Person:
Cores Esperón, Ángel

First Name

Ángel

Last Name

Cores Esperón

Affiliation

Universidad Complutense de Madrid

Faculty / Institute

Farmacia

Department

Química en Ciencias Farmacéuticas

Area

Química Orgánica

Identifiers

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Now showing 1 - 9 of 9

Bisavenathramide Analogues as Nrf2 Inductors and Neuroprotectors in In Vitro Models of Oxidative Stress and Hyperphosphorylation
(MDPI, 2021-06-10) Cores Esperón, Ángel; Abril, Sheila; Michalska, Patrycja; Duarte, Pablo; Olives Barba, Ana Isabel; Martín Carmona, María Antonia; Villacampa Sanz, Mercedes; León, Rafael; Menéndez Ramos, José Carlos
Oxidative stress is crucial to the outbreak and advancement of neurodegenerative diseases and is a common factor to many of them. We describe the synthesis of a library of derivatives of the 4-arylmethylen-2-pyrrolin-5-one framework by sequential application of a three-component reaction of primary amines, β-dicarbonyl compounds, and α-haloketones and a Knoevenagel condensation. These compounds can be viewed as cyclic amides of caffeic and ferulic acids, and are also structurally related to the bisavenanthramide family of natural antioxidants. Most members of the library showed low cytotoxicity and good activity as inductors of Nrf2, a transcription factor that acts as the master regulator of the antioxidant response associated with activation of the antioxidant response element (ARE). Nrf2-dependent protein expression was also proved by the significant increase in the levels of the HMOX1 and NQO1 proteins. Some compounds exerted neuroprotective properties in oxidative stress situations, such as rotenone/oligomycin-induced toxicity, and also against protein hyperphosphorylation induced by the phosphatase inhibitor okadaic acid. Compound 3i, which can be considered a good candidate for further hit-to-lead development against neurodegenerative diseases due to its well-balanced multitarget profile, was further characterized by proving its ability to reduce phosphorylated Tau levels.
Desarrollo del aula virtual como soporte del aprendizaje flexible, de las competencias relacionadas con la determinación estructural de compuestos orgánicos
(2019-04-04) González Matilla, Juan Francisco; Cuesta Elosegui, Elena de la; Menéndez Ramos, José Carlos; Villacampa Sanz, Mercedes; Ramos García, María teresa; Cores Esperón, Ángel
La mejora en la actividad docente y la eficacia del tiempo dedicado al aprendizaje por el alumno, están estrechamente ligadas al tiempo que dedica el alumno al aprendizaje fuera del aula. Con el desarrollo y avance de las TIC, en los últimos tiempos ha ganado terreno una práctica de aprendizaje que tiene su origen en la educación a distancia y que se conoce hoy como e-learning, educación virtual o, educación en línea. En este sentido hemos diseñado y elaborado una serie de fichas de problemas sobre determinación estructural de compuestos orgánicos. En este proyecto también se han elaborado vídeos tutoriales donde se indican las pautas necesarias para resolver los problemas de determinación estructural.
Natural product-related multitarget-directed ligands for the potential treatment of neurodegenerative diseases
(Universidad Complutense de Madrid, 2020-03-26) Cores Esperón, Ángel; Menéndez Ramos, José Carlos; Villacampa Sanz, Mercedes
Neurodegenerative diseases are characterized by the loss of neurons in the brain and/or spinal cord and constitute one of the most important health problems worldwide. Although these diseases have different etiologies and clinical manifestations, they share many mechanistic pathways, including: protein misfolding, neuroinflammation, impaired mitochondrial function, increase in oxidative stress, mitochondrial disfunction, alterations in calcium homeostasis, etc...
Bifunctional carbazole derivatives for simultaneous therapy and fluorescence imaging in prion disease murine cell models
(Elsevier, 2022-11-15) Staderini, Matteo; Vanni, Silvia; Colini Baldeschi, Arianna; Zattoni, Marco; Celauro, Luigi; Ferracin, Chiara; Bistaffa, Edoardo; Moda, Fabio; Pérez, Daniel I.; Martínez, Ana; Martín Carmona, María Antonia; Martín Cámara, Olmo; Cores Esperón, Ángel; Bianchini, Giulia; Kammerer, Robert; Menéndez Ramos, José Carlos; Legname, Giuseppe; Bolognesi, Maria Laura
