title: Inhibitory potential of chemical substitutions at bioinspired sites of β-D-galactopyranose on neoglycoprotein/cell surface binding of two classes of medically relevant lectins.
abstract: Galactose is the key contact site for plant AB-toxins and the human adhesion/growth-regulatory galectins. Natural anomeric extensions and 3'-substitutions enhance its reactivity, thus prompting us to test the potential of respective chemical substitutions of galactose in the quest to develop potent inhibitors. Biochemical screening of a respective glycoside library with 60 substances in a solid-phase assay was followed by examining the compounds' activity to protect cells from lectin binding. By testing 32 anomeric extensions, 18 compounds with additional 3'-substitution, three lactosides and two Lewis-type trisaccharides rather mild effects compared to the common haptenic inhibitor lactose were detected in both assays. When using trivalent glycoclusters marked enhancements with 6- to 8-fold increases were revealed for the toxin and three of four tested galectins. Since the most potent compound and also 3'-substituted thiogalactosides reduced cell growth of a human tumor line at millimolar concentrations, biocompatible substitutions and scaffolds will be required for further developments. The synthesis of suitable glycoclusters, presenting headgroups which exploit differences in ligand selection in interlectin comparison to reduce cross-reactivity, and the documented strategic combination of initial biochemical screening with cell assays are considered instrumental to advance inhibitor design.
authors.affiliation: PharmaQAM, Department of Chemistry, Université du Québec à Montréal, Canada.
authors.forename: Denis
authors.initials: D
authors.lastname: Giguère
authors.forename: Sabine
authors.initials: S
authors.lastname: André
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Bonin
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Bellefleur
authors.forename: Alexandre
authors.initials: A
authors.lastname: Provencal
authors.forename: Philipe
authors.initials: P
authors.lastname: Cloutier
authors.forename: Bernard
authors.initials: B
authors.lastname: Pucci
authors.forename: René
authors.initials: R
authors.lastname: Roy
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Gabius
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005690:Galactose / Q000737:chemistry* / Q000494:pharmacology*; D037161:Galectins / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D037102:Lectins / Q000378:metabolism*; D014784:Mistletoe / Q000737:chemistry; D008958:Models, Molecular; D011485:Protein Binding / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology
chemical_list: D037161:Galectins; D006023:Glycoproteins; D037102:Lectins; D054852:Small Molecule Libraries; D005690:Galactose