Differential mechanism of action of the CK1ε inhibitor GSD0054

In the current study, we explored for the first time, the mechanism of action of the new Casein kinase 1 ε (CK1ε) selective inhibitor GSD0054. Although GSD0054 behaved as a selective CK1ε inhibitor in enzymatic assays, we studied whether this inhibitory activity also occurred inside the cells. The effects of GSD0054 on β-catenin expression and disruption of cell cycle progression were studied in the human breast cancer cell lines MDA-MB-453 (β-catenin negative) and T-47D (β-catenin positive). We also performed molecular modeling studies using computational docking against CK1ε to explain and predict the mechanism of action of this compound. Moreover, the commercially available CK1ε inhibitor PF-4800567 and the CK1δ/ε inhibitors PF-670462 and IC261 were also studied for comparison purposes. GSD0054 showed anti-proliferative activity against MDA-MB-453 and T-47D cells despite the fact that MDA-MB-453 cells do not possess active β-catenin. However, selective cell killing occurred in the more resistant, β-catenin active, T-47D cells. CK1ε was confirmed as a cellular target, although other targets or alternative mechanisms of action could possibly explain the anti-proliferative activity in MDA-MB-453 cells.info:eu-repo/semantics/publishedVersio

Chemoselective Preparation of New Families of Phenolic-Organoselenium Hybrids—A Biological Assessment

Being aware of the enormous biological potential of organoselenium and polyphenolic compounds, we have accomplished the preparation of novel hybrids, combining both pharma-cophores in order to obtain new antioxidant and antiproliferative agents. Three different families have been accessed in a straightforward and chemoselective fashion: carbohydrate-containing N-acylisoselenoureas, N-arylisoselenocarbamates and N-arylselenocarbamates. The nature of the organoselenium framework, number and position of phenolic hydroxyl groups and substituents on the aromatic scaffolds afforded valuable structure–activity relationships for the biological as-says accomplished: antioxidant properties (antiradical activity, DNA-protective effects, Glutathione peroxidase (GPx) mimicry) and antiproliferative activity. Regarding the antioxidant activity, selenocar-bamates 24–27 behaved as excellent mimetics of GPx in the substoichiometric elimination of H2O2 as a Reactive Oxygen Species (ROS) model. Isoselenocarbamates and particularly their selenocarbamate isomers exhibited potent antiproliferative activity against non-small lung cell lines (A549, SW1573) in the low micromolar range, with similar potency to that shown by the chemotherapeutic agent cisplatin (cis-diaminodichloroplatin, CDDP) and occasionally with more potency than etoposide (VP-16).Ministerio de Ciencia e Innovación PID2020-116460RB-I00Junta de Andalucía FQM134Gobierno de las Islas Canarias ProID202001010

Masked Phenolic-Selenium Conjugates: Potent and Selective Antiproliferative Agents Overcoming P-gp Resistance

Cancer accounts for one of the most complex diseases nowadays due to its multifactorial nature. Despite the vast number of cytotoxic agents developed so far, good therapeutic approaches are not always reached. In recent years, multitarget drugs are gaining great attention against multifactorial diseases in contraposition to polypharmacy. Herein we have accomplished the conjugation of phenolic derivatives with an ample number of organochalcogen motifs with the aim of developing novel antiproliferative agents. Their antioxidant, and antiproliferative properties (against six tumour and one non-tumour cell lines) were analysed. Moreover, in order to predict P-gp-mediated chemoresistance, the P-glycoprotein assay was also conducted in order to determine whether compounds prepared herein could behave as substrates of that glycoprotein. Selenium derivatives were found to be significantly stronger antiproliferative agents than their sulfur isosters. Moreover, the length and the nature of the tether, together with the nature of the organoselenium scaffold were also found to be crucial features in the observed bioactivities. The lead compound, bearing a methylenedioxyphenyl moiety, and a diselenide functionality, showed a good activity (GI50 = 0.88-2.0 µM) and selectivity towards tumour cell lines (selectivity index: 14-32); moreover, compounds considered herein were not substrates for the P-gp efflux pump, thus avoiding the development of chemoresistance coming from such mechanism, commonly found for widely-used chemotherapeutic agents

Tuning the activity of iminosugars: novel N-alkylated deoxynojirimycin derivatives as strong BuChE inhibitors

