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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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Castilla J,Rísquez R,Cruz D,Higaki K,Nanba E,Ohno K,Suzuki Y,Díaz Y,Ortiz Mellet C,García Fernández JM,Castillón S

doi

10.1021/jm3006178

subject

Has Abstract

pub_date

2012-08-09 00:00:00

pages

6857-65

issue

15

eissn

0022-2623

issn

1520-4804

journal_volume

55

pub_type

杂志文章

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