A metal-free synthetic approach to peptide-based iminosugar clusters as novel multivalent glycosidase inhibitorsElectronic supplementary information (ESI) available: NMR spectra of compounds 7-13, MALDI-TOF spectra and LC chromatograms of 14-17, Lineweaver-Burk reciprocal plots for the inhibition of the Jack bean α-mannosidase by clusters 14-17. See DOI: 10.1039/c5ra20420h

• Main Authors: Zelli, Renaud, Bartolami, Eline, Longevial, Jean-François, Bessin, Yannick, Dumy, Pascal, Marra, Alberto, Ulrich, Sébastien
• Format: Article
• ISSN: 2046-2069
• DOI: 10.1039/c5ra20420h

Multivalent bioconjugates represent emerging tools for enzyme inhibition. In particular, iminosugar clusters have recently shown promising results for the inhibition of glycosidases. However, most of them are prepared by copper-mediated click reactions. We report herein a metal-free approach based on oxime ligation for preparing iminosugar clusters using cyclic and linear tetra-aldehyde peptide scaffolds and oxyamine iminosugars (40-70% yield). Glycosidase inhibition assays revealed the superiority of the clusters made of the linear scaffold, displaying up to a 77-fold increase of relative potency per iminosugar. Thus, this metal-free approach provides a rapid access to structurally-diverse iminosugar clusters for establishing structure-activity relationships in the context of multivalent glycosidase inhibition. Oxime ligation allowed the preparation of a set of iminosugar clusters from which new Jack bean α-mannosidase inhibitors were identified.