We describe here a rational design and synthesis of
(3-O-carboxymethyl)-β-d-galactopyranosyl
α-d-mannopyranoside which is 5 times as active as sialyl Lewis X in binding
to E-selectin and also effective against P-
and L-selectin. A new method for the 1,1-glycosidic bond formation
via coupling of protected trimethylsilyl
β-d-galactoside and α-mannosyl fluoride in the presence of
BF3·Et2O is described.
This paper describes the synthesis of 1,1-linked galactosyl mannosides as sialyl Lewis X mimetics that contain a spiro-ring to position the carboxylate group in a well-defined orientation. It was found that compound 4 is more active as a P-selectin inhibitor (IC50 = 19 microM) than the parent disaccharide 2, which contains a flexible carboxyl group (IC50 = 193 microM). This result is consistent with that observed in the previous NMR study of sialyl Lewis X bound to P-selectin. The chemistry described here should be useful for the development of selective inhibitors of E-, P-, and L-selectins.
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