Small molecules as structural and functional mimics of sialyl Lewis X tetrasaccharide in selectin inhibition: A remarkable enhancement of inhibition by additional negative charge and/or hydrophobic group

Several sialyl Lewis X (SLe(x)) mimics that contain the essential functional groups for receptor interaction and a negative charge or a hydrophobic group have been developed as inhibitors of E-, P-, and L-selectins. Some of the mimics exhibit selectin inhibition activities 10(3)-10(4)-fold more potent than does the natural ligand tetrasaccharide, with IC50 in the low micromolar to high nanomolar range. The syntheses of these mimics are relatively simple, using TMSOTf-Ac2O mediated C-glycosylation with concurrent selective deprotection of the primary benzyl group and enzymatic aldol addition reactions as key steps.