Funcionalizaciones estereoselectivas de iminolactonas quirales: aplicación a la síntesis de peptidomiméticos

En los últimos años, la elucidación del genoma humano y el descubrimiento de péptidos con importantes actividades biológicas tales como hormonas, neurotransmisores y neuromoduladores, ha provocado un aumento en el interés del uso de este tipo de moléculas con fines terapéuticos. Sin embargo el uso de péptidos como fármacos presenta numerosos inconvenientes: - Tienen poca estabilidad metabólica al ser susceptibles de proteólisis por la acción de diferentes proteasas. - Son rápidamente eliminados a través del hígado y riñón. - Presentan una baja biodisponibilidad en fluidos biológicos. - Su elevada flexibilidad conformacional les dificulta conferir la estructura secundaria bioactiva. En este contexto la preparación de compuestos de estructura peptídica más o menos modificada (peptidomiméticos) constituye un tema de gran interés puesto que permite modular las propiedades farmacológicas del péptido bioactivo original. Dado el creciente interés que despierta el empleo de péptidos con fines terapéuticos, el objetivo de la presente Tesis Doctoral se centra en el diseño y síntesis de peptidomiméticos conformacionalmente restringidos mediante funcionalizaciones estereoselectivas de iminolactonas quirales. Partiendo de un precursor común se pretende obtener aminoácidos tanto cíclicos como bicíclicos de diferente naturaleza que contengan en su estructura un centro cuaternario de estereoquímica definida. De este modo, la estructura de la memoria que se presenta a continuación queda organizada en los siguientes capítulos: Capítulo 1: Síntesis diastereoselectiva de dipéptidos conformacionalmente restringidos. En este primer capítulo se llevará a cabo el diseño y síntesis de dipéptidos conformacionalmente restringidos. La elongación del extremo C-terminal generará un tripéptido cíclico que será objeto de análisis, tanto conformacional como teórico-computacional, para evidenciar la posible existencia de un puente de hidrógeno intramolecular que justifique la formación de un mimético de giro-β. Capítulo 2: Síntesis diastereoselectiva de derivados cuaternarios de la prolina y del ácido pipecólico: retropéptidos cíclicos parcialmente modificados. Se pretenderá obtener aminoácidos cíclicos que a su vez contengan en su estructura una subunidad de tipo α,α-aminoácido disustituido y otra subunidad β-aminocarbonílica característica de los retropéptidos parcialmente modificados. De nuevo se tratará de evidenciar la posible formación de un puente de hidrógeno intramolecular, responsable de promover un giro en la molécula, mediante el análisis conformacional empleando técnicas de RMN de 1H. Capítulo 3: Adiciones diastereoselectivas intramoleculares de alil- y propargilsilanos a cationes iminio: síntesis de aminoácidos cíclicos y bicíclicos cuaternarios. La adición intramolecular de sistemas alil- y propargilsililo a iminolactonas quirales, vía catión iminio, permitirá obtener estructuras espirocíclicas precursoras de ácidos 1-aminocicloalcanocarboxílicos. La posterior funcionalización del nitrógeno presente en la molécula seguido de una reacción de metátesis con cierre de anillo o una reacción de hidroaminación intramolecular generará aminoácidos bicíclicos derivados de la prolina y del ácido pipecólico

Spirocycles as Rigidified sp3-Rich Scaffolds for a Fragment Collection.

Novel divergent methodology to access sp3-rich spirocyclic fragments is reported. First, a robust modular synthesis of bis-alkene amino ester building blocks was developed. Three different carbocycles and six heterocycles were then constructed to assemble eight spirocycles. Importantly, strategic exit vectors were incorporated within each scaffold to aid fragment growth and were elaborated via chemical modifications. Finally, computational methods demonstrate higher levels of rigidity, three-dimensionality, and structural diversity of the library compared to a commercial collection

Recent Applications of Diversity-Oriented Synthesis Toward Novel, 3-Dimensional Fragment Collections

Fragment-based drug discovery (FBDD) is a well-established approach for the discovery of novel medicines, illustrated by the approval of two FBBD-derived drugs. This methodology is based on the utilization of small “fragment” molecules (<300 Da) as starting points for drug discovery and optimization. Organic synthesis has been identified as a significant obstacle in FBDD, however, in particular owing to the lack of novel 3-dimensional (3D) fragment collections that feature useful synthetic vectors for modification of hit compounds. Diversity-oriented synthesis (DOS) is a synthetic strategy that aims to efficiently produce compound collections with high levels of structural diversity and three-dimensionality and is therefore well-suited for the construction of novel fragment collections. This Mini-Review highlights recent studies at the intersection of DOS and FBDD aiming to produce novel libraries of diverse, polycyclic, fragment-like compounds, and their application in fragment-based screening projects

Development of a Novel Cell-Permeable Protein-Protein Interaction Inhibitor for the Polo-box Domain of Polo-like Kinase 1.

