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

• Published in: European Journal of Medicinal Chemistry
• Main Authors: Monjas, Leticia, Arce, Mariana P., León, Rafael, Egea, Javier, Pérez, Concepción, Villarroya, Mercedes, López, Manuela G., Gil, Carmen, Conde, Santiago, Rodríguez-Franco, María Isabel
• Other Authors: Ministerio de Economía y Competitividad (España), Consejo Superior de Investigaciones Científicas (España), Instituto de Salud Carlos III, European Commission
• Format: Article in Journal/Newspaper
• Language: unknown
• Published: Elsevier 2017
• Subjects: Stroke; Mitochondrial oxidative stress; Alzheimer's disease; Neuroprotection; Human cholinesterases; Donepezil-based L- and D-Glu derivatives; Antarc*; Antarctica
• Online Access: http://hdl.handle.net/10261/148915; https://doi.org/10.1016/j.ejmech.2017.02.034; https://doi.org/10.13039/501100003329; https://doi.org/10.13039/501100003339; https://doi.org/10.13039/501100004587; https://doi.org/10.13039/501100000780

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. 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. This work was supported by the Spanish Ministry of Economy and Competitiveness (MINECO, grants SAF2015-64948-C2-1-R and SAF2012-31035) and Consejo Superior de Investigaciones Científicas (CSIC, grant PIE-201580E109) to M.I.R.-F; Instituto de Salud Carlos III (Miguel Servet contract and projects CP11/00165 and PI14/00372), European Commission - Marie Curie Actions FP7 (FP7- People-2012-CIG-322156), Bayer AG, From Targets to Drugs (grant 2015-03-1282) and Fundacion ...