Synthesis and Evaluation of Lipophilic Aza-C-glycosides as Inhibitors of Glucosylceramide Metabolism

Tom Wennekes, Richard J. B. H. N. van den Berg, Thomas Jan Boltje, Wilma E. Donker-Koopman, Bastiaan Kuijper, Gijsbert A. van der Marel, Anneke Strijland, Carlo P. Verhagen, Johannes M. F. G. Aerts, Herman S. Overkleeft

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The structure–activity relationship of lipophilic aza-C-glycosides as inhibitors of the three enzymes of glucosylceramide metabolism is investigated. A library of β-aza-C-glycosides was synthesized with variations in N-alkylation and the linker length/type to the lipophilic moiety. A cross-metathesis reaction was used to prepare a second library of α-aza-C-glycosides with D-gluco, L-ido and D-xylo iminosugar cores possessing analogous linker variations. Evaluation of both libraries did not reveal a potent or selective inhibitor of glucosylceramide synthase. However, β-aza-C-glycoside 43 was found to be a selective inhibitor of β-glucosidase 2. The α-aza-C-glycosides – especially with a D-xylo core (e.g. 80) – proved to be very potent and selective inhibitors of glucocerebrosidase.
Original languageEnglish
Pages (from-to)1258-1283
JournalEuropean Journal of Organic Chemistry
Volume2010
Issue number7
DOIs
Publication statusPublished - 2010
Externally publishedYes

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