We have designed unprecedented cholinesterase inhibitors based on 1-deoxynojirimycin as potential anti-Alzheimer’s agents. Compounds are comprised of three key structural motifs: the iminosugar, for interaction with cholinesterase catalytic anionic site (CAS); a hydrocarbon tether with variable lengths, and a fragment derived from 2-phenylethanol for promoting interactions with peripheral anionic site (PAS). Title compounds exhibited good selectivity towards BuChE, strongly depending on the substitution pattern and the length of the tether. The lead compounds were found to be strong mixed inhibitors of BuChE (IC50 = 1.8 and 1.9 µM). The presumptive binding mode of the lead compound was analysed using molecular docking simulations, revealing H-bond interactions with the catalytic subsite (His438) and CAS (Trp82 and Glu197) and van der Waals interactions with PAS (Thr284, Pro285, Asn289). They also lacked significant antiproliferative activity against tumour and non-tumour cells at 100 µM, making them promising new agents for tackling Alzheimer’s disease through the cholinergic approach.Dirección General de Investigación de España. CTQ2016-78703-PJunta de Andalucía. FQM134Fondo Europeo de Desarrollo Regional (FEDER) y Consejo Nacional de Ciencia y Tecnología de México (CONACYT). CB-2015/257465Ministerio de Ciencia, Innovación y Universidades y Agencia Estatal de Investigación de España y Fondos FEDER de la Unión Europea (MCIU/AEI/FEDER). PGC2018-094503-B-C2

Amortiguamiento térmico mediante la aplicación de sistemas pasivos de climatización sobre losas de azotea

Tesis de Maestría presentada a la Facultad de Ingeniería de la Universidad Veracruzana. Región Veracruz

Chemoselective Preparation of New Families of Phenolic-Organoselenium Hybrids—A Biological Assessment

Being aware of the enormous biological potential of organoselenium and polyphenolic compounds, we have accomplished the preparation of novel hybrids, combining both pharmacophores in order to obtain new antioxidant and antiproliferative agents. Three different families have been accessed in a straightforward and chemoselective fashion: carbohydrate-containing N-acylisoselenoureas, N-arylisoselenocarbamates and N-arylselenocarbamates. The nature of the organoselenium framework, number and position of phenolic hydroxyl groups and substituents on the aromatic scaffolds afforded valuable structure–activity relationships for the biological assays accomplished: antioxidant properties (antiradical activity, DNA-protective effects, Glutathione peroxidase (GPx) mimicry) and antiproliferative activity. Regarding the antioxidant activity, selenocarbamates 24–27 behaved as excellent mimetics of GPx in the substoichiometric elimination of H2O2 as a Reactive Oxygen Species (ROS) model. Isoselenocarbamates and particularly their selenocarbamate isomers exhibited potent antiproliferative activity against non-small lung cell lines (A549, SW1573) in the low micromolar range, with similar potency to that shown by the chemotherapeutic agent cisplatin (cis-diaminodichloroplatin, CDDP) and occasionally with more potency than etoposide (VP-16)

Oxa/thiazole-tetrahydropyran triazole-linked hybrids with selective antiproliferative activity against human tumour cells

Inspired by diverse marine bioactive compounds, the principle of molecular hybridization was applied to produce a series of new compounds combining diverse heterocyclic systems (oxa/thiazoles and tetrahydropyrans) via a triazole ring, attempting to increase the activity of individual building blocks. These new compounds exhibit a highly interesting antiproliferative activity against different human tumour cells and good selectivity when compared to normal cells. The formation of reactive oxygen species and the interaction with P-gp were also evaluated for the lead compounds.This research was supported by CSIC Grupos No. 654 and No. 983, PEDECIBA Química and the Spanish MINECO. Co-financed by the European Regional Development Fund (ERDF) (CTQ2014-56362-C2-1-P). G. V. would like to thank ANII (Agencia Nacional de Investigación e Innovación) for the award of a doctoral fellowship.Peer Reviewe

New tacrine dimers with antioxidant linkers as dual drugs: Anti-Alzheimer's and antiproliferative agents

