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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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2016
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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. |
format | Online Article Text |
id | pubmed-6274376 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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