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

Using the carbohydrate cancer marker, TN-antigen (α-GalNAc-OR), covalently linked to a bipyridine core, square planar complexes were formed by self-assembly upon simple addition of Cu(II) sulfate. The required α-d-GalNAc-OR building block was constructed from 2-azidoethyl 2-acetamido-2-deoxy-α-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-α-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 α-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 μM, respectively) when compared to the monomer (IC50 158.3 μM) while the Cu(II)-complexes showed up to a 259-fold increase potencies (IC50 0.61 μM) 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 μM).