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 IC50S of 3100, 509, and 88 microM (6200, 2040, and 703 microM, with respect to monomeric GlcNAc content). IC50s for the LacNAc series were 341, 143, and 86 microM (682, 574, and 692 microM, 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.
Zanini
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Department of Chemistry, University of Ottawa, Ontario, Canada.
Roy
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D000606:Amino Sugars / Q000096:biosynthesis* / Q000138:chemical synthesis* / Q000378:metabolism; D001704:Biopolymers / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D037102:Lectins / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009237:N-Acetyllactosamine Synthase / Q000378:metabolism; D009844:Oligosaccharides / Q000096:biosynthesis* / Q000138:chemical synthesis* / Q000378:metabolism; D037121:Plant Lectins; D014534:UDPglucose 4-Epimerase / Q000378:metabolism; D014532:Uridine Diphosphate Glucose / Q000378:metabolism; D014909:Wheat Germ Agglutinins / Q000378:metabolism
D000606:Amino Sugars; D001704:Biopolymers; D037102:Lectins; D009844:Oligosaccharides; D037121:Plant Lectins; D014909:Wheat Germ Agglutinins; C045629:erythrina lectin; C000458:N-acetyllactosamine; D009237:N-Acetyllactosamine Synthase; D014534:UDPglucose 4-Epimerase; D014532:Uridine Diphosphate Glucose