Perturbation Theory Model of Reactivity and Enantioselectivity of Palladium-catalyzed Heck-Heck cascade reactions

Enantioselective intramolecular Heck-Heck cascade reactions have emerged as an excellent tool for the construction of polycyclic frameworks, such as Lycorane alkaloids, Xestoquinone and analogues. However, it is particularly difficult to rationalize the effect of simultaneous changes in both the structure of many molecular entities and experimental conditions (temperature, time, solvent, ligand, catalyst loading, etc.) on reactivity and enantioselectivity. In this work, a computational model to predict the enantiomeric excess and the yield of Heck-Heck cascade reactions has been developed. The model combines Perturbation Theory (PT) and Quantitative Structure-Reactivity Relationships (QSRR) ideas for the prediction of two different outputs with the same equation (% ee and % yield). This model predicted 520 experimental outcomes with a correlation coefficient R = 0.89, standard error of estimates SEE = 1.19 %, and a cross-validation correlation coefficient q2 = 0.79. The use of the model has been illustrated with a case of study, the Heck-Heck cascade reaction of a 2,3-dialkenyl pyrrole using Pd(dba)2 and (R)-BINAP. For the first time, a 2000-points simulation in a ternary phase diagrams shows the effect of the concentration of the catalyst, the base, and ligand on the enantioselectivity of this reaction. The QSRR model also predicts trends in structural outcomes, such halides vs. triflates, or the ligand structure. Therefore, the model opens the door to the design of new chiral ligands and helps to find trends to improve the experimental results in enantioselective polyene cyclisationsMinisterio de Economía y Competitividad (CTQ2013-41229-P), Gobierno Vasco (IT-623-13

Neuroprotective mechanisms of multitarget 7-aminophenanthridin-6(5H)-one derivatives against metal-induced amyloid proteins generation and aggregation

Brain’s metals accumulation is associated with toxic proteins, like amyloid-proteins (Aβ), formation, accumulation, and aggregation, leading to neurodegeneration. Metals downregulate the correct folding, disaggregation, or degradation mechanisms of toxic proteins, as heat shock proteins (HSPs) and proteasome. The 7-amino-phenanthridin-6(5H)-one derivatives (APH) showed neuroprotective effects against metal-induced cell death through their antioxidant effect, independently of their chelating activity. However, additional neuroprotective mechanisms seem to be involved. We tested the most promising APH compounds (APH1-5, 10–100 μM) chemical ability to prevent metal-induced Aβ proteins aggregation; the APH1-5 effect on HSP70 and proteasome 20S (P20S) expression, the metals effect on Aβ formation and the involvement of HSP70 and P20S in the process, and the APH1-5 neuroprotective effects against Aβ proteins (1 μM) and metals in SN56 cells. Our results show that APH1-5 compounds chemically avoid metal-induced Aβ proteins aggregation and induce HSP70 and P20S expression. Additionally, iron and cadmium induced Aβ proteins formation through downregulation of HSP70 and P20S. Finally, APH1-5 compounds protected against Aβ proteins-induced neuronal cell death, reversing partially or completely this effect. These data may help to provide a new therapeutic approach against the neurotoxic effect induced by metals and other environmental pollutants, especially when mediated by toxic proteins

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

Neuroprotective Action of Multitarget 7-Aminophenanthridin-6(5H)-one Derivatives against Metal-Induced Cell Death and Oxidative Stress in SN56 Cells

Neurodegenerative diseases have been associated with brain metal accumulation, which produces oxidative stress (OS), matrix metalloproteinases (MMPs) induction, and neuronal cell death. Several metals have been reported to downregulate both the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and the antioxidant enzymes regulated by it, mediating OS induction and neurodegeneration. Among a recently discovered family of multitarget 7-amino-phenanthridin-6-one derivatives (APH) the most promising compounds were tested against metal-induced cell death and OS in SN56 cells. These compounds, designed to have chelating activity, are known to inhibit some MMPs and to present antioxidant and neuroprotective effects against hydrogen peroxide treatment to SN56 neuronal cells. However, the mechanisms that mediate this protective effect are not fully understood. The obtained results show that compounds APH1, APH2, APH3, APH4, and APH5 were only able to chelate iron and copper ions among all metals studied and that APH3, APH4, and APH5 were also able to chelate mercury ion. However, none of them was able to chelate zinc, cadmium, and aluminum, thus exhibiting selective chelating activity that can be partly responsible for their neuroprotective action. Otherwise, our results indicate that their antioxidant effect is mediated through induction of the Nrf2 pathway that leads to overexpression of antioxidant enzymes. Finally, these compounds exhibited neuroprotective effects, reversing partially or completely the cytotoxic effects induced by the metals studied depending on the compound used. APH4 was the most effective and safe compound

Virtualization of the practical teaching of Organic Chemistry (I and II) in Degree in Pharmacy and Double Degree in Pharmacy and Human Nutrition and Dietetics

El presente proyecto recoge las acciones llevadas a cabo para virtualizar en el campus virtual las prácticas de las asignaturas de Química Organica (I y II), con el fin de mejorar la comprensión del alumnado de las mismas. Se han realizado presentaciones en Power Point de los fundamentos de cada una de las prácticas así como un video demostrativo de su realización.This project gathers the actions carried out to virtualize in the virtual campus the practices of the subjects of Organic Chemistry (I and II), in order to improve the students' understanding of them. Power Point presentations of the fundamentals of each of the practices have been made as well as a video demonstration of their realizationUCMDepto. de Química en Ciencias FarmacéuticasFac. de FarmaciaFALSEsubmitte