The disulfide bond as a key motif for the construction of multivalent glycoclusters

• Published in: New journal of chemistry Vol. 46; no. 37; pp. 17682 - 17695
• Main Authors: Cano, María Emilia, Jara, Walter Emiliano, Cagnoni, Alejandro J, Brizzio, Emmanuel, Strumia, Miriam C, Repetto, Evangelina, Uhrig, María Laura
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 26.09.2022; Royal Society of Chemistry
• Subjects: Alkynes; Antigens; Chemical reactions; Chemistry; Chemistry, Multidisciplinary; Cycloaddition; Dimerization; Disaccharides; Lactose; Ligands; Methodology; Monosaccharides; Oxidation; Physical Sciences; Precursors; Science & Technology; Sugar; Titration calorimetry; LIBRARIES; DESIGN; OLIGOSACCHARIDES; LIGANDS; THIOOLIGOSACCHARIDES; GLYCODENDRIMERS; SIALIC-ACID; ANTIGENS; GENERATION; INHIBITORS
• ISSN: 1144-0546; 1369-9261
• DOI: 10.1039/d2nj03071c

In this work, we explored a synthetic dimerization methodology to easily increase the valency of multivalent ligands. First, we synthesized four thiopropargyl sugar derivatives through a one-pot thioglycosylation reaction, to be used as building blocks in copper catalyzed azide alkyne cycloaddition (CuAAC) reactions. While two of them were constructed from β-furanose monosaccharides ( d -Gal f and d -Ara f ), the others were based on disaccharides: lactose and a T-antigen analog. Then, starting from simple precursors, we prepared discrete dendrimer scaffolds carrying both the protected S-linked sugar moieties and a thioacetate group to explore the feasibility of dimerization by treatment under basic conditions where the sugar protecting groups were hydrolyzed. We demonstrated that the oxidation of sulfides to disulfides occurred in the same step, doubling the valency of the unprotected glycoclusters. This methodology showed to be compatible with all the protected sugars employed. Moreover, by using a trivalent precursor based on Behera's amine, a hexavalent ligand having lactose units was successfully obtained by the same synthetic methodology. Binding affinities to human galectin-3 were measured by Isothermal Titration Calorimetry showing dissociation constants in the micromolar range. S-Glycosylated dendrons having a thioacetate group in their focal points led to multivalent glycoclusters by spontaneous O 2 -oxidation of sulfides.