Synthetic introduction of aglyconic substitutions into carbohydrate ligands is an approach toward identifying potent inhibitors of medically relevant lectins. We tested a panel of 27 galactoside/lactoside derivatives harboring varying aglycone moieties together with some O-3/O-3′ functionality toward a biohazardous plant toxin and four human adhesion/growth-regulatory galectins. Differential sensitivity profiles of lectin binding with cases showing activity increase relative to galactose/lactose were revealed by systematic assessments using a solid-phase assay. Quantitative differences between the homologous human proteins could even be detected. Binding of substituted lactosides to galectins-1 and -3 was shown to be enthalpically driven. To determine the potential of substituted glycosides to protect cells from harmful lectin association, binding assays with human tumor cells were performed. Invariably, compounds were identified with increased potency relative to the unsubstituted parent sugars. However, aglyconic substitutions were shown to be able to convey cytotoxicity. This report directs further attention to examining additional 2′- and 3′-substitutions of the galactose core and the potential of ligand presentation in glycoclusters to enhance avidity and selectivity, continuing to use the herein applied strategic combination of a convenient biochemical test system with bioassays.
ASJC Scopus subject areas
- Materials Chemistry