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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

The result's identifiers

  • Result code in IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388971%3A_____%2F22%3A00555998" target="_blank" >RIV/61388971:_____/22:00555998 - isvavai.cz</a>

  • Result on the web

    <a href="https://www.mdpi.com/1422-0067/23/3/1037" target="_blank" >https://www.mdpi.com/1422-0067/23/3/1037</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.3390/ijms23031037" target="_blank" >10.3390/ijms23031037</a>

Alternative languages

  • Result language

    angličtina

  • Original language name

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

  • Original language description

    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.

  • Czech name

  • Czech description

Classification

  • Type

    J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database

  • CEP classification

  • OECD FORD branch

    10608 - Biochemistry and molecular biology

Result continuities

  • Project

    <a href="/en/project/GF21-01948L" target="_blank" >GF21-01948L: New glycomimetics for managing of age-related neurodegenerative diseases</a><br>

  • Continuities

    I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Others

  • Publication year

    2022

  • Confidentiality

    S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Data specific for result type

  • Name of the periodical

    International Journal of Molecular Sciences

  • ISSN

    1422-0067

  • e-ISSN

    1422-0067

  • Volume of the periodical

    23

  • Issue of the periodical within the volume

    3

  • Country of publishing house

    CH - SWITZERLAND

  • Number of pages

    18

  • Pages from-to

    1037

  • UT code for WoS article

    000754896600001

  • EID of the result in the Scopus database

    2-s2.0-85122862338