Prion diseases are characterized by the self-assembly of pathogenic misfolded scrapie isoforms (PrPSc) of the cellular prion protein (PrPC). In an effort to achieve a theranostic profile, symmetrical bifunctional carbazole derivatives were designed as fluorescent rigid analogues of GN8, a pharmacological chaperone that stabilizes the native PrPC conformation and prevents its pathogenic conversion. A focused library was synthesized via a four- step route, and a representative member was confirmed to have native fluorescence, including a band in the near- infrared region. After a cytotoxicity study, compounds were tested on the RML-infected ScGT1 neuronal cell line, by monitoring the levels of protease-resistant PrPSc. Small dialkylamino groups at the ends of the molecule were found to be optimal in terms of therapeutic index, and the bis-(dimethylaminoacetamido)carbazole derivative 2b was selected for further characterization. It showed activity in two cellClines infected with the mouse-adapted RML strain (ScGT1 and ScN2a). Unlike GN8, 2b did not affect PrP levels, which represents a potential advantage in terms of toxicity. Amyloid Seeding Assay (ASA) experiments showed the capacity of 2b to delay the aggregation of recombinant mouse PrP. Its ability to interfere with the amplification of the scrapie RML strain by Protein Misfolding Cyclic Amplification (PMCA) was shown to be higher than that of GN8, although 2b did not inhibit the amplification of human vCJD prion. Fluorescent staining of PrPSc aggregates by 2b was confirmed in living cells. 2b emerges as an initial hit compound for further medicinal chemistry optimization towards strain- independent anti-prion compounds.
Aprendizaje de las prácticas de laboratorio de Química Farmacéutica del Grado en Farmacia y Doble Grado en Farmacia y Nutrición a través del aula virtual
(2022-02-14) Menéndez Ramos, José Carlos; Hernáiz Gómez-Dégano, María José; Pedregal Freire, Carmen; Cabezas Baudot, Nieves; Villacampa Sanz, Mercedes; Campo Pérez, Carmen Luisa del; Salazar Martínez de Pisón, María Loreto; González Matilla, Juan Francisco; Hoyos Vidal, Pilar; Esteban García, Gemma; Martín Martín, Antonio; Rico Arjona, Rocío; Gómez-Carpintero Jiménez, Jorge; Martín Cámara, Olmo; Cores Esperón, Ángel
El podcast como recurso didáctico en las asignaturas de Química Orgánica y Farmacéutica en el Grado de Farmacia y doble Grado de Farmacia y Nutrición Humana y dietética
(2023-07-14) Ruiz Serrano, Miriam; Sánchez Cebrián, Juan Domingo; López-Alvarado Gutiérrez, María Pilar; Ramos García, María Teresa; Villacampa Sanz, Mercedes; Menéndez Ramos, José Carlos; Giorgi Poletti, Giorgio; Sarabia Vallejo, Álvaro; Cores Esperón, Ángel; Clerigué Louzado, José; León Martínez, Rafael; Herrero Gómez, Natalia; Rodríguez Cordero, María Luisa; Solera Viana, María; Cledera Crespo, María Pilar; Polo Parra, Sonia; Rico Arjona, Rocío
Este proyecto tiene como objetivo la creación, divulgación y uso didáctico de los podcasts como herramienta de difusión de contenidos científicos para el estudio y la profundización de las asignaturas de Química Orgánica y Química Farmacéutica. En este sentido, se pretende que el alumnado, habituado al uso de medios tecnológicos y redes sociales, aprenda a utilizar este recurso no sólo como un instrumento de entretenimiento, sino como un potente medio para el aprendizaje.
NRF2 Regulation Processes as a Source of Potential Drug Targets against Neurodegenerative Diseases
(MDPI, 2020-06-14) Cores Esperón, Ángel; Piquero Martí, Marta; Villacampa Sanz, Mercedes; León Martínez, Rafael; Menéndez Ramos, Juan Carlos
NRF2 acts by controlling gene expression, being the master regulator of the Phase II antioxidant response, and also being key to the control of neuroinflammation. NRF2 activity is regulated at several levels, including protein degradation by the proteasome, transcription, and post-transcription. The purpose of this review is to offer a concise and critical overview of the main mechanisms of NRF2 regulation and their actual or potential use as targets for the treatment of neurodegenerative diseases.
