Expeditious Synthesis of C-Glycosyl Barbiturate Ligands of Bacterial Lectins: From Monomer Design to Glycoclusters and Glycopolymers

The approach developed here offers a straightforward and efficient access to β-C-glycosyl barbiturate ligands, spanning from glycomimetics to multivalent C-neoglycoconjugates, with the aim of deciphering structural parameters impacting the binding to pathogenic lectins. We reinvestigated the Knoevenagel condensation of barbituratic acid on protecting-group free carbohydrates and successfully designed sodium and 5,5-disubstituted N,N-dimethyl barbiturate forms of D-galactose, L-fucose, melibiose, 2’-fucosyllactose, maltose and evaluated their binding affinity by isothermal titration calorimetry with LecA (galactose-binding lectin) and LecB (fucose-binding lectin) from Pseudomonas aeruginosa and RSL (fucose-binding lectin) from Ralstonia solanacearum. The barbiturate ring was shown detrimental for binding to LecA (KD in mM range) and even more to LecB (non-interaction) while RSL is much more tolerant especially in presence of an aromatic group (KD in μM range). However, distancing the barbiturate ring from ...