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2-Acetamido-2-deoxy-d-glucono-1,5-lactone Sulfonylhydrazones: Synthesis and Evaluation as Inhibitors of Human OGA and HexB Enzymes
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SYSNO ASEP 0555998 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title 2-Acetamido-2-deoxy-d-glucono-1,5-lactone Sulfonylhydrazones: Synthesis and Evaluation as Inhibitors of Human OGA and HexB Enzymes Author(s) Kiss, M. (HU)
Timari, I. (HU)
Barna, T. (HU)
Mészáros, Zuzana (MBU-M)
Slámová, Kristýna (MBU-M) RID, ORCID
Bojarová, Pavla (MBU-M) ORCID
Křen, Vladimír (MBU-M) RID, ORCID
Hayes, J. (GB)
Somsák, L. (HU)Article number 1037 Source Title International Journal of Molecular Sciences. - : MDPI
Roč. 23, č. 3 (2022)Number of pages 18 s. Language eng - English Country CH - Switzerland Keywords molecular-orbital methods ; o-glcnac ; glycosylidene carbenes ; force-field ; protein ; substrate ; link ; hOGA ; hHexB ; inhibitor ; glyconolactone sulfonylhydrazone ; Prime refinement ; qm ; MM optimization Subject RIV CE - Biochemistry OECD category Biochemistry and molecular biology R&D Projects GF21-01948L GA ČR - Czech Science Foundation (CSF) CA18132 EC - European Union Method of publishing Open access Institutional support MBU-M - RVO:61388971 UT WOS 000754896600001 EID SCOPUS 85122862338 DOI 10.3390/ijms23031037 Annotation 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. Workplace Institute of Microbiology Contact Eliška Spurná, eliska.spurna@biomed.cas.cz, Tel.: 241 062 231 Year of Publishing 2023 Electronic address https://www.mdpi.com/1422-0067/23/3/1037
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