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Universitat de Barcelona Departament de Farmacologia, Toxicologia i Química Terapèutica

Overview
Works: 28 works in 47 publications in 3 languages and 47 library holdings
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Most widely held works by Universitat de Barcelona
Enantio- and Diastereoselective Cyclocondensation Reactions : Stereocontrolled Access to Azabicycles and Application to Natural Product Synthesis by Elena Ghirardi( Book )

3 editions published in 2016 in English and held by 3 WorldCat member libraries worldwide

The first objective of this Thesis was the study of the preparation of octhydro-1H-cyclopenta[b]pyridines and octahydro-1H-indoles, through the synthesis of (R)-phenylglycinol derived tricyclic lactams. Following the previous reported methodology a carbon substituent would be present at the carbocyclic ring and we planned to find the conditions for controlling its absolute configuration. Unfortunately, the reaction of ketoester 4 and ketoacid 7, provided undesired enamines 8 and 9. On the other hand, the reaction of ketoacid derivatives 16 and 17 with (R)-phenylglycinol led to a mixture of epimeric amides 18. With the aim to extend the methodology, we planned to study the cyclocondensation reaction of (R)-phenylglycinol and (1S, 2R)-aminoindanol with C-3 and C-5 substituted cyclohexanepropionate derivatives. These reactions provided enantiopure tricyclic or pentacyclic lactams: in every run, a major lactam was isolated or identified, and a minor one was detected. The use of (1S, 2R)-aminoindanol resulted in better results. These tricyclic and pentacyclic lactams are precursors of C-8 (and C-6,8) substituted cis-decahydroquinolines. The conversion required the stereoselective reductive cleavage of C-O oxazolidine bond with simultaneous reduction of lactam carbonyl group, and debenzylation. A library of enantiopure cis-decahydroquinolines was obtained. To illustrate the usefulness of our method, we decided to undertake the synthesis of some alkaloids of Myrioneuron nutans family, which contain an 8-substituted cis-decahydroquinoline core. In particular, we prepared the enantiopure alcohol 82, which was described to be a common intermediate in the synthesis of various Mirioneuron nutans alkaloids. Our synthetic procedure greatly improved the previous results reported for the synthesis of this alcohol. The cyclocondensation reaction of (R)-phenylglycinol and (1S,2R)-aminoindanol with 3-alkyl-2-oxo-cyclohexane-1-acetate derivatives was finally considered. Reaction of (R)-phenylglycinol and 3-alkyl-2-oxocyclohexaneacetate derivatives 97-100 and 107 provided with high yield and stereoselectivity tricyclic lactams 110, 112a, 114, 116 and 118, which incorporate an alkyl or aryl substituent at C-10, while (1S,2R)-aminoindanol did not furnish so good outcomes. These reactions stereoselectively provided an additional minor hexahydroindole by-product. The absolute configuration of these compounds 111a, 113a, 115a and 117a was confirmed by X-ray crystallography. In the case of any or aryl substituent at C-10 of the tricyclic lactam, no by products were detected. We demonstrated that these unsaturated products derived from the opening of the oxazolidine ring of the minor lactams, which are epimers at C-10 of the major lactams, in the presence of acids. The stereoselective opening of the oxazolidine ring of the major lactams, in the presence of strong acids provided unsaturated compounds 111b, 113b, 115b and 117b, in which H-7 and H-7a resulted in cis relative disposition. In the case of lactam 118, with an aryl substituent at C-10, provided the unsaturated compound 125, in which H-7 and H-7a are in relative trans disposition. This different relative configuration can be accounted for by considering the structure rigidity of this system. Major tricyclic lactams were converted into C-7 exo substituted cis-octahydroindoles and cis-octahydroindolones, by selection of the appropriate reductive conditions. Hexahydroindolones 111b, 113b, 115b and 117b were converted stereoselectively into the corresponding enantiopure C-7 endo substituted cis-octahydroindolones, by catalytic hydrogenation of the carbon-carbon double bond, followed by elimination of the chiral inductor through reaction with sodium radical. Moreover, these hexahydroindolones and 125 were transformed into the corresponding trans-octahydroindolones 146c-149c and 126b by simultaneous reduction and debenzylation in sodium ammonia. The presence of the amide function allowed the stereoselective insertion of a new substituent by a-alkylation and a-amidoalkylation. Finally, in order to demonstrate the utility of this methodology, (+)-a-Lycorane was synthesized in only four steps, starting from easily available ketone 171, in 35% of overall yield, which resulted an improvement with respect to previously reported synthesis
Total Synthesis of Phlegmarine Alkaloids by Caroline Bosch( Book )

