title: Synthesis and biological activity of divalent ligands based on 3-deoxy-4-thiolactose, an isosteric analogue of lactose.
abstract: We report here the synthesis of divalent ligands containing 3-deoxy-4-thiolactose. This thiodisaccharide has been synthesized using the Michael addition of β-1-thiogalactose to the α,β-unsaturated system of sugar-derived dihydropyranones, followed by the reduction of the remaining carbonyl group. We were able to control the configuration (S) of the stereocenter linked to sulfur (C-4) of the reducing end by conducting the thioglycosylation at high temperature or by isomerization during the reduction of the 2-ulose thiodisaccharide with NaBH4/THF. The energy profile for this reaction on a model compound was calculated. The anomeric position of the 3-deoxy-4-thiolactose was functionalized with a terminal alkyne, which was coupled to azide-containing sugar scaffolds through CuAAC reaction to afford mono- and divalent ligands. The final products were competitive inhibitors of E. coli β-galactosidase in the micromolar range. Their binding affinities to peanut agglutinin (PNA) were determined by isothermal calorimetry, which showed a clear decrease in the Ka values for monovalent derivatives compared to lactose. This report contributes to establishing the role of a particular hydroxyl group of lactose in sugar-protein recognition processes.
authors.affiliation: CIHIDECAR-CONICET, Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón II, Ciudad Universitaria, 1428, Buenos Aires, Argentina.
authors.forename: Alejandro J
authors.initials: AJ
authors.lastname: Cagnoni
authors.forename: Oscar
authors.initials: O
authors.lastname: Varela
authors.forename: José
authors.initials: J
authors.lastname: Kovensky
authors.forename: María Laura
authors.initials: ML
authors.lastname: Uhrig
mesh_terms: D001667:Binding, Competitive; D057930:Click Chemistry; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D007785:Lactose / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D008024:Ligands; D015394:Molecular Structure; D013816:Thermodynamics; D001616:beta-Galactosidase / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D001616:beta-Galactosidase; D007785:Lactose