Examinando por Autor "González, Juan F"

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Discovery of 7-aminophenanthridin-6-one as a new scaffold for matrix metalloproteinase inhibitors with multitarget neuroprotective activity
(Elsevier, 2021-01-15) Rocchi, Damiano; Blázquez-Barbadillo, Cristina; Agamennone, Mariangela; Laghezza, Antonio; Tortorella, Paolo; Vicente-Zurdo, David; Rosales-Conrado, Noelia; Moyano, Paula; del Pino, Javier; González, Juan F; Menéndez, J. Carlos
Matrix metalloproteinases (MMPs) are zinc-dependent hydrolytic enzymes of great biological relevance, and some of them are key to the neuroinflammatory events and the brain damage associated to stroke. Non-zinc binding ligands are an emerging trend in drug discovery programs in this area due to their lower tendency to show off-target effects. 7-Amino-phenanthridin-6-one is disclosed as a new framework able to inhibit matrix metalloproteinases by binding to the distal part of the enzyme S1’ site, as shown by computational studies. A kinetic study revealed inhibition to be noncompetitive. Some of the compounds showed some degree of selectivity for the MMP-2 and MMP-9 enzymes, which are crucial for brain damage associated to ischemic stroke. Furthermore, some compounds also had a high neuroprotective activity against oxidative stress, which is also very relevant aspect of ischaemic stroke pathogenesis, both decreasing lipid peroxidation and protecting against the oxidative stress-induced reduction in cell viability. One of the compounds, bearing a 2-thienyl substituent at C-9 and a 4-methoxyphenylamino at C-7, had the best-balanced multitarget profile and was selected as a lead on which to base future structural manipulation
Neuroprotective Action of Multitarget 7-Aminophenanthridin-6(5H)-one Derivatives against Metal-Induced Cell Death and Oxidative Stress in SN56 Cells
(American Chemical Society, 2021-08-30) Moyano, Paula; Vicente-Zurdo, David; Blázquez-Barbadillo, Cristina; Menéndez, J. Carlos; González, Juan F; Rosales-Conrado, Noelia; del Pino, Javier
Neurodegenerative diseases have been associated with brain metal accumulation, which produces oxidative stress (OS), matrix metalloproteinases (MMPs) induction, and neuronal cell death. Several metals have been reported to downregulate both the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and the antioxidant enzymes regulated by it, mediating OS induction and neurodegeneration. Among a recently discovered family of multitarget 7-amino-phenanthridin-6-one derivatives (APH) the most promising compounds were tested against metal-induced cell death and OS in SN56 cells. These compounds, designed to have chelating activity, are known to inhibit some MMPs and to present antioxidant and neuroprotective effects against hydrogen peroxide treatment to SN56 neuronal cells. However, the mechanisms that mediate this protective effect are not fully understood. The obtained results show that compounds APH1, APH2, APH3, APH4, and APH5 were only able to chelate iron and copper ions among all metals studied and that APH3, APH4, and APH5 were also able to chelate mercury ion. However, none of them was able to chelate zinc, cadmium, and aluminum, thus exhibiting selective chelating activity that can be partly responsible for their neuroprotective action. Otherwise, our results indicate that their antioxidant effect is mediated through induction of the Nrf2 pathway that leads to overexpression of antioxidant enzymes. Finally, these compounds exhibited neuroprotective effects, reversing partially or completely the cytotoxic effects induced by the metals studied depending on the compound used. APH4 was the most effective and safe compound.
Neuroprotective mechanisms of multitarget 7-aminophenanthridin-6(5H)-one derivatives against metal-induced amyloid proteins generation and aggregation
(Elsevier, 2022-09) Moyano, Paula; Vicente-Zurdo, David; Blázquez-Barbadillo, Cristina; Menéndez, J. Carlos; González, Juan F; Rosales-Conrado, Noelia; del Pino, Javier
Brain's metals accumulation is associated with toxic proteins, like amyloid-proteins (Aβ), formation, accumulation, and aggregation, leading to neurodegeneration. Metals downregulate the correct folding, disaggregation, or degradation mechanisms of toxic proteins, as heat shock proteins (HSPs) and proteasome. The 7-amino-phenanthridin-6(5H)-one derivatives (APH) showed neuroprotective effects against metal-induced cell death through their antioxidant effect, independently of their chelating activity. However, additional neuroprotective mechanisms seem to be involved. We tested the most promising APH compounds (APH1-5, 10–100 μM) chemical ability to prevent metal-induced Aβ proteins aggregation; the APH1-5 effect on HSP70 and proteasome 20S (P20S) expression, the metals effect on Aβ formation and the involvement of HSP70 and P20S in the process, and the APH1-5 neuroprotective effects against Aβ proteins (1 μM) and metals in SN56 cells. Our results show that APH1-5 compounds chemically avoid metal-induced Aβ proteins aggregation and induce HSP70 and P20S expression. Additionally, iron and cadmium induced Aβ proteins formation through downregulation of HSP70 and P20S. Finally, APH1-5 compounds protected against Aβ proteins-induced neuronal cell death, reversing partially or completely this effect. These data may help to provide a new therapeutic approach against the neurotoxic effect induced by metals and other environmental pollutants, especially when mediated by toxic proteins