Polo-like kinase 1 (PLK1) is a key regulator of mitosis and a recognized drug target for cancer therapy. Inhibiting the polo-box domain of PLK1 offers potential advantages of increased selectivity and subsequently reduced toxicity compared with targeting the kinase domain. However, many if not all existing polo-box domain inhibitors have been shown to be unsuitable for further development. In this paper, we describe a novel compound series, which inhibits the protein-protein interactions of PLK1 via the polo-box domain. We combine high throughput screening with molecular modeling and computer-aided design, synthetic chemistry, and cell biology to address some of the common problems with protein-protein interaction inhibitors, such as solubility and potency. We use molecular modeling to improve the solubility of a hit series with initially poor physicochemical properties, enabling biophysical and biochemical characterization. We isolate and characterize enantiomers to improve potency and demonstrate on-target activity in both cell-free and cell-based assays, entirely consistent with the proposed binding model. The resulting compound series represents a promising starting point for further progression along the drug discovery pipeline and a new tool compound to study kinase-independent PLK functions

IL-6 serum levels predict severity and response to tocilizumab in COVID-19: An observational study

Background: Patients with coronavirus disaese 2019 (COVID-19) can develop a cytokine release syndrome that eventually leads to acute respiratory distress syndrome requiring invasive mechanical ventilation (IMV). Because IL-6 is a relevant cytokine in acute respiratory distress syndrome, the blockade of its receptor with tocilizumab (TCZ) could reduce mortality and/or morbidity in severe COVID-19. Objective: We sought to determine whether baseline IL-6 serum levels can predict the need for IMV and the response to TCZ. Methods: A retrospective observational study was performed in hospitalized patients diagnosed with COVID-19. Clinical information and laboratory findings, including IL-6 levels, were collected approximately 3 and 9 days after admission to be matched with preadministration and postadministration of TCZ. Multivariable logistic and linear regressions and survival analysis were performed depending on outcomes: need for IMV, evolution of arterial oxygen tension/fraction of inspired oxygen ratio, or mortality. Results: One hundred forty-six patients were studied, predominantly males (66%); median age was 63 years. Forty-four patients (30%) required IMV, and 58 patients (40%) received treatment with TCZ. IL-6 levels greater than 30 pg/mL was the best predictor for IMV (odds ratio, 7.1; P < .001). Early administration of TCZ was associated with improvement in oxygenation (arterial oxygen tension/fraction of inspired oxygen ratio) in patients with high IL-6 (P = .048). Patients with high IL-6 not treated with TCZ showed high mortality (hazard ratio, 4.6; P = .003), as well as those with low IL-6 treated with TCZ (hazard ratio, 3.6; P = .016). No relevant serious adverse events were observed in TCZ-treated patients. Conclusions: Baseline IL-6 greater than 30 pg/mL predicts IMV requirement in patients with COVID-19 and contributes to establish an adequate indication for TCZ administrationThis study was funded by Spanish Ministry of Economy, Industry and Competitiveness (MINECO) and Instituto de Salud Carlos III (grant nos. RD16/0011/0012 and PI18/ 0371 to I.G.A., grant no. PI19/00549 to A.A., and grant no. SAF2017-82886-R to F.S.-M.) and co-funded by the European Regional Development Fund. The study was also funded by ‘‘La Caixa Banking Foundation’’ (grant no. HR17-00016 to F.S.-M.) and ‘‘Fondos Supera COVID19’’ by Banco de Santander and CRUE. None of these sponsors have had any role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publicatio

Okupaciones y desalojos junto a otras utopías en el Antropoceno

Desde el ámbito de la arquitectura debemos entender que no generamos factores estables, son constantemente cambiantes y con negociaciones de 'oKupación' de diversa índole. Aprovechando esta condición y con la intención de paliar 'el problema' (Donna Haraway) se plantean hipótesis de futuros multiescalares que ponen de manifiesto la necesidad de un cambio social. Mediante el estudio antropológico de un entorno próximo conocido, la pedanía ilicitana de El Altet y sus inmediaciones, se trasparentarán y pondrán en crisis las 'relaciones tentaculares' entre individuos interespecie. Unos vínculos existentes pero supeditados al egocentrismo humano. Así pues, usaremos el potencial del panorama arquitectónico actual, donde se están diseñando arquitecturas adaptativas que trabajan con las reglas de diseño de la naturaleza. Un nuevo paradigma que permite hablar de la condición de biodiseño e introduce otras normas de proyecto, las cuales cuestionan el cambio en el proceso creativo mediante la imaginación de posibilidades alternativas. A partir de este horizonte proyectual se proponen imaginarios posthumanos mediante la creación de monstruos que pretenden poner en duda la fe ciega que nos reclama la cultura tecnocientífica, la supuesta cultura del conocimiento

