Enantioselective Synthesis and Pharmacological Evaluation of Aza-CGP37157–Lipoic Acid Hybrids for the Treatment of Alzheimer’s Disease

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

Bisavenathramide Analogues as Nrf2 Inductors and Neuroprotectors in In Vitro Models of Oxidative Stress and Hyperphosphorylation

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

Uso del vídeo tutorial como soporte multimedia para la comprensión de los mecanismos de las reacciones químicas en las competencias de la Química Orgánica

Depto. de Química en Ciencias FarmacéuticasFac. de FarmaciaFALSEsubmitte

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

Depto. de Química en Ciencias FarmacéuticasFac. de FarmaciaFALSEsubmitte

NRF2 Regulation Processes as a Source of Potential Drug Targets against Neurodegenerative Diseases

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

Quinones as Neuroprotective Agents

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.Ministerio de Ciencia e InnovaciónDepto. de Química en Ciencias FarmacéuticasTRUEpubDescuento UC

Empleo de Software libre para la enseñanza en el área de la Química Orgánica

Depto. de Química en Ciencias FarmacéuticasFac. de FarmaciaFALSEsubmitte

Development of a virtual classroom to support enhances learning, related to the field of structural determination of organic compounds

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.Improve the teaching process quality and effectiveness on student learning closely depends on the amount of time a student outside the classroom. The development and advance of ICT, have driven in the last years, to increase e-learning application in the present mode of education. In this context, we have designed and developed a collection issues and solutions in Organic Structural determination. In this project, we have also been produced tutorial videos, to solve structural determination questions.Universidad Complutense de MadridDepto. de Química en Ciencias FarmacéuticasFac. de FarmaciaFALSEsubmitte

Híbridos de curcumina y piperlongumina con un perfil multidiana ejercen neuroprotección en modelos in vitro de estrés oxidativo e hiperfosforilación

La curcumina muestra un amplio espectro de actividades de relevancia en el tratamiento de la enfermedad de Alzheimer (EA); sin embargo, se absorbe mal y también es química y metabólicamente inestable, lo que conduce a una biodisponibilidad oral muy baja. Se sintetizó una pequeña biblioteca de compuestos híbridos diseñados como análogos de la curcumina y que incorporan el fragmento estructural clave de la piperlongumina, un inhibidor natural de la neuroinflamación, mediante una ruta de dos pasos que combina una reacción de tres componentes entre aminas primarias, β-cetoésteres y α-haloésteres y una acilación promovida por bases con cloruros de cinamoilo. Se predijo que estos compuestos presentaban una buena absorción oral y permeabilidad al SNC, tenían buenas propiedades de barrido en el experimento in vitro con DPPH y en un ensayo celular basado en la oxidación de la diclorofluorescina a una especie fluorescente. Los compuestos mostraron una baja toxicidad en dos modelos celulares, fueron potentes inductores de la respuesta antioxidante de fase II Nrf2-ARE, inhibieron la agregación del péptido PHF6, estrechamente relacionado con la agregación de la proteína Tau y fueron activos contra la respuesta inflamatoria inducida por LPS. También proporcionaron neuroprotección frente a una agresión oxidativa inducida por la inhibición de la cadena respiratoria mitocondrial con la combinación rotenona-oligomicina A y frente a la hiperfosforilación de Tau inducida por el inhibidor de la fosfatasa ácido okadaico. Este perfil farmacológico multiobjetivo es muy prometedor en el desarrollo de tratamientos para la EA y proporciona una buena estructura de éxito para futuros esfuerzos de optimización.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.Ministerio de Ciencia e InnovaciónInstituto de Salud Carlos III y the European Regional Development funds (FEDER) (PI17/01700)Comunidad Autónoma de MadridDepto. de Farmacología, Farmacognosia y BotánicaDepto. de Química en Ciencias FarmacéuticasFac. de FarmaciaTRUEpu