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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

AutorMonjas, Leticia ; Arce, Mariana P. ; Leon, Rafael; Egea, Javier; Pérez, Concepción; Villarroya, Mercedes; Lopez, Manuela G.; Gil, Carmen ; Conde, Santiago; Rodríguez-Franco, María Isabel
Palabras claveStroke
Mitochondrial oxidative stress
Alzheimer's disease
Neuroprotection
Human cholinesterases
Donepezil-based L- and D-Glu derivatives
Fecha de publicación2017
EditorElsevier
CitaciónEuropean Journal of Medicinal Chemistry 130: 60-72 (2017)
ResumenPreviously, 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.
DescripciónSupplementary 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 editorhttp://dx.doi.org/10.1016/j.ejmech.2017.02.034
URIhttp://hdl.handle.net/10261/148915
DOI10.1016/j.ejmech.2017.02.034
Identificadoresdoi: 10.1016/j.ejmech.2017.02.034
issn: 0223-5234
e-issn: 1768-3254
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