Publicaciones 2011-2020

@article{RN346,
title = {Neuroprotective Effect of a New 7,8-Dihydroxycoumarin-Based Fe2+/Cu2+ Chelator in Cell and Animal Models of Parkinson's Disease},
author = { P. Aguirre and O. Garcia-Beltran and V. Tapia and Y. Munoz and B.K. Cassels and M. Nunez},
url = {/brokenurl#<Go to ISI>://WOS:000392459400021},
doi = {10.1021/acschemneuro.6b00309},
issn = {1948-7193},
year = {2017},
date = {2017-01-01},
journal = {Acs Chemical Neuroscience},
volume = {8},
number = {1},
pages = {178-185},
abstract = {Disturbed iron homeostasis, often coupled to mitochondrial dysfunction, plays an important role in the progression of common neurodegenerative diseases such as Parkinson's disease (PD). Recent studies have underlined the relevance of iron chelation therapy for the treatment of these diseases. Here we describe the synthesis, chemical, and biological characterization of the multifunctional chelator 7,8-dihydroxy-4-((methylamino)methyl)-2H-chromen-2-one (DHC12). Metal selectivity of DHC12 was Cu2+ similar to Fe2+ > Zn2+ > Fe3+. No binding capacity was detected for Hg2+, co(2+), ca(2+), Mnz+, Mg2+, Ni2+, Pb2+ or Cd2+. DHC12 accessed cells colocalizing with Mitotracker Orange, an indication of mitochondrial targeting. In addition, DHC12 chelated mitochondrial and cytoplasmic labile iron. Upon mitochondrial complex I inhibition, DHC12 protected plasma membrane and mitochondria against lipid peroxidation, as detected by the reduced formation of 4-hydroxynonenal adducts and oxidation of C11-BODIPY581/891. DHC12 also blocked the decrease in mitochondrial membrane potential, detected by tetrarnethylrhodamine distribution. DHC12 inhibited MAO-A and MAO-B activity. Oral administration of DHC12 to mice (0.25 mg/kg body weight) protected substantia nigra pars compacta (SNpc) neurons against MPTP-induced death. Taken together, our results support the concept that DHC12 is a mitochondrial-targeted neuroprotective iron-copper chelator and MAO-B inhibitor with potent antioxidant and mitochondria protective activities. Oral administration of low doses of DHC12 is a promising therapeutic strategy for the treatment of diseases with a mitochondrial iron accumulation component, such as PD.},
keywords = {activity, antioxidant antioxidant, basal brain chelator, complex content, coumarin-based coumarins, disease, ganglia, i, inhibitory-activity, iron iron-copper lipid-peroxidation, model, mouse neurodegeneration neurodegeneration, neuroprotection, niptp oxidative parkinsons stress, with},
pubstate = {published},
tppubtype = {article}
}