2 editions published between 2016 and 2017 in English and held by 2 WorldCat member libraries worldwide

This doctoral thesis consists in two main parts. The first part focus in the study of methodology development in order to bring modularity and diversification to compounds studied within the research group. It consists first in the development of an easy procedure to access enantiopure substituted octahydroindoles relevant for natural products synthesis, then in the diversification of a common building block used for the total synthesis of phlegmarine alkaloids allowing access to unprecedented heterocyclic tetrahydrocarbazoles compounds, but most importantly in the achievement of a methodology allowing access to any phlegmarine alkaloids from a simple common precursor i.e. using a unified methodology. A stereodivergent hydrogenation route is reported in each phlegmarine alkaloid series, allowing modulation of the diastereoselectivity in key intermediates of the synthetic approach. The second part focuses on synthetic applications of the methodology developed to allow to perform the first total synthesis of various phlegmarine alkaloids and also shed light on missassigned structures. These structure reassignments gave birth to a revised classification of the phlegmarine alkaloids and were confirmed by total synthesis using the unified methodology developed in the first part. All of the analytical data obtained during this project led us to the establishment of general rules to determine easily the stereochemistry of any phlegmarine type alkaloids. In summary, the first total syntheses of (+)-serratezomine E, ( - )-serralongamine, ( - )-huperzine K, huperzine M and ( - )-huperzine N have been achieved and the usefulness of the tandem intermolecular Michael reaction/intramolecular aldol reaction and in-situ intramolecular aza-Michael process has been extended to other series of azabicyclic compounds in enantiopure form
Mecanismos implicados en la neurodegeneración inducida por dieta grasa en modelos de senescencia by Verónica Palomera Ávalos( )

2 editions published in 2018 in Catalan and held by 2 WorldCat member libraries worldwide

La población mundial está envejeciendo, la mayoría de países del mundo están experimentando un aumento en el número y la proporción de personas mayores. Los últimos datos publicados de la ONU en 2017 informan que se espera que el número de personas mayores de 60 años o más se duplique para el 2050 y triplique para 2100; pasará de 962 millones en 2017 a 2.100 millones en 2050 y 3.100 millones en 2100. Al aumentar la esperanza de vida también se incrementan de manera paralela las patologías relacionadas con el envejecimiento y las enfermedades neurodegenerativas. La tasa de envejecimiento y la aparición de patologías relacionadas con la edad están moduladas por la respuesta al estrés y las vías de reparación que se disminuyen gradualmente, incluidas la proteostasis y el daño mitocondrial, entre otras cosas. Por otro lado, en los últimos años se ha observado también que la obesidad está creciendo en todo el mundo, en parte debido a un aumento en el consumo de dietas altas en grasas. Se ha establecido que la obesidad es un factor de riesgo para desarrollar enfermedades neurodegenerativas. En este contexto y dado que el envejecimiento junto con una dieta alta en grasa son los principales factores de riesgo para desarrollar diferentes trastornos neurodegenerativos nos planteamos estudiar cuales son los mecanismos implicados en la neurodegeneración inducidos por una dieta alta en grasas en modelos murinos y como el resveratrol que es un polifenol ampliamente conocido por sus efectos beneficiosos en la salud ejerce un efecto neuroprotector en el cerebro de los ratones. Para éste estudio utilizamos un modelo de ratón que presenta senescencia acelerada y otra cepa silvestre con envejecimiento normal. Los resultados en este trabajo demuestran que el estrés metabólico inducido por la dieta alta en grasa produce daños significativos en la memoria y el aprendizaje, además altera vías moleculares importantes implicadas en las enfermedades neurodegenerativas así como daño mitocondrial, aumento en la expresión de citocinas pro-inflamatorias y alteraciones en marcadores de estrés oxidativo en el hipocampo. Finalmente la mayoría de estos procesos alterados por el estrés metabólico fueron prevenidos por el resveratrol, ayudando al organismo a tener una mejor respuesta ante el daño provocado. En conclusión, los resultados obtenidos en esta tesis proponen que se puede utilizar el resveratrol como un tratamiento preventivo y que se puede considerar como una estrategia para reducir los efectos nocivos provocados por la edad y por la dieta alta en grasa y así poder tener un envejecimiento saludable con una mejor calidad de vida. -- TDX
Design and synthesis of sphingosine-1-phosphate lyase inhibitors and fluorogenic probes for the development of HTS assays by Pol Sanllehí Figuerola( Book )

