治療神經退化疾病之藥物的開發研究:具Neu5Gc和Neu5NH2部分之醣神經鞘醯胺脂質DSG-A類似物的合成

Studies on the Development of Medications for Treating Neurodegenerative Diseases: Synthesis of Ganglioside DSG-A’s Analogues with Neu5Gc and Neu5NH2 Moieties

陳羿諳(Yi-An Chen)

指導教授 ： 蔡祐輔

中原大學/理學院/化學研究所/碩士(2016年)

https://doi.org/10.6840/cycu201600890

摘要

本論文為全合成出天然物DSG-A的類似物，此天然物是在2008年Higuchi從海洋裡棘皮動物門(Echinoderms)中的棘冠海膽 (Diadema Setosum)的卵巢(ovary)中所分離出來的，其活性為40.8%比已經應用在臨床實驗上的GM1(25.4%)還要高出1.6倍。
我們將天然物DSG-A作為先導藥物(Lead compound)，對於的唾液酸部分進行修飾，將其氮上的官能基由原本的乙醯基(NAc)改變成2-羥基乙醯基N-glycolyl(NGc)及三氟乙醯基(NTFA)來做生物活性的測試，除此之外，為了增加化合物的水溶性以利日後生物活性測試，以及探討羥基及烯基是否會影響生物活性，於是我們將神經醯胺脂質上的部分做修飾，未來將完成DSG-A類似物YNGc-1、YNGc-2，YNGc-3、YNTFA-1、YNTFA-2及YNTFA-3。

關鍵字

神經退化疾病之藥物的開發研究, 唾液酸, 醣苷神經鞘醯胺

並列摘要

This paper is a natural product total synthesis of analogs of DSG-A , this is a natural product isolated from the ocean in 2008 Higuchi was Echinodermata (Echinoderms) in the spine crown urchin (Diadema Setosum) ovaries (ovary) in out an activity of 40.8% has been applied GM1 than in clinical trials ( 25.4% ) is much higher than 1.6 times .
We will as a pilot DSG-A natural product drugs (Lead compound), for the sialic acid moiety modified , its functional group on the nitrogen from the original acetyl (NAc) changed to 2-hydroxy- acetyl N-glycolyl (NGc) and trifluoroacetic acetyl (NTFA) to do the test biological activity , in addition , to increase the water-soluble compounds to facilitate future bioassay , and to explore and hydroxy alkenyl will affect biological activity , so we will be part of Ceramide lipid modification on doing in the future will be completed DSG-a analog YNGc-1, YNGc-2, YNGc-3, YNTFA-1, YNTFA-2 and YNTFA-3.

並列關鍵字

Synthesis of Ganglioside DSG-A’s Analogues

參考文獻

3. (a) Eriksson, P. S.; Perfilieva, E.; Bjork-Eriksson, T.; Alborn, A. M.; Nordborg, C.; Peterson, D. A.; Gage, F. H. Nature Med. 1998, 4, 1313. (b) Kornack, D.; Rakic, P. Proc. Natl. Acad. Sci. USA 1999, 96, 5768. (c) Lie, D. C. ; Song, H. Annu. Rev. Pharmacol. Toxicol. 2004, 44, 399. (d) Kiprianova, I.; Freiman, T. M.; Desiderato, S.; Schwab, S.; Galmbacher, R.; Gillardon, F.; Spranger, M. J. Neurosci. Res. 1999, 56, 21.

4. (a) Bregman, B. S. Curr. Opin. Neurobiol. 1998, 8, 800. (b) Bush, T.

8. Hadjiconstantinou, M.; Neff, N. H. J. Neurochem. 1998, 70, 1335.

9. Sonnino, S.; Chigoron, V. Biochim. Biophy. Acata 2000, 63, 1469.

10. Schengrund, C. L. Brain Res. Bull. 1990, 24, 131.