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Naturally Inspired Molecules as Multifunctional Agents for Alzheimer’s Disease Treatment

Alzheimer’s disease (AD) has been defined as a multi-factorial disorder resulting from a complex array of networked cellular and molecular mechanisms. In particular, elevated levels of Aβ protein and its aggregation products in the presence of metal ions proved to be highly neurotoxic and therapeuti...

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Autores principales: Rampa, Angela, Tarozzi, Andrea, Mancini, Francesca, Pruccoli, Letizia, Di Martino, Rita Maria Concetta, Gobbi, Silvia, Bisi, Alessandra, De Simone, Angela, Palomba, Francesco, Zaccheroni, Nelsi, Belluti, Federica
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274376/
https://www.ncbi.nlm.nih.gov/pubmed/27196880
http://dx.doi.org/10.3390/molecules21050643
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author Rampa, Angela
Tarozzi, Andrea
Mancini, Francesca
Pruccoli, Letizia
Di Martino, Rita Maria Concetta
Gobbi, Silvia
Bisi, Alessandra
De Simone, Angela
Palomba, Francesco
Zaccheroni, Nelsi
Belluti, Federica
author_facet Rampa, Angela
Tarozzi, Andrea
Mancini, Francesca
Pruccoli, Letizia
Di Martino, Rita Maria Concetta
Gobbi, Silvia
Bisi, Alessandra
De Simone, Angela
Palomba, Francesco
Zaccheroni, Nelsi
Belluti, Federica
author_sort Rampa, Angela
collection PubMed
description Alzheimer’s disease (AD) has been defined as a multi-factorial disorder resulting from a complex array of networked cellular and molecular mechanisms. In particular, elevated levels of Aβ protein and its aggregation products in the presence of metal ions proved to be highly neurotoxic and therapeutic strategies aimed at preventing Aβ generation and oxidative stress may represent an effective approach for AD treatment. A recent paradigm for the treatment of complex diseases such as AD suggests the employment of multifunctional compounds, single chemical entities capable of simultaneously modulating different targets involved in the pathology. In this paper, the “pharmacophores combination” strategy was applied, connecting the main scaffold of the BACE-1 ligand 1 to that of the chalcone 2, as metal chelating pharmacophore, to obtain a small library of compounds. Conjugate 5 emerged as the most interesting derivative, proving to inhibit BACE-1 with low-micromolar potency, and showing neuroprotective effects. In particular, 5 proved to be able to protect from metal-associated oxidative stress by hampering intracellular Cu(2+)-induced ROS formation without any direct neurotoxic effect.
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spelling pubmed-62743762018-12-28 Naturally Inspired Molecules as Multifunctional Agents for Alzheimer’s Disease Treatment Rampa, Angela Tarozzi, Andrea Mancini, Francesca Pruccoli, Letizia Di Martino, Rita Maria Concetta Gobbi, Silvia Bisi, Alessandra De Simone, Angela Palomba, Francesco Zaccheroni, Nelsi Belluti, Federica Molecules Article Alzheimer’s disease (AD) has been defined as a multi-factorial disorder resulting from a complex array of networked cellular and molecular mechanisms. In particular, elevated levels of Aβ protein and its aggregation products in the presence of metal ions proved to be highly neurotoxic and therapeutic strategies aimed at preventing Aβ generation and oxidative stress may represent an effective approach for AD treatment. A recent paradigm for the treatment of complex diseases such as AD suggests the employment of multifunctional compounds, single chemical entities capable of simultaneously modulating different targets involved in the pathology. In this paper, the “pharmacophores combination” strategy was applied, connecting the main scaffold of the BACE-1 ligand 1 to that of the chalcone 2, as metal chelating pharmacophore, to obtain a small library of compounds. Conjugate 5 emerged as the most interesting derivative, proving to inhibit BACE-1 with low-micromolar potency, and showing neuroprotective effects. In particular, 5 proved to be able to protect from metal-associated oxidative stress by hampering intracellular Cu(2+)-induced ROS formation without any direct neurotoxic effect. MDPI 2016-05-16 /pmc/articles/PMC6274376/ /pubmed/27196880 http://dx.doi.org/10.3390/molecules21050643 Text en © 2016 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Rampa, Angela
Tarozzi, Andrea
Mancini, Francesca
Pruccoli, Letizia
Di Martino, Rita Maria Concetta
Gobbi, Silvia
Bisi, Alessandra
De Simone, Angela
Palomba, Francesco
Zaccheroni, Nelsi
Belluti, Federica
Naturally Inspired Molecules as Multifunctional Agents for Alzheimer’s Disease Treatment
title Naturally Inspired Molecules as Multifunctional Agents for Alzheimer’s Disease Treatment
title_full Naturally Inspired Molecules as Multifunctional Agents for Alzheimer’s Disease Treatment
title_fullStr Naturally Inspired Molecules as Multifunctional Agents for Alzheimer’s Disease Treatment
title_full_unstemmed Naturally Inspired Molecules as Multifunctional Agents for Alzheimer’s Disease Treatment
title_short Naturally Inspired Molecules as Multifunctional Agents for Alzheimer’s Disease Treatment
title_sort naturally inspired molecules as multifunctional agents for alzheimer’s disease treatment
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274376/
https://www.ncbi.nlm.nih.gov/pubmed/27196880
http://dx.doi.org/10.3390/molecules21050643
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