2 editions published between 2016 and 2017 in English and held by 2 WorldCat member libraries worldwide

Sphingolipids (SLs) are essential structural and signaling molecules of eukaryotic cells. An important group of SLs metabolites are those showing a phosphate group at the C1- OH. Among them, sphingosine-1-phosphate (S1P) is a well-recognized signaling molecule that can act both as an intracellular second messenger and as a ligand of specific G-protein coupled receptors (S1P1-5), giving rise to a series of downstream signaling pathways involved in vascular development, control of cardiac rhythm, and immunity responses, among others. Sphingosine-1-phosphate lyase (S1PL) is a pyridoxal 5'-phosphate (PLP) dependent enzyme that catalyzes the irreversible degradation of S1P into ethanolamine phosphate and trans-2-hexadecenal in the endoplasmic reticulum. Together with S1P phosphatase, and sphingosine kinase, S1PL regulates the intracellular levels of S1P and contributes to the so-called 'sphingolipid rheostat', a system that controls cell fate based on the ratio of intracellular proliferative S1P and the apoptogenic sphingosine and ceramide. Notably, S1PL plays an important role in regulating the immune system, since its inhibition disrupts the S1P gradient that promotes T-cell egress from lymphoid tissues. In this context, S1PL has been validated as therapeutic target for the treatment of some autoimmune diseases, such as multiple sclerosis or rheumatoid arthritis. In light of the therapeutic potential associated to the modulation of S1PL activity, we undertook the design of new S1PL inhibitors based on two different approaches. Firstly, a structure-based drug design of S1PL inhibitors was performed using the crystal structures of the bacterial (StS1PL) and human (hS1PL) enzymes, which share a high level of sequence and structural similarities. Taking into account the common structural features of a series of hits, identified on a preliminary screening of potential S1PL inhibitors, and based on the results arising from docking studies using the hS1PL and StS1PL X-ray structures, a small library of putative S1PL inhibitors, derived from a common scaffold, were designed and synthesized. Compound RBM13, a previously reported fluorogenic S1PL substrate, was used in the development of an 'on-plate' assay for the S1PL activity determination using recombinant StS1PL and hS1PL as enzyme sources. Unfortunately, the rational design of new S1PL inhibitors was unsuccessful, as evidenced by the modest activities found for the designed inhibitors under our optimized assay conditions. In addition, although comparable kinetic parameters were determined for RBM13 against the two enzymes, a reference hS1PL inhibitor did not show any activity on the bacterial enzyme. In a second approach, two families of S1PL inhibitors were designed based on S1PL mechanistic considerations. In this sense, a small family of non-reactive analogs of some key enzyme reaction intermediates, as well as a series of stereodefined azide analogs of the natural S1P, were synthesized and tested against human and bacterial S1PL. Although compounds mimicking the intermediates of the catalytic process were weak inhibitors, all the azido phosphates behaved as competitive inhibitors in the low µM range on the two S1PL isozymes. These results suggested that StS1PL can be a reliable model for the design of hS1PL inhibitors that bind into the active site. However, the usefulness of this model protein is more limited if one wants to design compounds that target the active site access channel. Finally, two new coumarin-containing probes with potential applicability in HTS assays were designed and synthesized. Structurally, both compounds are formally derived from RBM13 by intercalation of a vinyl group between the amino alcohol phosphate moiety and the ether-linked coumarin group of the parent compound. Gratifyingly, both probes were validated as hS1PL substrates with better kinetic parameters than those determined for RBM13
Participación de la modulación epigenética en modelos murinos de envejecimiento y enfermedad de Alzheimer by Christian Griñán Ferré( Book )

2 editions published between 2016 and 2017 in Spanish and held by 2 WorldCat member libraries worldwide

