設計與合成誘發Th1免疫反應之長碳鏈上具有苯環取代基的α-galactosylceramide衍生物

Design and synthesis of phenyl-containing α- galactosylceramide analogues that induced Th1-biased immune responses

林昆賢(Kun-Hsien Lin)

指導教授 ： 陳仲瑄

共同指導教授 ： 翁啟惠(Chi-Huey Wong)

國立臺灣大學/理學院/化學研究所/博士(2012年)

https://doi.org/10.6342/NTU.2012.10333

摘要

在過去十多年的研究中發現，人體中含量極為稀少自然殺手T細胞（natural killer T cells），會以其細胞表面的T細胞受器（T cell receptor）去辨識抗原呈現細胞（antigen presenting cells）表面與CD1d蛋白質結合醣脂類抗原分子α-galactosylceramide（α-GalCer），此時自然殺手T細胞會釋出大量的細胞激素(cytokines)，如IFN-γ與IL-4，並活化整個免疫系統。但是α-GalCer在許多實驗及臨床實驗的結果並不理想，缺乏專一性引導Th1或Th2免疫反應的能力，於是吸引很多化學家爭相投入結構改良的研究，不過將近500個被合成出來的衍生物中，卻僅有不到10個化合物是有良好活性的，突顯出這個研究題目最大的難題，是在於
決定方向。

在本實驗室中，由吳博士（Dr. Douglass Wu）所研發出來之一系列fattyacyl chain上含有苯環取代基的α-GalCer短鏈衍生物，被證實的確比以往眾多合成出來之化合物，更具有專一性引導Th1免疫反應的功能，而苯環取代基上再增添一個氟原子（F）取代基的話，效果會更加顯著，此一發現為我們奠定了日後研究基礎。

在此篇論文中，將承續著相同的設計概念去進一步尋找活性更佳的衍生物，化合物C30、C34、C35、C36與C37等具有雙苯環結構的化合物就是在這樣的條件下合成出來的。在這五個化合物中，C34與其他四個化合物的活性相比較為突出，甚至在許多動物實驗的測試結果過後，顯示它的活性比前一代的化合物7DW8-5要好。最後，我們將嘗試著引入第二個氟原子取代基到苯環上面，以期進一步開發出活性更上層樓的C34衍生物，含雙氟原子類衍生物22在初步活性測試所得的結果比23要好，但與C34相較之下，仍需更多實驗數據以做進一步的比
較。

關鍵字

Th1免疫反應 ； 苯環取代基

並列摘要

The glycolipid which was presented by antigen presenting cells (APC) in the complex of CD1d, α-galactosylceramide (α-GalCer), had been found to activate invariant natural
killer T (iNKT) cells and induced the rapid secretion of T helper 1 (Th1) and Th2 cytokines. But α-GalCer was not an efficient immuno-modulator since both Th1 and Th2 cytokines were secreted in the process. Many researchers were working hard to try to improve the selectivity of cytokine secretions of α-GalCer analogues, yet only few of them could achieve this, suggesting the difficulty of this project. In our lab, a series of analogues with phenyl group at the end of truncated fatty acyl chain were proven to efficiently induce Th1-biased responses, and the activity of these analogues could be further improved by adding a fluoro atom on the para position of phenyl ring. This provided us a direction for further studies. Here in this thesis, C30, C34, C35, C36 and C37 were synthesized following the same principle. Among all, C34, an analogue with 4-(4-fluorophenoxy)phenylundecanoyl modification of N-acyl moiety of α-GalCer, was surprisingly found to have superior activities, even in comparison with those phenylcontaining analogues that were previously reported, such as 7DW8-5 or C23. In the end, we’re trying to introduce another fluoro atom onto the phenyl rings of C34, difluoroanaloges 22 was found to show better activity than 23. But the difference between 22 and C34 required further tests to distinguish.

並列關鍵字

Th1 responses ； phenyl-containing ； alpha-galactosylceramide

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