Compuestos nitrogenados fluorados:síntesis y reactividad.

RESUMEN La Tesis Doctoral se divide en tres capítulos distribuidos en introducción, objetivos, antecedentes bibliográficos, resultados y parte experimental. Capítulo 1. Consta de dos partes bien diferenciadas: En la primera se aborda la síntesis de oxazolidinonas fluoradas; para ello se emplean cloruros de imidoílo fluorados como compuestos de partida, los cuales a través de los compuestos intermedios b-aminosulfóxido y b-aminoalcohol quiral, conducen a las oxazolidinonas fluoradas primer objetivo de este capítulo. 11 En la segunda parte, se estudia la reactividad y diastereoselectividad de una de las oxazolidinonas fluoradas quirales como auxiliar quiral en comparación con la oxazolidinona descrita por Evans en 1981 (no fluorada), frente a reacciones de alquilación y de condensación aldólica. Capítulo 2. Se estudia la síntesis de derivados de uracilos y tiouracilos fluorados en disolución y en fase sólida, obtenidos en ambos casos a partir de b-enaminoésteres, que a su vez provienen de un precursor común: nitrilos fluorados. Además, se estudia la reactividad de los productos obtenidos frente a reacciones de alquilación del nitrógeno de la posición 1 y la síntesis de uracilos fluorados bicíclicos a través de reacciones de metátesis. Este capítulo se divide en tres apartados: 1º.- Síntesis de los uracilos fluorados en disolución: En primer lugar, se obtendrán b-enaminoésteres fluorados a partir de enolatos de éster y nitrilos fluorados. A continuación, se harán reaccionar estos derivados con isocianatos e isotiocianatos para la obtención de los (tio)uracilos fluorados. 2º.- Síntesis de los uracilos fluorados en fase sólida: La reacción de nitrilos fluorados con la resina de Wang previamente acetilada da lugar a b-enaminoésteres fluorados anclados a la resina de Wang, que de modo análogo al apartado anterior, se tratan con isocianatos e isotiocianatos para la obtención de los (tio)uracilos fluorados. 3º.- Síntesis de uracilos fluorados bicíclicos. La reacción de metátesis de los uracilos fluorados obtenidos en los apartados anteriores convenientemente funcionalizados conducen a dos nuevas familias de uracilos fluorados bicíclicos. Capítulo 3: En este capítulo se estudia la síntesis de pirimidinonas fluoradas a partir de la reacción de diiminas con derivados del ácido carbónico. Las diiminas empleadas se obtienen a su vez a partir de iminas y nitrilos fluorados ____________________________________________________________________________________________________The thesis is divided in three chapters distributed in introduction, objectives, background, results and experimental part. Chapter 1. It has two different parts: In the first part, the synthesis of chiral fluorinated oxazolidinones is described. The starting materials for the synthesis are fluorinated imidoyl chorides. In the second part, the reactivity and diastereoselectivity of the fluorinated oxazolidinones are studied in comparison with the non-fluorinated oxazolidinone in alquilation and aldolic reactions. Chapter 2. The chapter is divided in three parts. 1º. An efficient and convenient two-step synthesis of new fluorinated uracils is described. The first step involves the condensation of an ester enolate with a fluorinated nitrile to furnish fluorinated b-enamino esters. In turn, these compounds react with organic isocyanates or isothiocyanates to give C-6 fluorinated uracils or thioruacils, respectively, in excellent yields. 2º. This synthesis has been succesfully adapted to solid-phase conditions with high diversity, thereby facilitating the creation of small (thio)uracil libraries. 3º.The synthesis of new bicyclic uracils is described. The key step is a metathesis reaction. Chapter 3: The synthesis of fluorinated 2-pyrimidinones is described in this chapter. The first step involves the condensation of an imine enolate with a fluorinated nitrile to furnish fluorinated b-diimines. The reaction of the last with triphosgene afford the objective compounds