open11siWe have designed a series of tacrine-based homo- and heterodimers that incorporate an antioxidant tether (selenoureido, chalcogenide) as new dual compounds: for the treatment of Alzheimer's disease and as antiproliferative agents. Symmetrical homodimers bearing a dichalcogenide or selenide-based tether, the best compounds in the series, were found to be strong and highly selective electric eel AChE inhibitors, with inhibition constants within the low nanomolar range. This high inhibitory activity was confirmed on recombinant human AChE for the most interesting derivatives. The three most promising homodimers also showed a good inhibitory activity towards amyloid-β self aggregation. The symmetric disulfide derivative bis[5-(1â²,2â²,3â²,4â-tetrahydroacridin-9â²-ylamino)pentyl]disulfide (19) showed the best multipotent profile and was not neurotoxic on immortalized mouse cortical neurons even at 50 μM concentration. These results represent an improvement in activity and selectivity compared to parent tacrine, the first marketed drug against Alzheimer's disease. Title compounds also exhibited excellent in vitro antiproliferative activities against a panel of 6 human tumor cell lines, with GI50values within the submicromolar range for the most potent derivatives (0.12â0.95 μM); such values represent a spectacular increase compared to currently-used chemotherapeutic agents, such as 5-FU (up to 306âfold) and cisplatin (up to 162âfold). Cell cycle experiments indicated the accumulation of cells in the G1phase of the cycle, a different mechanism than the reported for cisplatin. The breast cancer cell lines turned out to be the most sensitive one of the panel tested.embargoed_20190929Roldán-Peña, Jesús M.; Alejandre-Ramos, Daniel; López, Oscar; Maya, Inés; Lagunes, Irene; Padrón, José M.; Peña-Altamira, Luis Emiliano; Bartolini, Manuela; Monti, Barbara; Bolognesi, Maria L.; Fernández-Bolaños, José G.Roldán-Peña, Jesús M.; Alejandre-Ramos, Daniel; López, O scar; Maya, Inés; Lagunes, Irene; Padrón, José M.; Peña-Altamira, Luis Emiliano; Bartolini, Manuela; Monti, Barbara; Bolognesi, Maria L.; Fernández-Bolaños, José G

Characterization of the genetic diversity of a population of Odocoileus virginianus veraecrucis in captivity using microsatellite markers

The genetic diversity and effective population size (Ne) of a population of Odocoileus virginianus veraecrucis in captivity were characterized in the Wildlife Management Unit “El Pochote”, located in Ixtaczoquitlán, Veracruz, Mexico. Blood tissue was collected from 20 individuals of the reproductive nucleus, its genomic DNA was extracted, and genetic diversity was characterized by six microsatellites amplified by PCR and visualized in polyacrylamide gels. With four polymorphic microsatellites, 66.7% of the population’s genetic variation was explained, which was characterized by an allelic diversity that fluctuated between 9 and 28 alleles (18 average alleles), suggesting a mean allelic diversity (Shannon index = 2.6 ± 0.25), but only 12 ± 2.9 effective alleles would be fixed in the next generation. The heterozygosity observed (Ho= 0.81) exceeded that expected (He= 0.79) and these were significantly different (P> 0.05), as a result of a low genetic structure in the population (fixation index F = -0.112 ± 0.03), due to the genetic heterogeneity that each sample contributed, since the specimens came from different geographical regions. The Ne was 625 individuals and a 1:25 male:female ratio, with which 100% of the genetic diversity observed can be maintained for 100 years. The information obtained in the study can help in the design of a reproductive management program to maintain the present genetic diversity, without risk of losses due to genetic drift and inbreeding.To the project “Caracterización de recursos zoogenéticos de las Altas Montañas, Veracruz: implicaciones de la filogeografía y modelación ecológica (PRODEP: 511-6/18-9245/PTC-896) for the financial and technical support of the study. To the Unidad de Manejo y Conservación de Recursos Genéticos y al Programa de Fortalecimiento de la Calidad Educativa of the Facultad de Ciencias Biológicas y Agropecuarias, Universidad Veracruzana, for the materials provided; and to the Instituto de Investigaciones en Recursos Cinegéticos (IREC), Spain, for the team and training to the first author.Peer reviewe

Characterization of the genetic diversity of a population of Odocoileus virginianus veraecrucis in captivity using microsatellite markers

The genetic diversity and effective population size (Ne) of a population of Odocoileus virginianus veraecrucis in captivity were characterized in the Wildlife Management Unit “El Pochote”, located in Ixtaczoquitlán, Veracruz, Mexico. Blood tissue was collected from 20 individuals of the reproductive nucleus, its genomic DNA was extracted, and genetic diversity was characterized by six microsatellites amplified by PCR and visualized in polyacrylamide gels. With four polymorphic microsatellites, 66.7% of the population’s genetic variation was explained, which was characterized by an allelic diversity that fluctuated between 9 and 28 alleles (18 average alleles), suggesting a mean allelic diversity (Shannon index = 2.6 ± 0.25), but only 12 ± 2.9 effective alleles would be fixed in the next generation. The heterozygosity observed (Ho= 0.81) exceeded that expected (He= 0.79) and these were significantly different (P> 0.05), as a result of a low genetic structure in the population (fixation index F = -0.112 ± 0.03), due to the genetic heterogeneity that each sample contributed, since the specimens came from different geographical regions. The Ne was 625 individuals and a 1:25 male:female ratio, with which 100% of the genetic diversity observed can be maintained for 100 years. The information obtained in the study can help in the design of a reproductive management program to maintain the present genetic diversity, without risk of losses due to genetic drift and inbreeding