Escherichia coli LacZ β-galactosidase inhibition by monohydroxy acetylated glycopyranosides: Role of the acetyl groups

• Inhibition properties of acetylated sugars to beta-galactoside from E. coli were established.
• Synthesis at multi-mg scale of small library of different regioselective monohydroxy-acetylated mono and disaccharides.
• Molecular docking studies were applied to determine the role of acetyl group in the inhibition process.
• The regioselective deprotection position is important for the inhibitory capacity of the molecule.
• A monohydroxy lactal derivative showed an interesting Ki value (95 μM) compared to known galactosidase inhibitors.

Escherichia coli LacZ β-galactosidase is an extensively employed glycosidase for many different scientific purposes. Here, we describe how acetyl moieties protecting hydroxyl groups of the glycosides make these molecules better inhibitors to the enzyme activity. In particular, the presence of a unique hydroxyl group in the peracetylated glycosides still enhanced the inhibitory capacity of the molecule more. Molecular docking studies showed that the acetylation in the carbohydrate structure helps the substrate to accommodate into the active site. From a small biocatalytic synthesized library of different monohydroxy acetylated glycosides we can conclude that galactosidic structures are better for inhibition capacity. The best inhibitors were two monohydroxy lactal derivatives. The one with the OH free, in C-6 of the galactosidic part of the disaccharide, was a better inhibitor (Ki of 95 μM) than that with the OH free in C-3 in the glucosidic part of the molecule (Ki of 143 μM).

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