Existe una correlación positiva entre el incremento de la esperanza de vida y el aumento de las enfermedades crónicas. Se ha establecido que el envejecimiento es el principal factor de riesgo en la aparición de trastornos neuropsiquiátricos, deterioro cognitivo, y las demencias, concretamente en la enfermedad de Alzheimer (EA). La epigenética ha demostrado jugar un papel importante en la función cognitiva. Por tanto, estudiar los mecanismos epigenéticos que subyacen en los efectos deletéreos del envejecimiento y el deterioro asociado a la EA, así como los factores que pueden modificarlos son de vital importancia para establecer nuevas estrategias ya sean farmacológicas o no, para prevenirlos o tratarlos. En este contexto, la primera parte de esta tesis se ha centrado en estudiar la participación de los mecanismos epigenéticos que intervienen en el envejecimiento, específicamente en el deterioro cognitivo en modelos animales de envejecimiento y de la EA. Para ello, hemos utilizado dos modelos de ratón de la EA que presentan alteraciones cognitivas y rasgos neuropatológicos de la enfermedad pero con factores causales iniciales diferentes, dichos modelos murinos son la cepa transgénica, 5xFAD y la cepa con senescencia acelerada, SAMP8. Nuestros resultados sugieren que existe una correlación entre los trastornos conductuales, la acumulación de la proteína ß- amiloide y las alteraciones epigenéticas en la metilación global (5-mC) del ADN y de expresión de ciertas enzimas epigenéticas, en el caso del modelo murino 5xFAD y una correlación entre el estrés oxidativo, la inflamación, los trastornos conductuales, el deterioro cognitivo y las alteraciones epigenéticas incluyendo la metilación (5-mC) e hidroximetilación (5-hmC) global del ADN, la acetilación de histonas H3 y H4 y cambios en la expresión de las enzimas epigenéticas que regulan dichas marcas en el modelo murino SAMP8. Además, se han establecido los procesos de estrés oxidativo y neuroinflamación como indicadores del estado microambiental de la célula sobre los cuales la epigenética se altera y modula de manera aberrante la expresión génica en los animales SAMP8 en referencia a los SAMR1 y con la edad. Por otra parte, hoy en día no existe ningún tratamiento eficaz para la EA. Esta falta de terapias junto con el cambio de paradigma que ha provocado la epigenética ha suscitado especial interés en la influencia del entorno, las experiencias y los hábitos de vida sobre la regulación de la expresión génica, tanto por su potencial regulador como terapéutico. Por lo que se ha descrito que la estimulación cognitiva mediante intervenciones de enriquecimiento ambiental (EE) produce cambios beneficiosos a nivel cerebral. Pocos, son los estudios de EE en ratones no transgénicos de EA y aún menos los relacionados con los mecanismos epigenéticos. Así, la segunda parte de esta tesis se ha centrado en demostrar, el efecto neuroprotector del EE y la participación de la modulación epigenética en dicho proceso. En este sentido, nuestros resultados confirman la modificación conductual, la reducción del deterioro cognitivo y de la neurodegeneración, como consecuencia de un incremento en la neurogénesis y plasticidad neuronal en el hipocampo de los ratones SAMP8. Dichos cambios correlacionan con la modificación de las marcas epigenéticas incluyendo la 5- mC e 5-hmC global del ADN y la acetilación global de las histonas H3 y H4, junto con alteraciones en la expresión génica de diversas enzimas epigenéticas que se traducen en una acción antioxidante, inducción de genes por el factor de transcripción NRF2 y antiinflamatoria reducción de la inducción de citoquinas proinflamatorias por el factor de transcripción NF-kß. De esta forma, los resultados presentados confirmar el papel clave de los mecanismos epigenéticos como factor principal en el proceso de envejecimiento, y la EA, así como el uso de las intervenciones con EE para determinar las modificaciones epigenéticas que pueden ayudar a entender los procesos que subyacen a la patología y descubrir nuevas dianas terapéuticas
Development of a divergent strategy towards the synthesis of lycopodium alkaloids by Gisela Saborit Villarroya( Book )

2 editions published in 2016 in English and held by 2 WorldCat member libraries worldwide

En la present tesi doctoral s'ha desenvolupat una estratègia per obtenir els esquelets dels quatre alcaloides licopodi representatius a partir d'un mateix intermedi sintètic comú 1, de manera semblant al procés que té lloc a la natura. Com que tant la licopodina, la licodina com la fawcettimina tenen una configuració diferent al C-7 de la que presenta la flegmarina s'han preparat 20 grams del compost 2 de forma racèmica i s'ha dut a terme la separació dels dos enantiòmers per HPLC preparatiu. Per a la síntesi de la flegmarina ha sigut necessari transformar l'estructura de cis-decahidroquinolina de 2 en la trans decahidroquinolina de la flegmarina. A continuació s'ha addicionat un fosfonat de piridina i s'ha procedit a la hidrogenació de la vinil piridina en dues condicions diferents
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2 editions published in 2018 in English and held by 2 WorldCat member libraries worldwide

