Acyclic Tethers Mimicking Subunits of Polysaccharide Ligands: Selectin Antagonists

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 LewisX 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.