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 and4-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 hydroxyalkylN-substituted galactonolactams is outlined. All syntheses began with derivatives of D-glucono-1,5- or 1,4-lactonesas starting compounds. They underwent substitution at C-4 via sulfur or nitrogen nucleophiles, yieldingproducts with galacto configuration. All synthesized compounds were found to inhibit the Penicillium fellutanumβ-galactofuranosidase. 4-Thio-D-galactonic acid 1,4-thiolactone was a weak inhibitor, while 4-deoxy-Dgalactono-1,4-lactam was the strongest (Ki = 88 ± 4 μM) within this series. Kinetic studies further revealed thatthis is a competitive inhibitor. Furthermore, a preliminary docking analysis with the β-galactofuranosidase fromStreptomyces 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 humanpathogens that contain galactofuranosyl structures, such as those responsible for leprosy and tuberculosis.