Más allá de El Altet. Una política regeneradora para volver a vincular a una población con su paisaje

Interesada en diseñar futuros más justos a nivel interespecie, continúo con la investigación realizada sobre el municipio de El Altet y sus ecosistemas durante el TFG. Ya que dicha pedanía evidencia el desvinculo social con el paisaje que le rodea, un hecho que se ha vuelto tan común en nuestras ciudades. Esta exploración genera un conocimiento preciso sobre las agencias presentes en los ecosistemas estudiados, sobre todo de las vegetales, que me permite diseñar espacios en el entorno urbano que replican las situaciones ya existentes en estas realidades. Una manera de provocar que el paisaje forme parte de nuestra rutina de cuidado diaria, además de volver a vincular a una población con esas especies más allá de la humana que son continuamente relegadas

Copper-Catalyzed Regioselective Synthesis of (<i>E</i>)-β-Fluorovinyl Sulfones

Organofluorine compounds are finding increasing application in a variety of fields such as pharmaceutical, agrochemical, and material sciences. However, given the scarcity of fluorine-containing natural products, advancement in this area depends almost entirely on the development of new synthetic methodologies. In this article, we present the synthesis of a series of previously undescribed (E)-&#946;-fluorovinyl sulfones via a simple copper-catalyzed addition of hydrogen fluoride to alkynyl sulfone starting materials in varying yields and E/Z selectivities. The hydrogenation of these products was also explored and compared with the hydrogenation of the related Z isomers. These new products may find interesting applications, given the versatility of vinyl sulfones in chemical synthesis and the unique properties of vinyl fluorides in biological settings

Living Life Through Sport : The Transition of Elite Spanish Student-Athletes to a University Degree in Physical Activity and Sports Sciences

Interest in studying the different transitions faced by elite athletes throughout their careers has grown significantly in recent years. While transition from secondary school to university is an important research area in Europe, there is a void of studies on how student-athletes experience the transition to specific degrees. One of the most sought-after university degrees among elite athletes in Spain is a degree in Physical Activity and Sport Sciences (PASS). The first aim of this study was to investigate the main demands, barriers, and resources perceived by elite student-athletes in various phases of dual career transition to a university degree in PASS. The second aim was to identify the transition pathways pursued depending on the subjective importance they attached to sport and education. Eleven elite student-athletes (M = 20.7, SD = 1.6 years) who were in their second and third year of the degree in PASS participated in semi-structured interviews. Deductive-inductive thematic analysis of the interview transcripts revealed three main themes: (a) general university transition issues, (b) PASS-specific transition issues, and (c) transition pathways. Our results show that the close link between sport and the content of the degree was perceived by the elite student-athletes as their main resource. This link, however, was also perceived as a major barrier as the compulsory practical subjects entailed a risk of injury or overtraining that could affect both athletic and academic development. We noticed how the importance they attached to sport or studies varied at different moments of the transition period, a phenomenon we termed "fluid transition pathways." Dual career promotion for elite athletes is an important part of European sports policy, and our findings provide new knowledge that could help Spanish PASS faculties develop specific assistance programs to support transitioning student-athletes

Recent Applications of Diversity-Oriented Synthesis Toward Novel, 3-Dimensional Fragment Collections.

Fragment-based drug discovery (FBDD) is a well-established approach for the discovery of novel medicines, illustrated by the approval of two FBBD-derived drugs. This methodology is based on the utilization of small "fragment" molecules (<300 Da) as starting points for drug discovery and optimization. Organic synthesis has been identified as a significant obstacle in FBDD, however, in particular owing to the lack of novel 3-dimensional (3D) fragment collections that feature useful synthetic vectors for modification of hit compounds. Diversity-oriented synthesis (DOS) is a synthetic strategy that aims to efficiently produce compound collections with high levels of structural diversity and three-dimensionality and is therefore well-suited for the construction of novel fragment collections. This Mini-Review highlights recent studies at the intersection of DOS and FBDD aiming to produce novel libraries of diverse, polycyclic, fragment-like compounds, and their application in fragment-based screening projects.Our research is supported by the EPSRC, BBSRC, MRC, Wellcome Trust, and ERC (FP7/2007-2013; 279337/DOS). S.L.K. thanks AstraZeneca for funding