在眾多的醣體中，腫瘤相關醣體抗原常大量表現在癌細胞表面，例如：Globo-系列鞘醣脂和9-OAc-GD2，因此，可以透過這些腫瘤相關醣體抗原區分腫瘤細胞和正常細胞。所以，腫瘤相關醣體抗原成為癌症免疫疫苗的標靶。此外，腫瘤相關醣體抗原與癌症腫瘤的增殖、入侵、轉移以及血管增生等現象有關。

Globo-系列鞘醣脂被發現大量表達於乳癌細胞表面，非還原端為九號位乙醯基修飾唾液酸的9-OAc-GD2被發現只會表現在癌細胞表面而不會存在於正常細胞。因此，本論文希望合成Globo-系列鞘醣脂及9-OAc-GD2來探討其在生物體內的作用機制，用以發展新的癌症治療方法。

在Globo-系列鞘醣脂的部分，本論文透過化學方法合成Lactose-Sph及Gb3-Sph，並且透過連續一鍋化酵素合成法合成Gb4-Sph, Gb5-Sph, Globo H-Sph及SSEA-4-Sph。最後將脂肪酸建構在醣體上，完成了Globo-系列鞘醣脂之合成。本論文亦利用多種酵素來建構9-OAc-GD2、9-NHAc-GD2及GD2，最後將GD2衍生物建構在DT上，完成GD2衍生物之疫苗。

Cancer cells can be distinguished from normal cells by displaying aberrant levels and types of tumor-associated carbohydrate antigens (TACAs) on their surfaces such as Globo-series glycosphingolipids and 9-OAc-GD2. As a result, TACAs were considered as promising targets for the design of anticancer vaccines. In addition, TACAs regulate tumor proliferation, invasion, metastasis and angiogenesis.

Globo-series glycosphingolipids were overexpressed on breast cancer cells, and 9-OAc-GD2 were only found on tumor cells but not on peripheral nerves and brain. Therefore, we would like to synthesize Globo-series glycosphingolipids and 9-OAc-GD2 analogues for realizing their roles in vivo and immunogenicity study.

For Globo-series glycosphingolipids, the synthetic pathway was initiated by glycosylation of lactose donor and sphingosine. After enzymatic synthesis of Gb4-, Gb5-, Globo H-, and SSEA-4-sphingosine, fatty acids were coupled with sphingosine to form Gb4, Gb5, Globo H and SSEA-4. On the other hand, we conducted a small library of carbohydrate-active enzymes to construct GD2 analogues, including GD2, 9-NHAc-GD2, and 9-OAc-GD2. These glycans were conjugated on DT for immunogenicity study.

中文摘要…I
Abstract…II
謝誌…III
目錄…VI
圖目錄…IX
表目錄…XII
流程目錄…XIII
縮寫對照表…XV
第一章 緒論…1
1-1 前言…1
1-2 腫瘤相關醣體抗原…2
1-2-1 抗原與免疫系統…4
1-2-2 抗原疫苗…7
1-3 醣神經胺醇脂…12
1-3-1 Globo-系列鞘醣脂…15
1-3-2 Ganglio-系列鞘醣脂…16
1-4 神經醯胺的重要性…19
1-4-1 神經醯胺影響生物體內的交互作用…19
1-4-2 神經醯胺對癌症相關病徵的影響…21
1-5 醣神經胺醇脂之合成策略…23
1-5-1 Globo-系列鞘醣脂之合成研究…23
1-5-2 Ganglio-系列鞘醣脂之合成研究…29
1-6 研究動機…34
第二章 Globo-系列鞘醣脂之合成…35
2-1 Globo-系列鞘醣脂之合成溯徑分析…35
2-2 鞘胺醇之合成…36
2-3 Lactose-Sph之建構…41
2-4 以酵素催化完成醣體之建構…42
2-5 Gb3-Sph之建構…45
2-6 脂肪酸之建構以完成Globo-系列鞘醣脂…46
2-7 結論…48
第三章 9-OAc-GD2及其衍生物之合成…49
3-1 9-OAc-GD2及其衍生物之合成溯徑分析…49
3-2 9-OAc-Sia之合成…51
3-3 6-NHAc-ManNAc之合成…53
3-4 9-OAc-GD3及其衍生物之建構…54
3-5 9-OAc-GD2及其衍生物之建構…61
3-6 9-OAc-GD2及其衍生物疫苗之建構…62
3-7 測試乙醯基水解程度…64
3-8 結論…67
第四章 未來展望…68
第五章 實驗部分…69
5-1 Reagents and Solvents…69
5-2 Spectra Notes…70
5-3 High-performance liquid chromatography (HPLC)…70
5-4 Synthetic Procedures and Characterization…71
5-5 General Procedure for GD2 analogues Glycoconjugates…120
5-6 Reaction condition of 9-OAc-GD2 hydrolysis…121
第六章 參考文獻與資料…122

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