Chemoenzymatic synthesis and lectin binding properties of dendritic N-acetyllactosamine

Proof that multivalency amplifies individual carbohydrate-protein interactions is growing. N-Acetylglucosamine (GlcNAc)-based dendrimers with valencies of two (9), four (10), and eight (11) were prepared in fair to excellent yields (65-99%) on the basis of the rational scaffolding of L-lysine on solid phase using established Fmoc and HOBt chemistry. These GlcNAc dendrimers were then further transformed enzymatically (79-90% yields) into dendritic N-acetyllactosamine (LacNAc) derivatives [di- (12), tetra- (13), and octavalent (14)] using UDPglucose, UDP-glucose 4'-epimerase, and GlcNAc beta-1,4-galactosyltransferase. GlcNAc and LacNAc dendrimers were used to inhibit lectin-porcine stomach mucin interactions. Wheat germ agglutinin and Erythrina cristagalli lectin were used for GlcNAc and LacNAc dendrimers, respectively. Di-, tetra-, and octavalent GlcNAc dendrimers exhibited IC(50)s of 3100, 509, and 88 mu M (6200, 2040, and 703 mu M, with respect to monomeric GlcNAc content). IC(50)s for the LacNAc series were 341, 143, and 86 mu M (682, 574, and 692 mu M, as compared with monomeric LacNAc content). These data represent more than 20-fold increases in inhibitory potential for dendritic GlcNAc as compared to that for monomeric GlcNAc. Studies with E. cristagalli do not reveal significant increased inhibitory potential with multivalency.