Development of New Multicomponent Processes based on Unexplored Chemistry of Isocyanides: Access to Heterocyclic Scaffolds and Applications by Ouldouz Ghashghaei( Book )

2 editions published in 2017 in English and held by 2 WorldCat member libraries worldwide

Nuevas aproximaciones a compuestos policíclicos complejos y transformaciones de los mismos by Ane Otermin Esteras( Book )

2 editions published between 2016 and 2017 in Spanish and held by 2 WorldCat member libraries worldwide

En esta Tesis doctoral, se ha puesto a punto una ruta sintética para acceder de manera rápida y eficaz, a compuestos policíclicos tipo "cinturón" que contienen dos dobles enlaces C=C casi paralelos y próximos en el espacio. El procedimiento implica una reacción domino Diels-Alder entre un difulveno (cis-2,5-di(ciclopenta-2,4-dien-1-iliden)-octahidropentaleno) y acetilendicarboxilato de dimetilo o N-metilmaleimida bajo irradiación con ultrasonidos. Con los compuestos obtenidos se han llevado a cabo una serie de transformaciones que han permitido preparar compuestos como 5,6,7,8,10,12a,13,13a-octahidro-3H-3,10,13- (epimetanotriil)-4,7:6,9-dimetanodiciclopenta[a, d][11]anuleno, un hidrocarburo C20H20, isomero del dodecaedrano, y su producto de hidrogenación parcial 2,3,5,6,7,8,10,11,12,12a,13,13a-dodecahidro-1H-3,10,13-(epimetanotriil)-4,7:6,9- dimetanodiciclopenta[a, d][11]anuleno. Con este último compuesto se ha llevado a cabo un estudio experimental de diversas reacciones transanulares (adiciones de bromo y iodo y cicloadición fotoquímica intramolecular [2+2]) así 1 como un estudio cinético por RMN de H del proceso de reversion del cicloaducto [2+2]al precursor diénico. La estructura de muchos de los compuestos preparados ha sido confirmada por difracción de rayos X. La adición de bromo a este compuesto ha sido también estudiada combinando cálculos de la teoría funcional de la densidad (DFT) y de la teoría del campo de reacción autoconsistente para tener en cuenta el efecto de solvatación, lo que ha permitido establecer el curso de este proceso. Por otro lado, se ha desarrollado tres nuevas rutas sintéticas para preparar el compuesto tetracíclcico 2-metil-1,3-dioxo-1,2,3,4,5,6,7,8-octahidro-3a,7,8-(epiprop[2]eno[1,1,3]triil)-5,8a- metanociclohepta[c]pirrol-7-carboxilato de metilo. Una de ellas implica un menor número de etapas (11 frente a 16) y un rendimiento global muy superior al obtenido previamente en la secuencia desarrollada en la Tesis doctoral de la Dra. Tània Gómez. Este compuesto es un intermedio clave para la preparación de un precursor de un triquinaceno con un doble enlace C=C piramidalizado, que consideramos podría dimerizar a través de una cicloadición térmica [2+2+2+2+2+2], dando lugar a un derivado del dodecaedrano
Open-chain building blocks from chiral lactams. Enantioselective synthesis of macrocyclic nitrogen-containing natural products by Guillaume Michel Pablo Guignard( Book )

2 editions published in 2016 in English and held by 2 WorldCat member libraries worldwide

