Synthesis of β-d-C-galactopyranosyl compounds including constrained derivatives from clickable building blocks and...

A set of nineteen C-galactopyranosyl ligands, which included constrained compounds based on a bicyclic trans-decalin type system. were synthesized via click chemistry from 2-(β-d-C-galactopyranosyl) ethylene azide intermediates. The compounds were evaluated for binding to various galectins and the most promising inhibitor from the series was a constrained 3-O-benzylated galactopyranose derivative, with a trifluorophenyltriazole appendage; the ligand showed a K_D = 180 μM for Gal-4N, which is ∼7-fold better than lactose and ∼2-fold improved compared to thiodigalactoside; the compound was ∼5-fold selective for Gal-4N compared to Gal-4C. Molecular modelling suggested that the triazole C-H has potential to be involved in a non-classical H-bond with Glu87 carboxylate of Gal-4N, supported by increased affinity observed for trifluorophenyl substituted triazole when compared to fluorophenyl/phenyl derivatives. The modelling indicates that the benzyl aromatic ring may have Pi-Pi interactions with Phe/Trp, accounting for its ability to improve affinity.