title: Development of adamantan-1-yl-methoxy-functionalized 1-deoxynojirimycin derivatives as selective inhibitors of glucosylceramide metabolism in man.
abstract: 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 beta-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.
authors.affiliation: Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: Wennekes
authors.forename: Richard J B H N
authors.initials: RJ
authors.lastname: van den Berg
authors.forename: Wilma
authors.initials: W
authors.lastname: Donker
authors.forename: Gijsbert A
authors.initials: GA
authors.lastname: van der Marel
authors.forename: Anneke
authors.initials: A
authors.lastname: Strijland
authors.forename: Johannes M F G
authors.initials: JM
authors.lastname: Aerts
authors.forename: Herman S
authors.initials: HS
authors.lastname: Overkleeft
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D005776:Gaucher Disease / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D005963:Glucosylceramides / Q000378:metabolism*; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure
chemical_list: D005963:Glucosylceramides; D017485:1-Deoxynojirimycin; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase