Cu(II)-self-assembling bipyridyl-glycoclusters and dendrimers bearing the Tn-antigen cancer marker: syntheses and lectin binding properties

Using the carbohydrate cancer marker, T-N-antigen (alpha-GalNAc-OR), covalently linked to a bipyridine core, square planar complexes were formed by self-assembly upon simple addition of Cu(11) sulfate. The required alpha-D-GalNAc-OR building block was constructed from 2-azidoethyl 2-acetamido-2-deoxy-alpha-D-glucopyranoside (GlcNAc) by epimerization at C-4 of a suitably protected derivative followed by conventional modifications to provide 2-aminoethyl 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-alpha-D-galactopyranoside. The 2-aminoethyl aglycone was further elongated into a key monomer having an aminocaproic acid spacer together with their corresponding dimers using a double N-alkylation strategy of their N-bromoacetyl derivatives using mono-Boc-1,4-diaminobutane, respectively. The building blocks containing the bipyridyl dimers, having either a short or a long spacer arm, together with the tetramer built from the short spacer derivative were prepared in a convergent manner using 2,2'-bipyridine-4,4'-dicarboxylic acid chloride and the aminated sugar derivatives, respectively. Copper(II)-nucleated GalNAc derivatives containing four and eight residues were obtained from an aqueous solution of the bipyridyl derivatives. The relative inhibitory potencies of these glycodendrimers were evaluated against monomeric allyl alpha-D-GalNAc using a solid-phase competition assay with asialoglycophorin and horseradish peroxidase-labeled lectin Vicia villosa. The di- and tetra-valent bipyridyl clusters showed up to 87-fold increased inhibitory properties (IC50 7.14, 1.82, 4.09 muM, respectively) when compared to the monomer (IC50 158.3 muM) while the Cu(II)-complexes showed up to a 259-fold increase potencies (IC50 0.61 muM) with the octamer showing the highest affinity. However, when expressed on a per-saccharide basis, the tetramer Cu(II) nucleated derivative, possessing the longest inter-sugar distances showed the highest affinity (IC50 0.63 muM). (C) 2003 Elsevier Science Ltd. All rights reserved.