Constrained H-type 2 blood group trisaccharide synthesized in a bioactive conformation via intramolecular glycosylation

The methyl glycoside of the II-type 2 trisaccharide 1 was synthesized in a constrained, bioactive conformation via intramolecular aglycon delivery. Co mputer modeling of the crystal structure of the Ulex europaeus I lectin wit h a docked H-type 2 trisaccharide suggested that the disaccharide Galp(1--> 4)GlcpNAc1-->OCH3 could be tethered in a bioactive conformation if Gal O-6 and GlcNAc O-3 are linked via a three-carbon tether. The ethyl 1-thiogalact opyranoside 13 was used to alkylate the methyl 2-acetamido-2-deoxy glucopyr anoside 7, and the resulting dimer was subjected to intramolecular glycosyl ation following protecting group manipulation. The tethered disaccharide 4 was glycosylated by the activated fucopyranosyl donor 3 to give the protect ed target molecule 17. Solid-phase binding assays showed that the tethered trisaccharide 2 was 3-fold less active than native II-type 2 trisaccharide 1 when assayed against the U, europaeus I lectin, whereas it was 250 times less active when assayed with the Psophocarpus tetragonolobus II lectin. Th e observed activities are consistent with published models for H-trisacchar ide interactions with Ulex: and Psophocarpus lectins and provide further ev idence that suggests reduction of oligosaccharide flexibility by intramolec ular tethering provides no significant gain in binding energy.