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

Abstract

Several sialyl Lewis X (SLex) 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 103−104-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.