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

• Published in: Journal of organic chemistry Vol. 72; no. 4; pp. 1088 - 1097
• Main Authors: Wennekes, Tom, van den Berg, Richard J. B. H. N, Donker, Wilma, van der Marel, Gijsbert A, Strijland, Anneke, Aerts, Johannes M. F. G, Overkleeft, Herman S
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 16.02.2007; Amer Chemical Soc
• Subjects: 1-Deoxynojirimycin - analogs & derivatives; 1-Deoxynojirimycin - chemical synthesis; 1-Deoxynojirimycin - pharmacology; Alicyclic compounds; Alicyclic compounds, terpenoids, prostaglandins, steroids; Carbohydrates with 4, 5, 6, ... C atoms, dissacharides and oligosaccharides; Carbohydrates. Nucleosides and nucleotides; Chemistry; Chemistry, Organic; Exact sciences and technology; Gaucher Disease - drug therapy; Gaucher Disease - enzymology; Gaucher Disease - metabolism; Glucosylceramides - metabolism; Glucosyltransferases - antagonists & inhibitors; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Humans; Inhibitory Concentration 50; Lipids; Molecular Structure; Organic chemistry; Physical Sciences; Preparations and properties; Science & Technology; IN-VITRO; GLUCOCEREBROSIDASE; DESIGN; IMINO SUGARS; BIOSYNTHESIS; MEMBRANE; DISEASE; STEREOSELECTIVE-SYNTHESIS; GLYCOSYLATION; N-BUTYLDEOXYNOJIRIMYCIN; Molecular flexibility; Enzyme; Nitrogen heterocycle; Lead compound; Sphingolipid; Lipids; Oside; Biosynthesis; Selectivity; Synthase; Miglustat; Metabolism; Glycolipid; Lipophilic compound; Functionalization; Iminoalditol; Piperidine derivatives; Sphingoglycolipid; Inhibitor; C-Glycoside; Chemical synthesis
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo061280p

In this article, we present a straightforward synthesis of adamantan-1-yl-methoxy-functionalized 1-deoxynojirimycin derivatives. The used synthetic routes are flexible and can be used to create a wide variety of lipophilic mono- and difunctionalized 1-deoxynojirimycin derivatives. The compounds reported here are lipophilic iminosugar based on lead compound 4, a potent inhibitor of the three enzymes involved in the metabolism of the glycosphingolipid glucosylceramide. Iminosugar-based inhibitors of glucosylceramide synthase, one of these three enzymes, have attracted increasing interest over the past decade due to the crucial role of this enzyme in glycosphingolipid biosynthesis. Combined with the fact that an increasing number of pathological processes are being linked to excessive glycosphingolipid levels, glucosylceramide synthase becomes a very attractive therapeutic and research target. Our results presented here demonstrate that relocating the lipophilic moiety from the nitrogen atom to other positions on the 1-deoxynojirimycin ring system does not lead to a more potent or selective inhibitor of glucosylceramide synthase. The β-aza-C-glycoside analogue (17) retained the best inhibitory potency for glucosylceramide synthase and is a more potent inhibitor than the therapeutic agent N-butyl-1-deoxynojirimycin (3), marketed as treatment for Gaucher disease under the commercial name Zavesca.