An efficient synthesis of new fluorinated uracil derivatives

A series of potentially biologically active fluorinated uracil derivatives has been prepared in three steps from oxazolines and fluorinated nitriles with good chemical yields.Fustero Lardies, Santos, [email protected] ; Sanz Cervera, Juan Francisco, [email protected] ; Asensio Martinez, Amparo, [email protected]

Carotid atherosclerotic disease predicts cardiovascular events in hemodialysis patients: A prospective study

Background To evaluate the predictive value of carotid atherosclerotic disease (CAD) and intima-media thickness (IMT) on incident cardiovascular disease and mortality in hemodialysis patients. Methods Multicenter, observational, prospective study including 110 patients, followed-up to 6 years. Carotid doppler ultrasonographic findings were classified in 4 degrees of severity: 1) IMT 0.9 mm, 3) carotid plaque with stenosis 50%. The associations between IMT and CAD and cardiovascular events, total and cardiovascular mortality were assessed. Results 83% of the patients had atherosclerotic plaques (CAD degrees 3-4). During follow-up, 29.1% of patients experienced cardiovascular events, and 28.2% died, 38.7% of cardiovascular origin. The presence of plaques was associated with cardiovascular events (p = 0.03) while calcified plaques were associated with both cardiovascular events (p = 0.01), cardiovascular mortality (p = 0.03) and non-significantly with overall mortality (p = 0.08) in the survival analysis. Carotid IMT was not associated with outcomes. Cardiovascular events correlated with CAD severity (HR 2.27, 95% CI 1.13-4.54), age (HR 1.04, 1.01-1.06), previous cardiovascular disease (HR 1.75, 1.05-4.42), dyslipidemia (HR 2.25, 1.11-4.53), lipoprotein (a) (HR 1.01, 1.00-1.02), troponin I (HR 3.89, 1.07-14.18), fibrinogen levels (HR 1.38, 0.98-1.94) and antiplatelet therapy (HR 2.14, 1.04-4.4). In an age-adjusted multivariate model, cardiovascular events were independently associated with previous coronary artery disease (HR 3.29, 1.52-7.15) and lipoprotein (a) (HR 1.01, 1.00-1.02). Conclusions The presence of carotid plaques and, especially, calcified plaques, are predictors of new cardiovascular events and cardiovascular mortality in hemodialysis patients, while IMT was not. The prognostic value of calcified plaques should be confirmed in future studies

Solution versus Fluorous versus Solid-Phase Synthesis of 2,5-Disubstituted 1,3-Azoles. Preliminary Antibacterial Activity Studies

A small library of compounds with an oxa(thia)zole scaffold and structural diversity in both positions 2 and 5 has been synthesized. Double acylation of a protected glycine affords intermediate α-amido-β-ketoesters, which in turn can be dehydrated to afford 1,3-oxazoles or reacted with Lawesson’s reagent to furnish 1,3-thiazoles. This procedure was designed with its adaptation to fluorous techniques in mind. Thus, when a protected glycine with a fluorous tag in the ester moiety is used as a starting material, the synthesis can be easily completed without column chromatography purification of intermediate compounds with good to excellent yields, thus affording a suitable entry to the preparation of small libraries of these bioactive compounds. The prepared oxa(thia)zoles were assayed for their antibacterial activity, and several of them were active against Staphylococcus aureus.Fil: Sanz Cervera, Juan F.. Universidad de Valencia; EspañaFil: Blasco, Raül. Universidad de Valencia; EspañaFil: Piera, Julio. Universidad de Valencia; EspañaFil: Cynamon, Michael. SUNY Upstate Medical University; Estados UnidosFil: Ibáñez, Ignacio. Universidad de Valencia; EspañaFil: Murguia, Marcelo Cesar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; ArgentinaFil: Fustero, Santos. Universidad de Valencia; Españ

Revalorization of cellulosic wastes from Posidonia oceanica and Arundo donax as catalytic materials based on affinity immobilization of an engineered β-galactosidase

