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Org Biomol Chem. 2017 May 3;15(17):3681-3705. doi: 10.1039/c7ob00443e.

Stereodivergent synthesis of right- and left-handed iminoxylitol heterodimers and monomers. Study of their impact on β-glucocerebrosidase activity.

Author information

1
Laboratoire de Synthèse Organique et Molécules Bioactives (SYBIO), Université de Strasbourg/CNRS (UMR 7509), Ecole Européenne de Chimie, Polymères et Matériaux (ECPM), 25 rue Becquerel, 67087 Strasbourg, France. philippe.compain@unistra.fr annebod@unistra.fr.

Abstract

A library of dimers and heterodimers of both enantiomers of 2-O-alkylated iminoxylitol derivatives has been synthesised and evaluated on β-glucocerebrosidase (GCase), the enzyme responsible for Gaucher disease (GD). Although the objective was to target simultaneously the active site and a secondary binding site of the glucosidase, the (-)-2-iminoxylitol moiety seemed detrimental for imiglucerase inhibition and no significant enhancement was obtained in G202R, N370S and L444P fibroblasts. However, all compounds having at least one (+)-2-O-alkyl iminoxylitol are GCase inhibitors in the nano molar range and are significant GCase activity enhancers in G202R fibroblats, as confirmed by a decrease of glucosylceramide levels and by co-localization studies.

PMID:
28401966
DOI:
10.1039/c7ob00443e
[Indexed for MEDLINE]

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