@article{RN322,
title = {Small Structural Changes on a Hydroquinone Scaffold Determine the Complex I Inhibition or Uncoupling of Tumoral Oxidative Phosphorylation},
author = { F.A. Urra and M. Cordova-Delgado and M. Lapier and A. Orellana-Manzano and L. Acevedo-Arevalo and H. Pessoa-Mahana and J.M. Gonz\'{a}lez-Vivanco and M. Martinez-Cifuentes and O. Ramirez-Rodriguez and J.P. Millas-Vargas and B. Weiss-Lopez and M. Pavani and J. Ferreira and R. Araya-Maturana},
url = {/brokenurl#<Go to ISI>://WOS:000378100100006},
doi = {10.1016/j.taap.2015.12.005},
issn = {0041-008x},
year = {2016},
date = {2016-01-01},
journal = {Toxicology and Applied Pharmacology},
volume = {291},
pages = {46-57},
publisher = {2015 Elsevier Inc},
abstract = {Mitochondria participate in several distinctiveness of cancer cell, being a promising target for the design of anti-cancer compounds. Previously, we described that ortho-carbonyl hydroquinone scaffold 14 inhibits the complex I-dependent respiration with selective anti-proliferative effect on mouse mammary adenocarcinoma TA3/Ha cancer cells; however, the structural requirements of this hydroquinone scaffold to affect the oxidative phosphorylation (OXPHOS) of cancer cells have not been studied in detail. Here, we characterize the mitochondrial metabolism of TA3/Ha cancer cells, which exhibit a high oxidative metabolism, and evaluate the effect of small structural changes of the hydroquinone scaffold 14 on the respiration of this cell line. Our results indicate that these structural changes modify the effect on OXPHOS, obtaining compounds with three alternative actions: inhibitors of complex I-dependent respiration, uncoupler of OXPHOS and compounds with both actions. To confirm this, the effect of a bicyclic hydroquinone (9) was evaluated in isolated mitochondria. Hydroquinone 9 increased mitochondrial respiration in state 4o without effects on the ADP-stimulated respiration (state 3(ADP)), decreasing the complexes I and II-dependent respiratory control ratio. The effect on mitochondrial respiration was reversed by 6-ketocholestanol addition, indicating that this hydroquinone is a protonophoric uncoupling agent. In intact TA3/Ha cells, hydroquinone 9 caused mitochondrial depolarization, decreasing intracellular ATP and NAD(P)H levels and GSH/GSSG ratio, and slightly increasing the ROS levels. Moreover, it exhibited selective NAD(P)H availability-dependent anti-proliferative effect on cancer cells. Therefore, our results indicate that the ortho-carbonyl hydroquinone scaffold offers the possibility to design compounds with specific actions on OXPHOS of cancer cells.},
keywords = {anti-cancer apoptosis, calu-6 cancer-cells, cell cells, complex derivatives, dysfunction, energy-metabolism, hydroquinones, i, liver-mitochondria, mitochondrial oxidative phosphorylation, respiration, ta3, uncouplers},
pubstate = {published},
tppubtype = {article}
}

@article{RN285,
title = {Gastroprotective Activity of Synthetic Coumarins: Role of Endogenous Prostaglandins, Nitric Oxide, Non-Protein Sulfhydryls and Vanilloid Receptors},
author = { B. Sepulveda and C. Quispe and M. Simirgiotis and A. Torres-Benitez and J. Reyes-Ortiz and C. Areche and O. Garcia-Beltran},
url = {/brokenurl#<Go to ISI>://WOS:000389519100023},
doi = {10.1016/j.bmcl.2016.10.056},
issn = {0960-894x},
year = {2016},
date = {2016-01-01},
journal = {Bioorganic & Medicinal Chemistry Letters},
volume = {26},
number = {23},
pages = {5732-5735},
publisher = {2016 Elsevier Ltd.},
abstract = {Natural or synthetic coumarins showed gastroprotective and antiulcer activity in animal models. In this study, we have synthetized twenty coumarins using classic methods to evaluate their gastroprotective effects on the ethanol/HCl-induced gastric lesion model in mice at 20 mg/kg. Among the coumarins synthetized, compounds 6 and 10 showed the greatest gastroprotective activity being as active as lansoprazole at 20 mg/kg and reducing gastric lesions by 75 and 76%, respectively. Then, in a second experiment, compounds 6 and 10 were re-evaluated in order to understand the possible mode of gastroprotective activity. Regarding coumarin 6, the protective effect was reduced by pre-treatment of the mice with N-ethylmaleimide and l-NAME suggesting that sulfhydryl compounds and endogenous nitric oxide are involved in its gastroprotective activity. While for coumarin 10 the effect was reduced by pre-treatment with indomethacin suggesting that prostaglandins are positively involved in its gastroprotective activity.},
keywords = {anhydrase applications, carbonic-anhydrases, coumarins, cysteine, defense derivatives, gastroprotective, glutathione, heck heterocycles, i, inhibition, isozymes reaction, scaffold, therapeutic ulcer},
pubstate = {published},
tppubtype = {article}
}