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: Denis Giguère, Sabine André, Marc-André Bonin, Marc-André Bellefleur, Alexandre Provencal, Philipe Cloutier, Bernard Pucci, René Roy, Hans-Joachim Gabius
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 19 Issue 10 Pg. 3280-7 (May 15 2011) ISSN: 1464-3391 [Electronic] England
• PMID: 21524586 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Galectins
• Glycoproteins
• Lectins
• Small Molecule Libraries
• Galactose

Topics

• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Galactose (chemistry, pharmacology)
• Galectins (metabolism)
• Glycoproteins (metabolism)
• Humans
• Jurkat Cells
• Lectins (metabolism)
• Mistletoe (chemistry)
• Models, Molecular
• Protein Binding (drug effects)
• Small Molecule Libraries (chemistry, pharmacology)