1. (R)-Phenylglycinol-derived oxazolopiperidone lactams can be converted to enantiopure open-chain amino ester scaffolds by alkaline hydrolysis of the N-Boc 2-piperidones resulting from the reductive cleavage of the oxazolidine ring. 2. Lithium amidotrihydroborate (LiNH2BH3) reduction of diversely substituted (R)-phenylglycinol-derived oxazolopiperidone lactams brought about the reductive opening of both the oxazolidine and lactam rings, providing general access to structurally diverse enantiopure amino diols A bearing a variety of substitution patterns, substituents (alkyl, benzyl, aryl, protected hydroxy), and stereochemistries. 3. Reductive removal of the phenylethanol moiety present in the amino diols prepared by the above procedure, followed by treatment of the resulting primary amines with (Boc)2O provides a general synthetic entry to enantiopure N-Boc 5-aminopentanols bearing substitutents at the 2-, 3-, 4-, 2,2-, 2,3-, 2,4-, and 3,4- positions. 4. The oxidative removal of the phenylglycinol moiety of amino diols A (previously O-silylated) using the I2/aq NH3 system constitutes an excellent procedure for the straightforward preparation of enantiopure substituted 5-hydroxypentanenitrile derivatives. 5. The m-CPBA-promoted oxidative removal of the phenylglycinol moiety of amino diols A (previously O-silylated) constitutes an excellent procedure for the straightforward preparation of enantiopure substituted 5-hydroxypentanoic acid derivatives. 6. As both enantiomers of phenylglycinol are commercially available, both enantiomers of a target 5-aminopentanol, 5-hydroxypentanoic acid, and 5-hydroxypentanenitrile are accessible through the above methodology. 7. The synthetic value of the open-chain amino diols A has been demonstrated with their use as key scaffolds for the enantioselective synthesis of the Haliclona alkaloids haliclorensin C (first total synthesis), haliclorensin (total), halitulin (formal), and isohaliclorensin (formal). 8. The synthetic value of the open-chain amino diols 5-hydroxypentanoic acids, and 5-hydroxypentanenitriles prepared from (S)-phenylglycinol-derived lactams has been demonstrated with their use as key scaffolds for the synthesis of the natural macrolactam fluvirucinin B1. 9. The approach we have developed significantly expands the potential of phenylglycinol-derived d-lactams, which have been converted for the first time to enantiopure open-chain building blocks
Novel ᴫ-functional components of micro- and nanoparticles for nanomedicine by María Elisa Alea Reyes( Book )

2 editions published in 2017 in English and held by 2 WorldCat member libraries worldwide

"The present thesis is included in the area of Nanomedicine and supramolecular chemistry, focused on the design and preparation of different nano and microtools for delivery, therapy and sensing. Initially, the synthesis and characterization of structures derived from gemini-type pyridinium amphiphiles were reported. They have the ability to play multiple roles such as transfer agent and stabilizer, as well as ionophores, and also are responsible for the preparation, stability, and delivery properties of the gold nanoparticles (AuNPs), which gold core is stabilized by the anions present in the bis-pyridinium salts. The gold nanoparticles synthesized proved stable and to have low polydispersity and showed the ability to incorporate piroxicam. Therefore, the in vitro release of 3·AuNPs and 4·AuNPs at two different pH values (7.4 and 5.5) proves a faster release profile at pH 7.4, indicating their suitability as promising materials for delivery in physiological conditions. On the other hand, this report also includes the synthesis and characterization of porphyrin derivatives as photosensitizers in particular metalloporphyrins and their subsequent incorporation to different vehicles such as gold nanoparticles, microparticles (polysilicon-gold) and gold nanorods for their use in photodynamic therapy, due to their capacity to produce reactive oxygen species after irradiation, inducing the cell death. The successfully functionalization of this vehicles were followed by UV-visible absorption spectroscopy, High-Resolution Transmission Electron Microscopy (HRTEM) or Transmission Electron Microscopy (TEM), Dynamic Light Scattering (DLS), X-ray Photoelectron Spectroscopy (XPS), Thermogravimetric analysis (TGA), Fluorescence Spectroscopy, contact angle measurements and fluorescence microscopy. Additionally, the formation of self-assembled monolayers (SAMs) on polysilicon substrates (wafers and microparticles) was investigated, using different immobilization methodologies (covalent and non-covalent) in order to obtain a functionalization protocol which can be easily repetitive and effective. Firstly, this substrates were functionalized with two groups of compounds (pyridinium and imidazolium salts) used as host in the subsequent incorporation of the Zn(II) porphyrin with a high potential to be used in PDT. The immobilization of the different hosts was following by contact angle, while the presence of the Zn(II) porphyrin was confirmed by fluorescence microscopy. The concentration of the photosensitizer incorporated on the polysilicon microparticles was found in the range of 2.2-2.6 µM. On the other hand, a release study of the incorporated porphyrin during a week was performed, resulting in a very low percentage of the total incorporated porphyrin. This result indicates that a stable interaction is established between the porphyrin and the host on the surface. Finally, we describe the non-covalent functionalization of polysilicon substrates (wafers and microparticles) with gemini-type amphiphilic bipyridinium salts (1·4PF6- 3·4PF6), witch act as host for the subsequent incorporation of the neurotransmitters Dopamine hydrochloride (Dop), Serotonin hydrochloride (Ser), Adrenaline hydrochloride (Adr) and Noradrenaline hydrochloride (Nor), in order to obtain the optimum system potentially suitable for sensors of compounds with electron rich groups. The successfully functionalization of the polysilicon substrates was followed by contact angle measurements. Additionally, fluorescence microscopy was used to detect the complex bis-bipyridinium salt-neurotransmitter in both substrates showed an increase on the fluorescence intensity on the substrates functionalized with the bis- bipyridinium salts and subsequent incorporation of the neurotransmitters respect to the controls. Polysilicon surfaces functionalized with 1·4PF6 and subsequent incorporation of Dop or Ser showed the higher values of fluorescence intensity of 71 and 72%, respectively. In this context the bis-bipyridinium 1·4PF6 and neurotransmitters Dop or Ser were selected to functionalize polysilicon microparticles. 1·4PF6 was neither cytotoxic nor genotoxic to the cell lines studied 3T3/NIH, HepG2 and CaCo-2 at the maximum concentration tested of 500 µg/mL. With our work, we set up the non- covalent functionalization methodology to develop a microsystem potentially useful for drug sensors purposes." -- TDX
Efecto del síndrome metabólico provocado por una dieta rica en grasa en ratones APPswe/PS1dE9, modelo experimental de la enfermedad de Alzheimer, y posibles terapias farmacológicas by Miren Ettcheto Arriola( )

