Synthesis of galactofuranosyl-(1 → 5)-thiodisaccharide glycomimetics as inhibitors of a β-D-galactofuranosidase

Abstract

The first synthesis of methyl β-D-galactofuranosyl-(1 → 5)-thiofuranosides is reported. These molecules, which have the 6-deoxy-5-thio derivative of L-altrofuranose (16) or D-galactofuranose (18) as the reducing end, are mimetics of the motif β-D-Galf-(1 → 5)-D-Galf found in glycoconjugates of many pathogenic microorganisms. The conformational preferences of 16 and 18 in solution were assessed by means of molecular modeling and NMR techniques. These thiodisaccharides have been evaluated as inhibitors of the β-D-galactofuranosidase from Penicillium fellutanum. The kinetics of the inhibition showed that they behave as competitive inhibitors. As expected, compound 18 (Ki = 0.15 mM), with the same configuration for the reducing end as the natural substrate of the enzyme, was a stronger inhibitor than 16 (Ki = 2.23 mM).