2-Acetamido-2-deoxy-d-glucono-1,5-lactone Sulfonylhydrazones: Synthesis and Evaluation as Inhibitors of Human OGA and HexB Enzymes

Abstract

Inhibition of the human O-linked β-N-acetylglucosaminidase (hOGA, GH84) enzyme is pharmacologically relevant in several diseases such as neurodegenerative and cardiovascular disorders, type 2 diabetes, and cancer. Human lysosomal hexosaminidases (hHexA and hHexB, GH20) are mechanistically related enzymes; therefore, selective inhibition of these enzymes is crucial in terms of potential applications. In order to extend the structure–activity relationships of OGA inhibitors, a series of 2-acetamido-2-deoxy-d-glucono-1,5-lactone sulfonylhydrazones was prepared from d-glucosamine. The synthetic sequence involved condensation of N-acetyl-3,4,6-tri-O-acetyl-d-glucosamine with arenesulfonylhydrazines, followed by MnO2 oxidation to the corresponding glucono-1,5-lactone sulfonylhydrazones. Removal of the O-acetyl protecting groups by NH3/MeOH furnished the test compounds. Evaluation of these compounds by enzyme kinetic methods against hOGA and hHexB revealed potent nanomolar competitive inhibition of both enzymes, with no significant selectivity towards either. The most efficient inhibitor of hOGA was 2-acetamido-2-deoxy-d-glucono-1,5-lactone 1-naphthalenesulfonylhydrazone (5f, Ki = 27 nM). This compound had a Ki of 6.8 nM towards hHexB. To assess the binding mode of these inhibitors to hOGA, computational studies (Prime protein–ligand refinement and QM/MM optimizations) were performed, which suggested the binding preference of the glucono-1,5-lactone sulfonylhydrazones in an s-cis conformation for all test compounds.

Synthesis and anti-inflammatory activities of two new N-acetyl glucosamine derivatives

“…Considering that NAG products were typically recommended via oral administration for an adult at a dose of 20 mg/kg/day (an equivalent amount of less than 0.2 mg/kg/day tin in BNAGs) 10 , it is concluded that BNAGs would be very safe agents as either dietary supplements or medical drugs. To our knowledge, only several chemical modifications of NAG have been published, including replacement of 6-hydroxyl by deoxy, fluoro, thiol group or amino substituents 13 , functionalization of 1-hydroxyl to produce a library of 2-acetamido-2-deoxy-D-glucono-1,5-lactone arenesulfonylhydrazones 16 , as well as single or multiple acetylation 12 . As such, BNAG1 and BNAG2 were the bi-deoxygenated derivatives of NAG reported for the first time.…”

“…These findings were in accordance with our current and previously reported data 21 . Furthermore, several NAG derivatives with different 1-hydroxyl substitutions have been proven as OGA inhibitors which could lead to an accumulation of protein O-GlcNAc 16 , 25 – 27 . As such, we hypothesize that NAG, BNAG1 and BNAG2 might suppress immune response through the inhibition of OGA, and the reason why BNAG1 displays better activity than BNAG2 or NAG is due to its 1-deoxygenation.…”