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

• DOI: 10.1016/j.ejmech.2017.02.034
• Publication Date: 2017-02-22T15:46:46Z
• Authors: Leticia Monjas; Mariana P. Arce; Rafael León; Javier Egea; Concepción Pérez; Mercedes Villarroya; Manuela G. López; Carmen Gil; Santiago Conde; María Isabel Rodr...
• Keywords: 0303 health sciences; Mitochondrial oxidative stress; Alzheimer's disease; Donepezil-based L- and D-Glu derivatives; Calcium Channel Blockers; Hippocampus; Neuroprotection; Brain Ischemia; Rats; 3. Good health; Stroke; 03 medical and health sciences; Neuroprotective Agents; Glutamates; Piperidines; Alzheimer Disease; Human cholinesterases; Indans; Animals; Humans; Donepezil; Cholinesterase Inhibitors; Solid-Phase Synthesis Techniques

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.