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

0555998 - MBÚ 2023 RIV CH eng J - Journal Article
Kiss, M. - Timari, I. - Barna, T. - Mészáros, Zuzana - Slámová, Kristýna - Bojarová, Pavla - Křen, Vladimír - Hayes, J. - Somsák, L.
2-Acetamido-2-deoxy-d-glucono-1,5-lactone Sulfonylhydrazones: Synthesis and Evaluation as Inhibitors of Human OGA and HexB Enzymes.
International Journal of Molecular Sciences. Roč. 23, č. 3 (2022), č. článku 1037. E-ISSN 1422-0067
R&D Projects: GA ČR(CZ) GF21-01948L; EC(CZ) CA18132
Institutional support: RVO:61388971
Keywords : molecular-orbital methods * o-glcnac * glycosylidene carbenes * force-field * protein * substrate * link * hOGA * hHexB * inhibitor * glyconolactone sulfonylhydrazone * Prime refinement * qm * MM optimization
OECD category: Biochemistry and molecular biology
Impact factor: 5.6, year: 2022
Method of publishing: Open access
https://www.mdpi.com/1422-0067/23/3/1037

Inhibition of the human O-linked beta-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, K-i = 27 nM). This compound had a K-i 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.
Permanent Link: http://hdl.handle.net/11104/0330366