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

廖敬倫(Ching-Lun Liao)

指導教授 ： 林俊宏

國立臺灣大學/生命科學院/生化科學研究所/碩士(2007年)

https://doi.org/10.6342/NTU.2007.01773

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。

關鍵字

α-半乳糖神經醯胺 ； 自然殺手T細胞 ； 限制構形

並列摘要

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.

並列關鍵字

α-Galactosylceramide ； Natural Killer T Cells ； Conformationally Constrained

參考文獻

(1)Wilson, S. B.; Delovitch, T. L. Nat. Rev. Immunol. 2003, 3, 211-222.

(2)Van Kaer, L. Nat. Rev. Immunol. 2005, 5, 31-42.

(3)Kronenberg , M. Annu. Rev. Immunol. 2005, 23, 877-900.

(8)Zeng, Z.; Castano, A. R.; Segelke, B. W.; Stura, E. A.; Peterson, P. A.; Wilson, I. A. Science 1997, 277, 339-345.

(27)Lin, H. C.; Yang, W. B.; Gu, Y. F.; Chen, C. Y.; Wu, C. Y.; Lin, C. H. Org. Lett. 2003, 5, 1087-1089.