- 學位論文
具神經再生活性之醣苷神經鞘胺酯質的研究:醣苷神經鞘胺酯質DSG-1之類似物DSG-1a的合成
Study on the Synthesis of Glycosphingolipids with Neuritogenic Bioactivity: Synthesi of Glycosphingolipids DSG-1 Analogue DSG-1a
摘要
神經退化或受損引發的疾病，一直困擾人類。如何解決此些問題，也是研究的重要之一課題。 具神經再生活性的醣苷神經鞘胺脂質DSG-1(Diadema Setosum Ganglioside)，是由海洋生物-刺冠海膽(Diadema Setosum)的卵巢(ovary)中所分離得到。由於所具的生物活性，及加以文獻只見少數相關的合成，所以引發本實驗室對DSG-1及其類似物DSG-1a之全合成研究的興趣。 DSG-1a與DSG-1的差異，乃在於植物神經鞘胺醇之碳鏈的不同，DSG-1a者為十七個碳，而DSG-1者為十八個碳；其餘的組成(5Ac-唾液酸、葡萄糖與十八烷酸)與結構(NeuAcα2→6Glcβ1→1 ceramide)皆相同。 本論文研究最終的目地，乃期能以一鍋化兩步糖苷化反應策略，合成相關之醣苷神經鞘胺酯質化合物。為達成此目標，本論文先著手逐步反應合成化合物DSG-1a，以證實合成設計的可行性。 為達一鍋化兩步醣苷化反應的目地，本論文採用直交醣苷化反應策略。即在唾液酸醣體Neu-3，我們引進PhS-離去基；而在葡萄糖建構單元體Glc-15，我們以-STaz作為離去基。 醣供體唾液酸Neu-3與醣受體葡萄糖Glc-15進行醣苷化反應，製得產率為63 %的雙醣混合物NG-1，其α:β為3.2 : 1.0。雙醣混合物NG-1與植物神經鞘胺醇衍生物Lyx-9進行醣苷化反應，得到單一β-組態(葡萄糖部分)產物NGL-1αβ及NGL-1ββ，產率為62 %。 醣酯質化合物NGL-1αβ，後續經由醣胺化反應及去保護基反應，可成功合成目標物DSG-1a。
關鍵字
醣苷神經鞘胺酯質並列摘要
The diseases caused by the nerve degeneration and never damage bring humanity big trouble. For this reason, It is emergent to search and develop efficient methods or efficacious drugs to enhance never regeneration for scientists. Ganglioside DSG-1, isolated from the the ovary of the sea urchin Diadema setosum, and possesses NeuAc (N-acetylneuraminic acid) α2→6Glcβ1→1Cer, displays neuritogenic activity toward the rat pheochromocytoma cell line PC-12 cell in the presence of NGF. Due to the difficulty of observing enough purity and amount of DSG-1 from natural resources for clinical use, none of related synthesis in literatures, we propose to chemically prepare the DSG-1 compound and its analogues DSG-1a and then explore the bioactivity of never regeneration. However, the difference between DSG-1a and DSG-1 is the length of carbon chain of phytosphingosine moiety. The length of carbon chain of phytosphingosine is seventeen carbons for DSG-1a and eighteen carbons for DSG-1. To develop the one-pot two-step glycosylations to conform the essence of “Green Chemistry” for the synthetic methods, we adopt the orthogonal leaving-group stratagey. That is we assemble a leaving group PhS- at anomeric carbon of Neu-3 and introduce TazS- as leaving group at anomeric carbon of Glc-15. Glycosylation of glycosyl donor Neu-3 with glycosyl acceptor Glc-15 afforded a disaccharide NG-1 as a ca. 3.2:1.0 in mixture of α- and β-stereoisomers in 63% yield. The disaccharides containing phytosphingosine NGL-1αβ and NGL-1ββ (62% yield) were prepared by the glycosylation of disaccharide NG-1 and phytosphingosine derivative LYX-9 and the stereochemistry of glucose moiety was single β -configuration. The synthesis of the target compound DSG-1a was achieved by the amidization, debenzylation, and deacetylation of NGL-1αβ.