Cu(II)-Self-Assembling Bipyridyl-Glycoclusters and Dendrimers Bearing the Tn-Antigen Cancer Marker: Syntheses and Lectin Binding Properties.

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Abstract Using the carbohydrate cancer marker, T N -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 (IC 50 7.14, 1.82, 4.09 μM, respectively) when compared to the monomer (IC 50 158.3 μM) while the Cu(II)-complexes showed up to a 259-fold increase potencies (IC 50 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 (IC 50 0.63 μM).