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

Autor: Pingitore V; Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, C/ Prof. García González, 1, 41012-Sevilla, Spain., Martínez-Bailén M; Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, C/ Prof. García González, 1, 41012-Sevilla, Spain., 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., 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., 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., Slámová K; Laboratory of Biotransformation, Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, 14220 Prague 4, Czech Republic., Křen V; Laboratory of Biotransformation, Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, 14220 Prague 4, Czech Republic., 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., Robina I; Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, C/ Prof. García González, 1, 41012-Sevilla, Spain., 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.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2022 Mar; Vol. 120, pp. 105650. Date of Electronic Publication: 2022 Feb 02.
DOI: 10.1016/j.bioorg.2022.105650
Abstrakt: 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 4 times more selective for hOGA over hHexB) and the inhibition potency (by one order of magnitude). Docking studies were performed to explain the selectivity of inhibition observed in compound 7A.
(Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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