- 學位論文
合成八號位置修飾的唾液酸衍生物及神經節苷脂 LLG-5
Synthesis of C-8 Modified Sialosides and toward Synthesis of Ganglioside LLG-5
摘要
神經節苷脂在生物體中扮演許多的角色，如細胞辨識、細胞-細胞間的交互作用、細胞分化及細胞的訊息傳遞等。而從棘皮動物中分離出的新型神經節苷脂，在神經生長因子的輔助下，則可刺激大鼠 PC-12 細胞，增加神經再生的活性，為治療帕金森氏症等神經系統疾病的潛力藥物，文獻報導中指出，非還原端之唾液酸在 C-8 修飾有甲基及硫酸根的神經節苷脂其刺激神經再生活性更好。 本論文以有機合成的方法將唾液酸 C-8 修飾為甲基及硫酸根，但在進行 O-甲基化時，面臨唾液酸 C-5 之 N-甲基化之競爭反應，合成策略改為將 NHAc 轉換為疊氮基（N3）進行唾液酸 C-8 甲基化反應後，再還原疊氮基為胺基來進行醯胺鍵生成反應，完成唾液酸 C-8 甲基化且 C-5 分別修飾為 NHAc 及 NHGc 的唾液酸衍生物。 以市售的唾液酸（Neu5Ac）為起始物，分別經過 17 步及 13 步可合成出 C-8 修飾成甲基的Neu5Ac8Me 和硫酸根的Neu5Ac8SO3-Na+，總產率分別為 12% 及 20%。相同的策略亦運用在合成神經節苷脂 LLG-5 非還原端的雙唾液酸（8-OMeNeuGcα2→11NeuGcα2）片段，另外，亦由（S）-甘油醛縮丙酮 48及 phosphonium salt 46為起始物經由 Wittig 反應，合成 LLG-5 另一核心片段─脂肪醯鏈，以利後續 LLG-5 之全合成研究。
並列摘要
Gangliosides play important roles in essential biological events including cellular recognition, cell-cell interaction, cell differentiation, and cellular transduction. In addition, the slight modification of terminal sialic acid (N-acetylneuraminic acid, Neu5Ac) in the oligosaccharide chain of ganglioside imparts changes in biological activities of the parent gangliosides. The O-methylation and O-sulfation at C-8 position of non-reducing end Neu5Ac are the two most common modification, especially found in ethinodermatous gangliosides (EGs). The C-8 methylated or sulfated EGs displayed a broad spectrum neuritogenic activity on rat pheochromocytoma PC-12 cell in the presence of nerve growth factor. Consequently, EGs are regarded as potential drug to cure nervous system diseases such as Parkinson's disease. In order to synthesize C-8 modified Neu5Ac derivatives, this thesis has developed a new chemical strategy by changing N3 in place of NHAc at the C-5 position of Neu5Ac to avoid competing N-methylation. The C-8 modified Neu5Ac derivatives, Neu5Ac8Me and Neu5Ac8SO3-Na+, were successfully synthesized by a linear 17-and 13-step sequences, with an overall yields of 12% and 20%, respectively, starting from Neu5Ac. Furthermore, the C-8 modified non-reducing end disialic acid (8-OMeNeuGcα2→11NeuGcα2) of the LLG-5 ganglioside was also prepared by following similar approach. On the other hand, the fatty acyl chain of the ganglioside LLG-5 was synthesized via the Wittig reaction using acetonide-protected (S)-glyceraldehyde 48 and phosphonium salt 46. The assembly moieties of the C-8 modified 8-OMeNeuGcα2→11NeuGcα2 disialic acid and the fatty acyl chain towards the synthesis of LLG-5 is currently underway.