-GalCer是由海棉中的天然物加以衍生而來的分子,早期發現其具有抗癌活性。在後來的研究中指出α-GalCer可以與CD1d結合,藉由T細胞受器刺激NKT細胞,進而釋放出會產生TH1或TH2免疫反應的細胞激素,例如干擾素-γ (IFN-γ) 或間白素-4 ( IL-4)。
修飾α-GalCer的結構可能會導致刺激活性的改變,或是使細胞激素的釋放產生變化。許多報導已經描述了α-GalCer被NKT細胞辨視所需要的結構特徵,而在這些研究當中,卻鮮少有人去探討醣基構形對於活性的影響。在此,我們設計及合成了一系列含限制構形的α-GalCer類似物,並且以不同的脂肪醯鏈加以修飾。在醣化反應的關鍵步驟中,則使用exo-glycals 化學提供高度的立體選擇性。我們也藉由測試細胞激素的釋放以探討這些分子是否具有刺激NKT 細胞的能力。 Natural killer T (NKT) cells are a novel subset of T cells that express both T-cell and natural killer (NK)-cell markers. NKT cells recognize non-classical MHC class I molecule CD1d in conjunction with glycolipid antigens. Among the reported glycolipids presented by human or mouse CD1d, α-galactosylceramide (α-GalCer) shows the highest immune-stimulatory activities. α-GalCer is derived from a marine sponge natural product and has been shown to possess antitumor activity. Further studies indicate that α-GalCer can bind to CD1d and activate NKT cells through T cell receptor (TCR) recognition to produce T helper 1 (TH1) and T helper 2 (TH2) cytokines, such as interferon-γ (IFN-γ) and interleukin-4 (IL-4), respectively. Modification of α-GalCer may alter the level of stimulatory activity and/or switch the cytokine pattern released by NKT cells. Several reports have described the structural requirement for α-GalCer recognition by CD1d-restricted NKT cells, but few of them studied the effect of sugar conformation. Herein we designed and synthesized conformationally constrained α-GalCer analogues with different fatty acyl chains. The key step employs the glycosylation of exo-glycals, offering the advantage of exclusive stereoselectivity. We also evaluated their ability to activate mouse NKT cells by measuring cytokine release profiles. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/28793 |
全文授權: | 有償授權 |
顯示於系所單位: | 生化科學研究所 |
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