Stereodivergent synthesis of right- and left-handed iminoxylitol heterodimers and monomers. Study of their impact on β-glucocerebrosidase activity. Issue 17 (12th April 2017)

• Record Type: Journal Article
• Authors: Stauffert, Fabien; Serra-Vinardell, Jenny; Gómez-Grau, Marta; Michelakakis, Helen; Mavridou, Irene; Grinberg, Daniel; Vilageliu, Lluïsa; Casas, Josefina; Bodlenner, Anne; Delgado, Antonio; Compain, Philippe
• Is Part Of: Organic & biomolecular chemistry. Volume 15:Issue 17(2017)
• Page Start: 3681
• Page End: 3705
• Publication Date: 2017-04-12
• Subjects: Chemistry, Organic -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1039/c7ob00443e
• Languages: English
• ISSNs: 1477-0520

Abstract

Abstract : Unprecedented Janus-faced iminosugars act as pharmacological chaperones for the treatment of Gaucher disease. 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.