Počet záznamů: 1
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 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název 2-Acetamido-2-deoxy-d-glucono-1,5-lactone Sulfonylhydrazones: Synthesis and Evaluation as Inhibitors of Human OGA and HexB Enzymes Tvůrce(i) 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)Číslo článku 1037 Zdroj.dok. International Journal of Molecular Sciences. - : MDPI
Roč. 23, č. 3 (2022)Poč.str. 18 s. Jazyk dok. eng - angličtina Země vyd. CH - Švýcarsko Klíč. slova molecular-orbital methods ; o-glcnac ; glycosylidene carbenes ; force-field ; protein ; substrate ; link ; hOGA ; hHexB ; inhibitor ; glyconolactone sulfonylhydrazone ; Prime refinement ; qm ; MM optimization Vědní obor RIV CE - Biochemie Obor OECD Biochemistry and molecular biology CEP GF21-01948L GA ČR - Grantová agentura ČR CA18132 EC - European Union Způsob publikování Open access Institucionální podpora MBU-M - RVO:61388971 UT WOS 000754896600001 EID SCOPUS 85122862338 DOI 10.3390/ijms23031037 Anotace 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. Pracoviště Mikrobiologický ústav Kontakt Eliška Spurná, eliska.spurna@biomed.cas.cz, Tel.: 241 062 231 Rok sběru 2023 Elektronická adresa https://www.mdpi.com/1422-0067/23/3/1037
Počet záznamů: 1