Benzyl Glycosides of Thiodisaccharides. Influence of C-2 Configuration of the Reducing End and Substitution at Benzyl on the Inhibition of the E. coli β-Galactosidase

Abstract

Analogues of 4-thiolactose having the 4-thioglucose at the reducing end replaced by a benzyl 3-deoxy-4-thiopentopyranoside are potent inhibitors of the β-galactosidase from E. coli. As already proved, the glycosidic benzyl substituent shows interactions within the enzyme active site. Therefore, we synthesized this type of thiodisaccharides having the benzyl group substituted by an electron withdrawing (NO2) or donating (NHAc) groups, which may also participate in hydrogen bonding. The key step in the synthesis was the conjugate addition of a 1-thiogalactose derivative to a pentose-derived enone to give diastereoselectively the 2-ketothiodisaccaride (C-4 was S). Reduction of the keto group led to the pair of isomers with opposite configuration at C-2. These derivatives were useful to assess the influence of the C-2 stereochemistry on the activity. All the thiodisaccharides acted as inhibitors of the β-galactosidase. The extent of the inhibition depends mostly on the configuration at C-2. Those having the β-1,2-cis relationship were the strongest inhibitors (Ki ≈ 10 μM). However, the substituent on the benzyl had a small incidence on the inhibitory activity. The type of inhibition of the glycomimetic was determined.