Enhanced Stability and Bioactivity of Natural Anticancer Topoisomerase I Inhibitors through Cyclodextrin Complexation
(MDPI, 2021-10-03) González Ruiz, Víctor; Cores Esperón, Ángel; Martín Cámara, Olmo; Orellana, Karen; Cervera Carrascón, Víctor Enrique; Michalska, Patrycja; León, Rafael; Olives Barba, Ana Isabel; Martín Carmona, M. Antonia; Menéndez Ramos, José Carlos
The use of cyclodextrins as drug nano-carrier systems for drug delivery is gaining importance in the pharmaceutical industry due to the interesting pharmacokinetic properties of the resulting inclusion complexes. In the present work, complexes of the anti-cancer alkaloids camptothecin and luotonin A have been prepared with β-cyclodextrin and hydroxypropyl-β-cyclodextrin. These cyclodextrin complexes were characterized by nuclear magnetic resonance spectroscopy (NMR). The variations in the 1H-NMR and 13C-NMR chemical shifts allowed to establish the inclusion modes of the compounds into the cyclodextrin cavities, which were supported by docking and molecular dynamics studies. The efficiency of the complexation was quantified by UV-Vis spectrophotometry and spectrofluorimetry, which showed that the protonation equilibria of camptothecin and luotonin A were drastically hampered upon formation of the inclusion complexes. The stabilization of camptothecin towards hydrolysis inside the cyclodextrin cavity was verified by the quantitation of the active lactone form by reverse phase liquid chromatography fluorimetric detection, both in basic conditions and in the presence of serum albumin. The antitumor activity of luotonin A and camptothecin complexes were studied in several cancer cell lines (breast, lung, hepatic carcinoma, ovarian carcinoma and human neuroblastoma) and an enhanced activity was found compared to the free alkaloids, particularly in the case of hydroxypropyl-β-cyclodextrin derivatives. This result shows that the cyclodextrin inclusion strategy has much potential towards reaching the goal of employing luotonin A or its analogues as stable analogues of camptothecin.
Enantioselective Synthesis and Pharmacological Evaluation of Aza-CGP37157–Lipoic Acid Hybrids for the Treatment of Alzheimer’s Disease
(MPDI, 2022-01-04) Cores Esperón, Ángel; Michalska, Patrycja; Pérez, José Miguel; Crisman, Enrique; Gómez, Clara; Villacampa Sanz, Mercedes; Menéndez Ramos, José Carlos; León, Rafael
Hybrids based on an aza-analogue of CGP37157, a mitochondrial Na+/Ca2+ exchanger antagonist, and lipoic acid were obtained in order to combine in a single molecule the antioxidant and NRF2 induction properties of lipoic acid and the neuroprotective activity of CGP37157. The four possible enantiomers of the hybrid structure were synthesized by using as the key step a fully diastereoselective reduction induced by Ellman’s chiral auxiliary. After computational druggability studies that predicted good ADME profiles and blood–brain permeation for all compounds, the DPPH assay showed moderate oxidant scavenger capacity. Following a cytotoxicity evaluation that proved the compounds to be non-neurotoxic at the concentrations tested, they were assayed for NRF2 induction capacity and for anti-inflammatory properties and measured by their ability to inhibit nitrite production in the lipopolysaccharide-stimulated BV2 microglial cell model. Moreover, the compounds were studied for their neuroprotective effect in a model of oxidative stress achieved by treatment of SH-SY5Y neuroblastoma cells with the rotenone–oligomycin combination and also in a model of hyperphosphorylation induced by treatment with okadaic acid. The stereocenter configuration showed a critical influence in NRF2 induction properties, and also in the neuroprotection against oxidative stress experiment, leading to the identification of the compound with S and R configuration as an interesting hit with a good neuroprotective profile against oxidative stress and hyperphosphorylation, together with a relevant anti-neuroinflammatory activity. This interesting multitarget profile will be further characterized in future work.