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Investigation of the enantioselectivity of acetylcholinesterase and butyrylcholinesterase upon inhibition by tacrine-iminosugar heterodimers

The copper-catalysed azide-alkyne cycloaddition was applied to prepare three enantiomeric pairs of heterodimers containing a tacrine residue and a 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) or 1,4-dideoxy-1,4-imino-L-arabinitol (LAB) moiety held together via linkers of variable lengths containing a 1,...

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Detalles Bibliográficos
Autores principales: Vaaland, I. Caroline, López, Óscar, Puerta, Adrián, Fernandes, Miguel X., Padrón, José M., Fernández-Bolaños, José G., Sydnes, Magne O., Lindbäck, Emil
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9721440/
https://www.ncbi.nlm.nih.gov/pubmed/36458374
http://dx.doi.org/10.1080/14756366.2022.2150762
Descripción
Sumario:The copper-catalysed azide-alkyne cycloaddition was applied to prepare three enantiomeric pairs of heterodimers containing a tacrine residue and a 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) or 1,4-dideoxy-1,4-imino-L-arabinitol (LAB) moiety held together via linkers of variable lengths containing a 1,2,3-triazole ring and 3, 4, or 7 CH(2) groups. The heterodimers were tested as inhibitors of butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE). The enantiomeric heterodimers with the longest linkers exhibited the highest inhibition potencies for AChE (IC(50) = 9.7 nM and 11 nM) and BuChE (IC(50) = 8.1 nM and 9.1 nM). AChE exhibited the highest enantioselectivity (ca. 4-fold). The enantiomeric pairs of the heterodimers were found to be inactive (GI(50) > 100 µM), or to have weak antiproliferative properties (GI(50) = 84–97 µM) against a panel of human cancer cells.