ABSTRACT
A series of lipidated guanidino and urea derivatives of 1,5-dideoxy-1,5-imino-d-xylitol were prepared from d-xylose using a concise synthetic protocol. Inhibition assays with a panel of glycosidases revealed that the guanidino analogues display potent inhibition against human recombinant ß-glucocerebrosidase with IC50 values in the low nanomolar range. Related urea analogues of 1,5-dideoxy-1,5-imino-d-xylitol were also synthesized and evaluated in the same fashion and found to be selective for ß-galactosidase from bovine liver. No inhibition of human recombinant ß-glucocerebrosidase was observed for the urea analogues. Computational studies provided insight into the potent activity of analogues bearing the substituted guanidine moiety in the inhibition of lysosomal glucocerebrosidase (GBA).
Subject(s)
Enzyme Inhibitors/chemistry , Glucosylceramidase/antagonists & inhibitors , Guanidine/chemistry , Xylitol/chemistry , Animals , Binding Sites , Cattle , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/metabolism , Glucosylceramidase/genetics , Glucosylceramidase/metabolism , Humans , Liver/enzymology , Molecular Docking Simulation , Protein Binding , Protein Structure, Tertiary , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/isolation & purification , Structure-Activity Relationship , Xylitol/chemical synthesis , Xylitol/metabolism , beta-Galactosidase/antagonists & inhibitors , beta-Galactosidase/metabolismABSTRACT
A series of bicyclic isourea derivatives were prepared from 1-deoxynojirimycin using a concise synthetic protocol proceeding via a guanidino intermediate. Inhibition assays with a panel of glycosidases revealed that these deoxynojirimycin-derived bicyclic isoureas display very potent inhibition against human recombinant ß-glucocerebrosidase with IC50 values in the low nanomolar range.
