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

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 chemoen...

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Bibliographic Details
Published in:European Journal of Medicinal Chemistry
Main Authors: Monjas, Leticia, Arce, Mariana P., Leon, Rafael, Egea, Javier, Perez, Concepcion, Villarroya, Mercedes, Lopez, Manuela G., Gil, Carmen, Conde, Santiago, Isabel Rodriguez-Franco, Maria
Format: Article in Journal/Newspaper
Language:English
Published: 2017
Subjects:
Donepezil-based L and D-Glu derivatives
Human cholinesterases
Neuroprotection
Mitochondrial oxidative stress
Alzheimer ' s disease
Stroke
LIPASE-CATALYZED SYNTHESIS
ACETYLCHOLINESTERASE INHIBITORS
OXIDATIVE STRESS
NEUROPROTECTIVE PROPERTIES
MULTIFUNCTIONAL AGENTS
COMPOUND ITH33/IQM9.21
N-BENZYLPIPERIDINE
IN-VITRO
MULTITARGET
HYBRIDS
Antarc*
Antarctica
Online Access:http://hdl.handle.net/11370/ed0d9b14-9aef-4eb7-a658-4f4f0cd41be4
https://research.rug.nl/en/publications/enzymatic-and-solidphase-synthesis-of-new-donepezilbased-land-dglutamic-acid-derivatives-and-their-pharmacological-evaluation-in-models-related-to-alzheimer--s-disease-and-cerebral-ischemia(ed0d9b14-9aef-4eb7-a658-4f4f0cd41be4).html
https://doi.org/10.1016/j.ejmech.2017.02.034
Description
Summary: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 alpha-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-(1benzylpiperidin-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 antiAlzheimer and anti-stroke lead compounds. (C) 2017 Elsevier Masson SAS. All rights reserved.

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