Person:
Cores Esperón, Ángel

First Name

Ángel

Last Name

Cores Esperón

URI

https://hdl.handle.net/20.500.14352/80718

Affiliation

Universidad Complutense de Madrid

Faculty / Institute

Farmacia

Department

Química en Ciencias Farmacéuticas

Area

Química Orgánica

Identifiers

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Search Results

Now showing 1 - 10 of 12

Discovery of the first dual GSK3β inhibitor/Nrf2 inducer. A new multitarget therapeutic strategy for Alzheimer’s disease
(Scientific Reports, 2017) Gameiro, Isabel; Michalska Dziama, Patrycja; Tenti, Giammarco; Cores Esperón, Ángel; Buendia, Izaskun; Rojo, Ana I.; Georgakopoulos, Nikolaos D.; López, Manuela G.; Hernández, Jesús M.; Ramos García, María Teresa; Wells, Geoffrey; Cuadrado, Antonio; Menéndez Ramos, José Carlos; León Martínez, Rafael
The formation of neurofibrillary tangles (NFTs), oxidative stress and neuroinflammation have emerged as key targets for the treatment of Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder. These pathological hallmarks are closely related to the over-activity of the enzyme GSK3β and the downregulation of the defense pathway Nrf2-EpRE observed in AD patients. Herein, we report the synthesis and pharmacological evaluation of a new family of multitarget 2,4-dihydropyrano[2,3-c]pyrazoles as dual GSK3β inhibitors and Nrf2 inducers. These compounds are able to inhibit GSK3β and induce the Nrf2 phase II antioxidant and anti-inflammatory pathway at micromolar concentrations, showing interesting structure-activity relationships. The association of both activities has resulted in a remarkable anti-inflammatory ability with an interesting neuroprotective profile on in vitro models of neuronal death induced by oxidative stress and energy depletion and AD. Furthermore, none of the compounds exhibited in vitro neurotoxicity or hepatotoxicity and hence they had improved safety profiles compared to the known electrophilic Nrf2 inducers. In conclusion, the combination of both activities in this family of multitarget compounds confers them a notable interest for the development of lead compounds for the treatment of AD.
Quinones as Neuroprotective Agents
(Antioxidants, 2023) Cores Esperón, Ángel; Carmona Zafra, Noelia; Clerigué Louzado, José; Villacampa Sanz, Mercedes; Menéndez Ramos, José Carlos
Quinones can in principle be viewed as a double-edged sword in the treatment of neurodegenerative diseases, since they are often cytoprotective but can also be cytotoxic due to covalent and redox modification of biomolecules. Nevertheless, low doses of moderately electrophilic quinones are generally cytoprotective, mainly due to their ability to activate the Keap1/Nrf2 pathway and thus induce the expression of detoxifying enzymes. Some natural quinones have relevant roles in important physiological processes. One of them is coenzyme Q10, which takes part in the oxidative phosphorylation processes involved in cell energy production, as a proton and electron carrier in the mitochondrial respiratory chain, and shows neuroprotective effects relevant to Alzheimer’s and Parkinson’s diseases. Additional neuroprotective quinones that can be regarded as coenzyme Q10 analogues are idobenone, mitoquinone and plastoquinone. Other endogenous quinones with neuroprotective activities include tocopherol-derived quinones, most notably vatiquinone, and vitamin K. A final group of non-endogenous quinones with neuroprotective activity is discussed, comprising embelin, APX-3330, cannabinoid-derived quinones, asterriquinones and other indolylquinones, pyrroloquinolinequinone and its analogues, geldanamycin and its analogues, rifampicin quinone, memoquin and a number of hybrid structures combining quinones with amino acids, cholinesterase inhibitors and non-steroidal anti-inflammatory drugs.
Bisavenathramide Analogues as Nrf2 Inductors and Neuroprotectors in In Vitro Models of Oxidative Stress and Hyperphosphorylation
(Antioxidants, 2021) Cores Esperón, Ángel; Abril Comesaña, Sheila; Michalska Dziama, Patrycja; Duarte, Pablo; Olives Barba, Ana Isabel; Martín Carmona, María Antonia; Villacampa Sanz, Mercedes; León Martínez, 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.
Bifunctional carbazole derivatives for simultaneous therapy and fluorescence imaging in prion disease murine cell models
(European Journal of Medicinal Chemistry, 2022) 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.
NRF2 Regulation Processes as a Source of Potential Drug Targets against Neurodegenerative Diseases
(Biomolecules, 2020) Cores Esperón, Ángel; Piquero Martí, Marta; Villacampa Sanz, Mercedes; León Martínez, Rafael; Menéndez Ramos, José 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.
Curcumin-Piperlongumine Hybrids with a Multitarget Profile Elicit Neuroprotection in In Vitro Models of Oxidative Stress and Hyperphosphorylation
(Antioxidants, 2021) Cores Esperón, Ángel; Carmona Zafra, Noelia; Martín Cámara, Olmo; Sánchez Cebrián, Juan Domingo; Duarte, Pablo; Villacampa Sanz, Mercedes; Bermejo Bescos, María De La Paloma; Martín-Aragón Álvarez, Sagrario; León Martínez, Rafael; Menéndez Ramos, José Carlos
Curcumin shows a broad spectrum of activities of relevance in the treatment of Alzheimer’s disease (AD); however, it is poorly absorbed and is also chemically and metabolically unstable, leading to a very low oral bioavailability. A small library of hybrid compounds designed as curcumin analogues and incorporating the key structural fragment of piperlongumine, a natural neuroinflammation inhibitor, were synthesized by a two-step route that combines a three-component reaction between primary amines, β-ketoesters and α-haloesters and a base-promoted acylation with cinnamoyl chlorides. These compounds were predicted to have good oral absorption and CNS permeation, had good scavenging properties in the in vitro DPPH experiment and in a cellular assay based on the oxidation of dichlorofluorescin to a fluorescent species. The compounds showed low toxicity in two cellular models, were potent inductors of the Nrf2-ARE phase II antioxidant response, inhibited PHF6 peptide aggregation, closely related to Tau protein aggregation and were active against the LPS-induced inflammatory response. They also afforded neuroprotection against an oxidative insult induced by inhibition of the mitochondrial respiratory chain with the rotenone-oligomycin A combination and against Tau hyperphosphorylation induced by the phosphatase inhibitor okadaic acid. This multitarget pharmacological profile is highly promising in the development of treatments for AD and provides a good hit structure for future optimization efforts.
Project number: 96
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) 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.
Natural product-related multitarget-directed ligands for the potential treatment of neurodegenerative diseases
(2020) 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...
Enhanced Stability and Bioactivity of Natural Anticancer Topoisomerase I Inhibitors through Cyclodextrin Complexation
(Pharmaceutics, 2021) González Ruiz, Víctor; Cores Esperón, Ángel; Martín Cámara, Olmo; Serrano Orellana, Karen; Michalska Dziama, Patrycja; Cervera Carrascón, Víctor Enrique; León Martínez, Rafael; Olives Barba, Ana Isabel; Martín Carmona, María 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
(Antioxidants, 2022) Cores Esperón, Ángel; Michalska Dziama, Patrycja; Pérez Moreno, José Miguel; Crisman Vigil, Enrique; Gómez Serrano, Clara; Villacampa Sanz, Mercedes; Menéndez Ramos, José Carlos; León Martínez, 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.