Synthesis of multivalent lactose derivatives by 1,3-dipolar cycloadditions: selective galectin-1 inhibition |
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Authors: | Tejler Johan Tullberg Erik Frejd Torbjörn Leffler Hakon Nilsson Ulf J |
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Affiliation: | Organic Chemistry, Lund University, PO Box 124, SE-221 00 Lund, Sweden. |
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Abstract: | 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 Kd value as low as 3.2 microM 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. |
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Keywords: | Galectin Lectin Triazole Multivalence Cluster effect Inhibition |
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