Discovery of human hexosaminidase inhibitors by in situ screening of a library of mono- and divalent pyrrolidine iminosugars.

Acetylglucosaminidase Enzyme Inhibitors / pharmacology Humans Imino Sugars / pharmacology Pyrrolidines / pharmacology Structure-Activity Relationship beta-N-Acetylhexosaminidases
Click reaction Glycosidase inhibitors Hexosaminidases Iminosugars In situ screening Multivalency

Journal

Bioorganic chemistry
ISSN: 1090-2120
Titre abrégé: Bioorg Chem
Pays: United States
ID NLM: 1303703

Informations de publication

Date de publication:
03 2022
Historique:
received: 09 12 2021
revised: 24 01 2022
accepted: 28 01 2022
pubmed: 11 2 2022
medline: 14 6 2022
entrez: 10 2 2022
Statut: ppublish

Résumé

Two libraries of mono- and dimeric pyrrolidine iminosugars were synthesized by CuAAC and (thio)urea-bond-forming reactions from the respective azido/aminohexylpyrrolidine iminosugar precursors. The resulting monomeric and dimeric compounds were screened for inhibition of β-N-acetylglucosaminidase from Jack beans, the plant ortholog of human lysosomal hexosaminidases. A selection of the best inhibitors of these libraries was then evaluated against human lysosomal β-N-acetylhexosaminidase B (hHexB) and human nucleocytoplasmic β-N-acetylglucosaminidase (hOGA). This evaluation identified a potent (nM) and selective monomeric inhibitor of hOGA (compound 7A) that showed a 6770-fold higher affinity for this enzyme than for hHexB. The corresponding dimeric derivative (compound 9D) further remarkably improved the selectivity in the inhibition of hOGA (2.7 × 10

Identifiants

DOI: 10.1016/j.bioorg.2022.105650 PMID: 35144103
pubmed: 35144103
pii: S0045-2068(22)00055-4
doi: 10.1016/j.bioorg.2022.105650
pii:
doi:

Substances chimiques

Enzyme Inhibitors 0
Imino Sugars 0
Pyrrolidines 0
Acetylglucosaminidase EC 3.2.1.52
beta-N-Acetylhexosaminidases EC 3.2.1.52

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

105650

Informations de copyright

Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Auteurs

Valeria Pingitore (V)

Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, C/ Prof. García González, 1, 41012-Sevilla, Spain.

Macarena Martínez-Bailén (M)

Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, C/ Prof. García González, 1, 41012-Sevilla, Spain.

Ana T Carmona (AT)

Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, C/ Prof. García González, 1, 41012-Sevilla, Spain. Electronic address: anatere@us.es.

Zuzana Mészáros (Z)

Laboratory of Biotransformation, Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, 14220 Prague 4, Czech Republic; Faculty of Food and Biochemical Technology, University of Chemistry and Technology Prague, Technická 1903/3, CZ-16628 Praha 6, Czech Republic.

Natalia Kulik (N)

Laboratory of Structural Biology and Informatics, Institute of Microbiology of the Czech Academy of Sciences, Zámek 136, CZ-37333 Nové Hrady, Czech Republic.

Kristýna Slámová (K)

Laboratory of Biotransformation, Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, 14220 Prague 4, Czech Republic.

Vladimír Křen (V)

Laboratory of Biotransformation, Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, 14220 Prague 4, Czech Republic.

Pavla Bojarová (P)

Laboratory of Biotransformation, Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, 14220 Prague 4, Czech Republic. Electronic address: bojarova@biomed.cas.cz.

Inmaculada Robina (I)

Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, C/ Prof. García González, 1, 41012-Sevilla, Spain.

Antonio J Moreno-Vargas (AJ)

Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, C/ Prof. García González, 1, 41012-Sevilla, Spain. Electronic address: ajmoreno@us.es.

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Classifications MeSH

questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Glycosidases › Hexosaminidases › beta-N-Acetylhexosaminidases › Acetylglucosaminidase › Discovery of human hexosaminidase inhibitors...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Discovery of human hexosaminidase inhibitors...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Discovery of human hexosaminidase inhibitors...
questionsmedicales.fr › Glucides › Iminosucres › Discovery of human hexosaminidase inhibitors...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pyrrolidines › Discovery of human hexosaminidase inhibitors...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Relation structure-activité › Discovery of human hexosaminidase inhibitors...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Glycosidases › Hexosaminidases › beta-N-Acetylhexosaminidases › Discovery of human hexosaminidase inhibitors...