Development of Adamantan-1-yl-methoxy-Functionalized 1-Deoxynojirimycin Derivatives as Selective Inhibitors of Glucosylceramide Metabolism in Man

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• 作者：Tom Wennekes ; Richard J. B. H. N. van den Berg ; Wilma Donker ; Gijsbert A. van der Marel ; Anneke Strijland ; Johannes M. F. G. Aerts ; Herman S. Overkleeft
• 刊名：Journal of Organic Chemistry
• 出版年：2007
• 出版时间：February 16, 2007
• 年：2007
• 卷：72
• 期：4
• 页码：1088 - 1097
• 全文大小：333K
• 年卷期：v.72,no.4(February 16, 2007)
• ISSN：1520-6904

文摘

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In this article, we present a straightforward synthesis of adamantan-1-yl-methoxy-functionalized1-deoxynojirimycin derivatives. The used synthetic routes are flexible and can be used to create a widevariety of lipophilic mono- and difunctionalized 1-deoxynojirimycin derivatives. The compounds reportedhere are lipophilic iminosugar based on lead compound 4, a potent inhibitor of the three enzymes involvedin the metabolism of the glycosphingolipid glucosylceramide. Iminosugar-based inhibitors of glucosylceramide synthase, one of these three enzymes, have attracted increasing interest over the past decadedue to the crucial role of this enzyme in glycosphingolipid biosynthesis. Combined with the fact that anincreasing number of pathological processes are being linked to excessive glycosphingolipid levels,glucosylceramide synthase becomes a very attractive therapeutic and research target. Our results presentedhere demonstrate that relocating the lipophilic moiety from the nitrogen atom to other positions on the1-deoxynojirimycin ring system does not lead to a more potent or selective inhibitor of glucosylceramidesynthase. The mages/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-aza-C-glycoside analogue (17) retained the best inhibitory potency for glucosylceramidesynthase and is a more potent inhibitor than the therapeutic agent N-butyl-1-deoxynojirimycin (3), marketedas treatment for Gaucher disease under the commercial name Zavesca.