title: Acyclic tethers mimicking subunits of polysaccharide ligands: selectin antagonists.
abstract: We report on the design and synthesis of molecules having E- and P-selectins blocking activity both in vitro and in vivo. The GlcNAc component of the selectin ligand sialyl Lewis(X) was replaced by an acyclic tether that links two saccharide units. The minimization of intramolecular dipole-dipole interactions and the gauche effect would be at the origin of the conformational bias imposed by this acyclic tether. The stereoselective synthesis of these molecules, their biochemical and biological evaluations using surface plasmon resonance spectroscopy (SPR), and in vivo assays are described. Because the structure of our analogues differs from the most potent E-selectin antagonists reported, our acyclic analogues offer new opportunities for chemical diversity.
authors.affiliation: Bio-Organic Chemistry Laboratory, Institut de Recherches Cliniques de Montréal (IRCM) , Montréal, Québec H2W 1R7, Canada.
authors.forename: Mickael
authors.initials: M
authors.lastname: Calosso
authors.affiliation: Bio-Organic Chemistry Laboratory, Institut de Recherches Cliniques de Montréal (IRCM) , Montréal, Québec H2W 1R7, Canada.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Tambutet
authors.affiliation: Bio-Organic Chemistry Laboratory, Institut de Recherches Cliniques de Montréal (IRCM) , Montréal, Québec H2W 1R7, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Charpentier
authors.affiliation: Bio-Organic Chemistry Laboratory, Institut de Recherches Cliniques de Montréal (IRCM) , Montréal, Québec H2W 1R7, Canada.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: St-Pierre
authors.affiliation: Bio-Organic Chemistry Laboratory, Institut de Recherches Cliniques de Montréal (IRCM) , Montréal, Québec H2W 1R7, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Vaillancourt
authors.affiliation: Bio-Organic Chemistry Laboratory, Institut de Recherches Cliniques de Montréal (IRCM) , Montréal, Québec H2W 1R7, Canada.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Bencheqroun
authors.affiliation: Département de Pharmacologie, Université de Montréal , Montréal, Québec H3C 3J7, Canada.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Gratton
authors.affiliation: Bio-Organic Chemistry Laboratory, Institut de Recherches Cliniques de Montréal (IRCM) , Montréal, Québec H2W 1R7, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Prévost
authors.affiliation: Bio-Organic Chemistry Laboratory, Institut de Recherches Cliniques de Montréal (IRCM) , Montréal, Québec H2W 1R7, Canada ; Département de Chimie, Université de Montréal , Montréal, Québec H3C 3J7, Canada ; Department of Chemistry, McGill University , Montréal, Québec H3A 2K6, Canada.
authors.forename: Yvan
authors.initials: Y
authors.lastname: Guindon
keywords: Polysaccharide-based ligands; carbohydrate recognition domain; selectin antagonists; sialyl LewisX; surface plasmon resonance spectroscopy