Por favor, use este identificador para citar o enlazar a este item:
http://hdl.handle.net/10261/148915
COMPARTIR / EXPORTAR:
SHARE CORE BASE | |
Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL | DATACITE | |
Título: | Enzymatic and solid-phase synthesis of new donepezil-based L- and D-glutamic acid derivatives and their pharmacological evaluation in models related to Alzheimer's disease and cerebral ischemia |
Autor: | Monjas, Leticia CSIC ORCID; Arce, Mariana P. CSIC; León, Rafael CSIC ORCID ; Egea, Javier; Pérez, Concepción CSIC ORCID; Villarroya, Mercedes; López, Manuela G.; Gil, Carmen CSIC ORCID ; Conde, Santiago CSIC; Rodríguez-Franco, María Isabel CSIC ORCID | Palabras clave: | Stroke Mitochondrial oxidative stress Alzheimer's disease Neuroprotection Human cholinesterases Donepezil-based L- and D-Glu derivatives |
Fecha de publicación: | 2017 | Editor: | Elsevier | Citación: | European Journal of Medicinal Chemistry 130: 60-72 (2017) | Resumen: | Previously, we have described N-Bz-L-Glu[NH-2-(1-benzylpiperidin-4-yl)ethyl]-O-nHex (IQM9.21, L-1) as an interesting multifunctional neuroprotective compound for the potential treatment of neurodegenerative diseases. Here, we describe new derivatives and different synthetic routes, such as chemoenzymatic and solid-phase synthesis, aiming to improve the previously described route in solution. The lipase-catalysed amidation of L- and D-Glu diesters with N-benzyl-4-(2-aminoethyl)piperidine has been studied, using Candida antarctica and Mucor miehei lipases. In all cases, the α-amidated compound was obtained as the main product, pointing out that regioselectivity was independent of the reacting Glu enantiomer and the nature of the lipase. An efficient solid-phase route has been used to produce new donepezil-based L- and D-Glu derivatives, resulting in good yield. At micromolar concentrations, the new compounds inhibited human cholinesterases and protected neurons against toxic insults related to Alzheimer's disease and cerebral ischemia. The CNS-permeable compounds N-Cbz-L-Glu(OEt)-[NH-2-(1-benzylpiperidin-4-yl)ethyl] (L-3) and L-1 blocked the voltage-dependent calcium channels and L-3 protected rat hippocampal slices against oxygen-glucose deprivation, becoming promising anti-Alzheimer and anti-stroke lead compounds. | Descripción: | Supplementary data associated with this article can be found in the online version, at http://dx.doi.org/10.1016/j.ejmech.2017.02. 034. These data include MOL files and InChiKeys of the most important compounds described in this article. | Versión del editor: | http://dx.doi.org/10.1016/j.ejmech.2017.02.034 | URI: | http://hdl.handle.net/10261/148915 | DOI: | 10.1016/j.ejmech.2017.02.034 | Identificadores: | doi: 10.1016/j.ejmech.2017.02.034 issn: 0223-5234 e-issn: 1768-3254 |
Aparece en las colecciones: | (IQM) Artículos (CIB) Artículos |
Ficheros en este ítem:
Fichero | Descripción | Tamaño | Formato | |
---|---|---|---|---|
Enzymatic and solid-phase synthesis.pdf | 902,13 kB | Adobe PDF | Visualizar/Abrir |
CORE Recommender
SCOPUSTM
Citations
20
checked on 25-abr-2024
WEB OF SCIENCETM
Citations
18
checked on 24-feb-2024
Page view(s)
366
checked on 27-abr-2024
Download(s)
554
checked on 27-abr-2024
Google ScholarTM
Check
Altmetric
Altmetric
NOTA: Los ítems de Digital.CSIC están protegidos por copyright, con todos los derechos reservados, a menos que se indique lo contrario.