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

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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.

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

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Publication details

The article was received on 22 Feb 2017, accepted on 30 Mar 2017 and first published on 12 Apr 2017


Article type: Paper
DOI: 10.1039/C7OB00443E
Citation: Org. Biomol. Chem., 2017, Advance Article
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    Stereodivergent synthesis of right- and left-handed iminoxylitol heterodimers and monomers. Study of their impact on β-glucocerebrosidase activity

    F. Stauffert, J. Serra-Vinardell, M. Gómez-Grau, H. Michelakakis, I. Mavridou, D. Grinberg, L. Vilageliu, J. Casas, A. Bodlenner, A. Delgado and P. Compain, Org. Biomol. Chem., 2017, Advance Article , DOI: 10.1039/C7OB00443E

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