The Chelate Effect Multivalent Ligands That Can Span Two Saccharide Binding Sites Within the ConA Tetramer Are the Most Potent Inhibitors

Multipoint binding leads to an amplification in specificity, perhaps at least partly accounting for the high selectivity of multidentate ligand binding by ConA. In multipoint binding, multiple saccharide epitopes would coincidentally contact ConA, and if this model is important, ligands that could simultaneously occupy more than one saccharide binding site within the ConA tetramer would be expected to be more potent inhibitors. The large distance between the binding grooves, predicted to be approximately 65 A from X-ray crystallographic analysis, is easily spanned by linear polymers. Although few polymerization strategies offer control over polymer size, ROMP can be used to generate polymers of defined length.

Figure 12 Kiessling's C-gluco- (8) and mannopyranosides (9) demonstrate increased functional affinity and specificity when displayed as bivalent mannose (13) and glucose (12) ligands.

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Figure 12 Kiessling's C-gluco- (8) and mannopyranosides (9) demonstrate increased functional affinity and specificity when displayed as bivalent mannose (13) and glucose (12) ligands.

Kanai et al. set out to prepare and determine the ConA inhibitory potencies of series of mannose-substituted oligomers differing in length (Fig. 13) [84]. Studies by the Grubbs group suggested that ruthenium carbene complexes can carry out living polymerization with the initiation step approximately eightfold faster than propagation [82]. Therefore, by varying the ratio of monomer 14 to initiator 15 in the reaction mixture, multidentate mannose ligands 16a-c of controlled length could be assembled. The effect of polymer length on inhibitory potency was assessed in a ConA-mediated cell agglutination assay. Interestingly, the relative potency of the

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