Synthesis of multivalent lactose derivatives by 1,3-dipolar cycloadditions: selective galectin-1 inhibition

Acetylene derivatives of phenylalanine, phenethylamine and the multifunctional unnatural amino acids, phenyl-bis-alanine and phenyl-tris-alanine, were synthesized and functionalized with 2-azidoethyl beta-D-galactopyranosyl-(1 -> 4)-beta-D-glucopyranoside via regioselective copper(I)-mediated 1,3-dipolar cycloaddition to give a panel of mono-, di- and trivalent lactoside derivatives. Evaluation of the compounds as inhibitors against the tumour- and inflammation-related galectin-1, -3, 4N, 4C, -4, -7, -8N and -9N revealed a divalent compound with a K-d value as low as 3.2 mu M for galectin-1, which corresponded to a relative potency of 30 per lactose unit as compared to the natural disaccharide ligand lactose. This divalent compound had at least one order of magnitude higher affinity for galectin-1 than for any of the other galectins investigated. (c) 2006 Elsevier Ltd. All rights reserved.