title: Conformationally-locked N-glycosides with selective β-glucosidase inhibitory activity: identification of a new non-iminosugar-type pharmacological chaperone for Gaucher disease.
abstract: A series of conformationally locked N-glycosides having a cis-1,2-fused pyranose-1,3-oxazoline-2-thione structure and bearing different substituents at the exocyclic sulfur has been prepared. The polyhydroxylated bicyclic system was built in only three steps by treatment of the corresponding readily available 1,2-anhydrosugar with KSCN using TiO(TFA)(2) as catalyst, followed by S-alkylation and acetyl deprotection. In vitro screening against several glycosidase enzymes showed highly specific inhibition of mammalian β-glucosidase with a marked dependence of the potency upon the nature of the exocyclic substituent. The most potent representative, bearing an S-(ω-hydroxyhexadecyl) substituent, was further assayed as inhibitor of the human lysosomal β-glucocerebrosidase and as pharmacological chaperone in Gaucher disease fibroblasts. Activity enhancements in N370S/N370S mutants analogous to those achieved with the reference compound ambroxol were attained with a more favorable chaperone/inhibitor balance.
authors: Department de Química Analítica i Química Orgànica, Universitat Rovira i Virgili , C/Marcel·lí Domingo s/n, 43007 Tarragona, Spain.
authors: Javier
authors: J
authors: Castilla
authors: Rocío
authors: R
authors: Rísquez
authors: Deysi
authors: D
authors: Cruz
authors: Katsumi
authors: K
authors: Higaki
authors: Eiji
authors: E
authors: Nanba
authors: Kousaku
authors: K
authors: Ohno
authors: Yoshiyuki
authors: Y
authors: Suzuki
authors: Yolanda
authors: Y
authors: Díaz
authors: Carmen
authors: C
authors: Ortiz Mellet
authors: José M
authors: JM
authors: García Fernández
authors: Sergio
authors: S
authors: Castillón
mesh_terms: D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D005776:Gaucher Disease / Q000188:drug therapy*; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors* / Q000235:genetics; D006027:Glycosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008968:Molecular Conformation; D009154:Mutation; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012867:Skin / Q000166:cytology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013871:Thiones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D006027:Glycosides; D010080:Oxazoles; D013871:Thiones; D005962:Glucosylceramidase