Premium
Synthesis and Evaluation of Lipophilic Aza‐C‐glycosides as Inhibitors of Glucosylceramide Metabolism
Author(s) -
Wennekes Tom,
van den Berg Richard J. B. H. N.,
Boltje Thomas J.,
DonkerKoopman Wilma E.,
Kuijper Bastiaan,
van der Marel Gijsbert A.,
Strijland Anneke,
Verhagen Carlo P.,
Aerts Johannes M. F. G.,
Overkleeft Herman S.
Publication year - 2010
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.200901208
Subject(s) - chemistry , glycoside , iminosugar , linker , stereochemistry , moiety , metathesis , enzyme , alkylation , glucocerebrosidase , glycoside hydrolase , biochemistry , organic chemistry , catalysis , polymer , computer science , polymerization , operating system
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.