臺灣博碩士論文加值系統

從大鼠的嗜鉻腫瘤PC12細胞實驗得知，神經節苷脂Hp-s1的神經再生活性比臨床應用的GM-1來得好。為了尋找更具活性的Hp-s1，我們將Hp-s1中間的葡萄醣，置換成α-D-葡萄醣(glucose)、α-D-半乳醣(galactose)、β-D-半乳醣、α-D-甘露醣(mannose)以及β-D-甘露醣，合成出了新的Hp-s1衍生物2a-2f，並且對這些衍生物做了生物活性測試，而本篇論文第一部份主要著重在Hp-s1之β-D-甘露醣衍生物2f合成。
控制唾液酸醣鏈結反應之立體位向，一直是醣化學上具有挑戰性的課題之一。因此本論文的第二部份中，我們研究並做了多種不同條件的唾液酸醣鏈結反應，透過更改促進劑類型、反應溫度、反應物當量數等，找到了建構唾液酸α位向產物之最佳化條件。

Ganglioside Hp-s1 2 has better neuritogenic activity than GM1 in rat pheochromocytoma 12 cells. In order to explore the roles of glucosyl moiety of Hp-s1 in neurology, we have designed and synthesized new analogues (2a-2f). The glucosyl moiety was replaced with α-glucose, α-galactose, β-galactose, α- mannose, and β-mannose and their biological activities on SHSY5Y cells and natural killer T (NKT) cells were evaluated. In the first part of this thesis, we are focused on the synthesis of ganglioside Hp-s1 analogue Neu5Ac α(2→6)Man β(1→1)Cer 2f.
Controlling the stereoselectivity in sialylation is one of the challenges in sialic acid glycosylation. Therefore, in the second part of this thesis, we designed and shown several kinds conditions, for p-tolyl thiosialoside donors to couple with α-methylglucoside acceptor such as various reactant equivalents, promoters and reaction temperature. Finally we found an optimized condition with excellent α-sialylation yields.

謝誌....................................................i
縮寫表................................................iii
摘要...................................................vi
Abstract..............................................vii
目次.................................................viii
表目次................................................xii
圖目次............................................xiii
流程目次.............................................xv
第一部分：...............................................1
簡潔合成神經節苷脂Hp-s1之衍生物............................1
Concise Synthesis of Ganglioside Hp-s1 Analogue Neu5Ac α(2→6)Man β(1→1)Cer.....................................1
一、 緒論................................................2
(一) 前言..................................................................................................2
(二) 阿茲海默症(Alzheimer’s disease, AD) ...........................................3
(三) 神經生長因子(Nerve growth factor, NGF)及PC-12細胞..............4
1. 神經生長因子(nerve growth factor, NGF)......................................5
2. PC-12細胞.........................................................................................5
(四) 醣苷神經鞘胺脂質(Glycosphingolipids, GSLs) ............................6
(五) 神經節苷脂Hp-s1...........................................................................8
(六) 醣苷鍵的立體位向選擇性..............................................................9
1. 變旋異構效應(anomeric effect) ...................................................10
(1) 超共軛效應(hyperconjugation)..............................................11
(2) 偶極穩定能(dipole stabilization) ..........................................12
(3) 電子斥力(electronic repulsion) .............................................12
2. 溶劑效應(solvent effect) .............................................................13
3. 鄰基效應(neighboring group effect) ..........................................13
4. 甘露醣醣苷鍵之位向探討...........................................................14
(1) 甘露醣醣苷鍵之立體位向選擇性.........................................14
(2) 合成具β位向之甘露醣衍生物研究.....................................15
○1 利用活化試劑PhSOTf與DTBMP....................................15
○2 活化試劑組合 BSP/TTBP/Tf2O.........................................16
(七) 神經節苷脂Hp-s1及其衍生物之合成歷史.................................18
1. 2012年中原大學蔡祐輔教授利用chemoselective activation
glycosylation進行Hp-s1衍生物之全合成...................................18
2. 2013年本實驗室完成神經節苷脂Hp-s1之全合成......................20
(八) 研究目標........................................................................................25
二、 結果與討論.......................................................................................26
(一) 神經節苷脂Hp-s1衍生物2a-2f之逆合成分析............................26
(二) Hp-s1衍生物2a之合成...................................................................27
(三) Hp-s1衍生物2b之合成...................................................................29
(四) Hp-s1衍生物2d之合成...................................................................30
(五) Hp-s1衍生物2c之合成...................................................................32
(六) Hp-s1衍生物2e之合成...................................................................34
(七) Hp-s1衍生物2f之合成....................................................................36
1. 製備甘露醣衍生物52....................................................................36
2. 醣脂質88之合成...........................................................................38
3. 化合物88的位向鑑定...................................................................39
4. 醣脂質55之合成...........................................................................42
5. Hp-s1衍生物2f之合成...................................................................42
三、結論....................................................................................................44
第二部分：................................................................................................47
唾液酸醣予體的立體選擇性研究………………………………………47
Study of Stereoselectivity of Sialic Acid Donors……………………….47
四、緒論.....................................................................................................48
(一) 前言................................................................................................48
(二) 唾液酸醣鏈結鍵的位向探討..........................................................49
(三) 唾液酸醣苷鍵之合成策略..............................................................49
1. Hasegawa教授研究團隊................................................................49
2. David Crich教授研究團隊.............................................................49
(1) N-Acetyl-5-N,4-O-carbonyl-protected thiosialoside.................51
(2) 1-Adamantanyl thiosialoside.....................................................54
3. 孫斌教授研究團隊........................................................................55
(四) 研究目標..........................................................................................57
五、結果與討論.........................................................................................59
(一) 唾液酸醣予體125之合成..............................................................59
(二) 葡萄醣醣受體100之合成............................................................59
(三) 唾液酸醣予體之立體選擇性研究...............................................60
(四) 雙醣化合物127及128之立體位向鑑定............................63
(1) 雙醣化合物127之立體位向鑑定............................................63
(2) 雙醣化合物128之立體位向鑑定............................................64
(五) 唾液酸醣鏈結反應最佳化條件之應用.....................................65六、結論....................................................................................................66
七、實驗部分............................................................................................67
(一) 一般實驗敘述...............................................................................67
(二) 實驗步驟與物理數據...................................................................68
八、參考文獻.........................................................................................98
九、化合物核磁共振光譜圖..................................................................105
十、附錄.............................................................................................132

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