N-Acyl Derivatives of 4-Phenoxyaniline as Neuroprotective Agents

Neuronal cell death is the main cause behind the progressive loss of brain function in age‐related neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Despite the differing etiologies of these neurological diseases, the underlying neuronal damage is triggered by common mechanis...

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Published in:	ChemMedChem Vol. 9; no. 10; pp. 2260 - 2273
Main Authors:	Barho, Marlene T., Oppermann, Sina, Schrader, Florian C., Degenhardt, Inga, Elsässer, Katharina, Wegscheid-Gerlach, Christof, Culmsee, Carsten, Schlitzer, Martin
Format:	Journal Article
Language:	English
Published:	Weinheim WILEY-VCH Verlag 01-10-2014 WILEY‐VCH Verlag Wiley Subscription Services, Inc
Subjects:	Aniline Compounds - chemistry apoptosis Cell Line Magnetic Resonance Spectroscopy medicinal chemistry Molecular Docking Simulation N-acyl-4-phenoxyanilines neurochemistry neuroprotection Neuroprotective Agents - pharmacology Spectrometry, Mass, Electrospray Ionization apoptosis N-acyl-4-phenoxyanilines neurochemistry neuroprotection medicinal chemistry
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Summary:	Neuronal cell death is the main cause behind the progressive loss of brain function in age‐related neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Despite the differing etiologies of these neurological diseases, the underlying neuronal damage is triggered by common mechanisms such as oxidative stress, impaired calcium homeostasis, and disrupted mitochondrial integrity and function. In particular, mitochondrial fragmentation, mitochondrial membrane permeability, and the release of death‐promoting factors into the cytosol have been revealed as the “point of no return” in programmed cell death in neurons. Recent studies revealed a pivotal role for the pro‐apoptotic Bcl‐2‐family protein Bid in models of neuronal cell death, which confirmed Bid as a potential drug target. Herein, we present N‐acyl‐substituted derivatives of 4‐phenoxyaniline that were screened for their potential to attenuate Bid‐mediated neurotoxicity. These compounds provided significant protection against glutamate‐ and Bid‐induced toxicity in cultured neurons. Substitution of the amino group in the 4‐phenoxyaniline scaffold with 4‐piperidine carboxylic acid and N‐hydroxyethyl‐4‐piperidine carboxylic acid yielded compounds that displayed significant neuroprotective activity at concentrations as low as 1 μM. Furthermore, findings of a tBid‐overexpression assay and real‐time measurements of cell impedance support the hypothesis that these compounds indeed address the Bid protein. A Bidding war: The pro‐apoptotic Bcl‐2‐family protein Bid plays a pivotal role in neuronal cell death, which makes Bid a potential drug target. We developed N‐acyl‐substituted derivatives of 4‐phenoxyaniline that provide significant protection against glutamate‐ and Bid‐induced toxicity in cultured neurons.
Bibliography:	ArticleID:CMDC201402195 istex:FAFF7F0A2D4F7F4D434DD8C43CB76E4B33BF03FE ark:/67375/WNG-NSJDX305-D These authors contributed equally to this work. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1860-7179 1860-7187
DOI:	10.1002/cmdc.201402195