Catalytic materials obtained by enzyme immobilization have multiple potential applications in the food industry. The choice of the immobilization method and support may be critical to define the properties of the immobilized enzyme compared to the soluble form. Although the use of immobilized enzymes shows multiple advantages, their catalytic efficiency is compromised in many instances. Molecular engineering techniques have been used to generate hybrid proteins where the enzyme of interest is fused to a module with affinity to a specific biopolymer. Binding of the hybrid TmLac-CBM2 protein, in which the β-galactosidase from Thermotoga maritima is fused to a carbohydrate-binding module from Pyrococcus furiosus, to cellulosic material from aquatic biomass wastes (such as Posidonia oceanica and Arundo donax) has been assayed. Both species generate environmental wastes that could be revalorized if converted into bioactive materials. Cellulose cryogels, but not films, from P. oceanica were able to bind the TmLac-CBM2 hybrid, with a higher immobilization yield (90%) than that from A. donax cellulose cryogels (60%). However, fractions containing also hemicellulose were less effective as immobilization supports in both cases, with yields of 47% and 30%, respectively. Cellulose cryogels loaded with β-galactosidase were able to hydrolyse lactose with the same efficiency as the free form of the enzyme. In contrast, enzyme-loaded cellulose films were inactive. This study represents a proof of concept for the valorisation of cellulosic wastes as bioactive materials. Furthermore, it provides information about the interaction specificity between the binding module and the cellulosic support, useful for other enzymes.This research was supported by grants from Spain's ‘Secretaría de Estado de Investigación, Desarrollo e Innovación’ (AGL2016-75245-R), Agencia Estatal de Investigación (AEI, Grant PCI2018-092886) and cofunded by the European Union's Horizon 2020 research and innovation programme (ERA-Net SUSFOOD2). MJF was supported by a Ramon y Cajal contract (RYC2014-158) from the Spanish Ministerio de Economia; Industria y Competitividad. The authors thank the Central Support Service for Experimental Research (SCSIE) of the University of Valencia for the electronic microscopy service.Peer reviewe

Carotid atherosclerotic disease predicts cardiovascular events in hemodialysis patients: A prospective study

Background To evaluate the predictive value of carotid atherosclerotic disease (CAD) and intima-media thickness (IMT) on incident cardiovascular disease and mortality in hemodialysis patients. Methods Multicenter, observational, prospective study including 110 patients, followed-up to 6 years. Carotid doppler ultrasonographic findings were classified in 4 degrees of severity: 1) IMT 0.9 mm, 3) carotid plaque with stenosis 50%. The associations between IMT and CAD and cardiovascular events, total and cardiovascular mortality were assessed. Results 83% of the patients had atherosclerotic plaques (CAD degrees 3-4). During follow-up, 29.1% of patients experienced cardiovascular events, and 28.2% died, 38.7% of cardiovascular origin. The presence of plaques was associated with cardiovascular events (p = 0.03) while calcified plaques were associated with both cardiovascular events (p = 0.01), cardiovascular mortality (p = 0.03) and non-significantly with overall mortality (p = 0.08) in the survival analysis. Carotid IMT was not associated with outcomes. Cardiovascular events correlated with CAD severity (HR 2.27, 95% CI 1.13-4.54), age (HR 1.04, 1.01-1.06), previous cardiovascular disease (HR 1.75, 1.05-4.42), dyslipidemia (HR 2.25, 1.11-4.53), lipoprotein (a) (HR 1.01, 1.00-1.02), troponin I (HR 3.89, 1.07-14.18), fibrinogen levels (HR 1.38, 0.98-1.94) and antiplatelet therapy (HR 2.14, 1.04-4.4). In an age-adjusted multivariate model, cardiovascular events were independently associated with previous coronary artery disease (HR 3.29, 1.52-7.15) and lipoprotein (a) (HR 1.01, 1.00-1.02). Conclusions The presence of carotid plaques and, especially, calcified plaques, are predictors of new cardiovascular events and cardiovascular mortality in hemodialysis patients, while IMT was not. The prognostic value of calcified plaques should be confirmed in future studies

Apuntes de Urbanística

1979/198

Apuntes de Urbanística

1979/198

Apunts d'Urbanística II

1979/198