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 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.
Tejler
Johan
J
Organic Chemistry, Lund University, PO Box 124, SE-221 00 Lund, Sweden.
Tullberg
Erik
E
Frejd
Torbjörn
T
Leffler
Hakon
H
Nilsson
Ulf J
UJ
D000114:Acetylene / Q000031:analogs & derivatives / Q000138:chemical synthesis; D037483:Galectin 1 / Q000037:antagonists & inhibitors*; D007785:Lactose / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D014230:Triazoles / Q000138:chemical synthesis
D037483:Galectin 1; D014230:Triazoles; D007785:Lactose; D000114:Acetylene