Thiodisaccharide sulfoxides: Absolute configuration of the so sulfur atom and influence on the biological activity towards the β-galactosidase from E. coli

Abstract

Benzyl 3-deoxy-4-S-(β-D-galactopyranosyl)-4-thio-β-D-threopentopyranoside (3) is a potent inhibitor of the β-galactosidase from Escherichia coli synthesized in our laboratory. The 2′,3′,4′,6′-tetra-O-acetyl derivative of this thiodisaccharide was oxidized with m-chloroperoxybenzoic acid to give a 2:1 diastereomeric mixture of sulfoxides 2S and 2R. The absolute configurations of their sulfur stereocenters were determined by using NMR techniques and by taking into account the anisotropic effects of the S=O group in the major conformers. O-Deacetylation of 2S and 2R afforded the free thiodisaccharide S-oxides 4S and 4R, which were evaluated as inhibitors of the above-mentioned enzyme. The kinetic studies showed that 4S and 4R are competitive inhibitors of the enzyme with Ki values of 0.19 and 0.45 mM, respectively. Further enzymatic reactions demonstrated that 4S is also a substrate of the β-galactosidase, as it was diastereoselectively hydrolyzed, with 4R remaining unchanged under the same conditions.