TY - JOUR
T1 - Synthesis and Evaluation of Lipophilic Aza-C-glycosides as Inhibitors of Glucosylceramide Metabolism
AU - Wennekes, Tom
AU - van den Berg, Richard J. B. H. N.
AU - Boltje, Thomas Jan
AU - Donker-Koopman, Wilma E.
AU - Kuijper, Bastiaan
AU - van der Marel, Gijsbert A.
AU - Strijland, Anneke
AU - Verhagen, Carlo P.
AU - Aerts, Johannes M. F. G.
AU - Overkleeft, Herman S.
PY - 2010
Y1 - 2010
N2 - 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.
AB - 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.
U2 - 10.1002/ejoc.200901208
DO - 10.1002/ejoc.200901208
M3 - Article
SN - 0075-4617
VL - 2010
SP - 1258
EP - 1283
JO - European Journal of Organic Chemistry
JF - European Journal of Organic Chemistry
IS - 7
ER -