Synthesis of S- or N-glycomimetics of d-galactono-1,4-lactone: inhibitors of a β-galactofuranosidase

Abstract

In the search for β-galactofuranosidase inhibitors, the synthesis of 4-thio-D-galactonic acid 1,4-thiolactone and 4-deoxy-D-galactono-1,4-lactam was undertaken. These compounds are analogs of D-galactono-1,4-lactone, a known inhibitor of the enzyme. Additionally, a synthetic route to access benzyl, alkyl and hydroxyalkyl N-substituted galactonolactams is outlined. All syntheses began with derivatives of D-glucono-1,5- or 1,4-lactones as starting compounds. They underwent substitution at C-4 via sulfur or nitrogen nucleophiles, yielding products with galacto configuration. All synthesized compounds were found to inhibit the Penicillium fellutanum β-galactofuranosidase. 4-Thio-D-galactonic acid 1,4-thiolactone was a weak inhibitor, while 4-deoxy-D-galactono-1,4-lactam was the strongest (K_i = 88 ± 4 µM) within this series. Kinetic studies further revealed that this is a competitive inhibitor. Furthermore, a preliminary docking analysis with the β-galactofuranosidase from Streptomyces sp. JHA19 ORF 1110 demonstrated that the lactam is also a potential inhibitor of this enzyme. Inhibition of β-galactofuranosidases may serve as a novel chemotherapeutic approach for treating human pathogens that contain galactofuranosyl structures, such as those responsible for leprosy and tuberculosis.