結合化學與酵素方法合成具神經增生活性之神經節苷脂LLG-5中Neu5Gc-α-(2,3)-Lac-β-Phytosphingosine片段

Chemoenzymatic Synthesis of Neuritogenic-Active Ganglioside LLG-5 Precursor: the Neu5Gc-α-(2,3)-Lac-β-Phytosphingosine Moiety

陳安宜(Chen, An Yi)

指導教授 ： 林俊成

國立清華大學/理學院/化學系/碩士(2015年)

https://doi.org/10.6843/NTHU.2015.00101

摘要

LLG-5為Higuchi的研究團隊從海星Linckia laevigata身上純化分離所得到的神經節苷脂，並鑑定其結構為8-OMeNeuGcα2→11NeuGcα2→11NeuGcα2→3Galβ1→4Glcβ1→1Cer，同時亦證明在神經生長因子的輔助下，LLG-5具有神經增生的活性，顯示此化合物具有成為治療帕金森氏症等神經系統疾病的藥物潛力。
LLG-5前趨物之合成方法如下：為了可以快速建立植物鞘胺醇（phytosphingosinee）上三個立體中心的結構，我們以來蘇糖（D-lyxose） 做為起始物，經由Wittig反應引入所需的碳鏈長度，得到植物鞘胺醇的類似物，接著再進行Mitsunobu反應將C-2位置的羥基轉為疊氮官能基。接著植物鞘胺醇受體和乳糖衍生物予體進行醣基化反應得到植物神經鞘乳糖脂質（lactosyl phytosphingosine）。具有Neu5Cbz之GM3衍生物合成則是利用建構好的植物神經鞘乳糖脂質為受體與CMP-Neu5Cbz予體，在唾液酸轉移酶的催化下，進行唾液酸醣基化反應，即可生成單一α-位向唾液酸苷鍵結之唾液酸基化醣脂質。總結上述，以乳糖為起始物，經過5個步驟成功合成出LLG-5前趨物，總產率12%。

關鍵字

神經節苷脂 ； 植物鞘胺醇 ； 唾液酸化 ； 醣 ； 醣脂質

並列摘要

A new ganglioside, LLG-5 was purified from starfish Linckia laevigata by Higuchi group in 2005 and the structure was determined as 8-OMe-NeuGcα2→11NeuGcα2→11NeuGcα2→3Galβ1→4Glcβ1→1Cer. Moreover, LLG-5 displays neuritogenic activity toward rat pheochromocytoma PC-12 cells in the presence of nerve growth factor. The activity is greater than that of the mammalian ganglioside GM1. Therefore, LLG-5 is regarded as a potential drug to cure nervous system disease such as Parkinson's disease.
In our synthetic approach toward LLG-5, D-lyxose was chosen as the starting material to efficiently construct three stereogenic centers of phytosphingosine, and the lipid chain was introduced via Wittig olefination. After coupling of D-lyxose with lipid Wittig reagent, the hydroxyl group on C2 of the resulting hydroxyl lipid was converted to azido group by Mitsunobu reaction. With the phytosphingosine acceptor in hand, different lactose donors were prepared to investigate their glycosylation with phytosphingosine. The GM3 derivative with Neu5NCbz was synthesized by enzymatic sialylation using CMP-Neu5NCbz and the above lactosyl lipid. By using enzymatic synthesis, we can obtain the exclusively α sialylated glycolipid. In conclusion, we have successfully synthesized the LLG-5 precursor in 12% yield with 5 steps (from lactose).

並列關鍵字

Ganglioside ； Phytosphingosine ； Sialylation ； Carbohydrate ； Glycolipid

參考文獻

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