2 editions published in 2018 in Spanish and held by 2 WorldCat member libraries worldwide

La enfermedad de Alzheimer (EA) es el tipo de demencia progresiva más común. En base al incremento de la prevalencia esperada, es considera la epidemia del siglo XXI. En consecuencia, surge una gran necesidad de encontrar un tratamiento eficaz contra esta patología. Diversos estudios han relacionado la diabetes mellitus del tipo 2 (DMT2) con esta enfermedad neurodegenerativa. De hecho, estudios epidemiológicos han confirmado que las personas con DMT2 presentan mayor prevalencia de desarrollar la EA y viceversa. Uno de los principales problemas es que no existen marcadores precoces para poder detectar la enfermedad y tratarla en estadios previos a la muerte neuronal por lo que el primer estudio de esta tesis doctoral se ha centrado en la detección molecular de estos marcadores en el modelo de ratón APPswe/PS1dE9, modelo experimental de la EA familiar alimentados con dieta en rica en grasa a 3 meses de edad. Los resultados obtenidos demostraron la disminución de los niveles proteicos de IDE, ADAM10 Y PGC1alfa, además de pNMDAR2B, lo cual favorece el incremento de beta1-40 y beta1-42 insoluble y beta1- 40 soluble, favoreciendo la temprana neuropatología de la EA. Diversos estudios epidemiológicos han demuestrado que el tratamiento crónico con antiinflamatorios previene el desarrollo de la EA o al menos retrasa su progresión. Uno de los principales problemas del uso crónico de estos fármacos es la toxicidad gástrica que provocan, por lo que este trabajo se ha centrado en el estudio del tratamiento con dexibuprofeno (DXI), enantiomero activo del ibuprofeno, durante 3 meses en ratones APPswe/PS1dE9 hembras de 6 meses de edad. Los resultados obtenidos han demostrado que el tratamiento crónico del DXI disminuye la activación glial y, por consiguiente, la liberación de citocinas proinflamatorias. Esta situación resulta en una reducción de la fosforilación de TAU a través de vía de señalización de c-ABL/CABLES/pCDK5 y de la insulina. Además, los ratones tratados mostraron niveles proteicos más bajos de BACE1 lo que conduce al incremento de p-CREB y disminución de la beta1- 42 soluble e insoluble, lo cual conduce la disminución de placas beta amiloide. Acorde con esto, IDE también mostró un incremento en los animales tratados, datos que concuerdan con la mejora cognitiva observada. Por todo ello, el tratamiento crónico con DXI podría constituir un fármaco potencial para la EA. Como se ha comentado previamente, se ha descrito que existe una relación directa entre la DMT2 asociada a la ingesta de la dieta rica en grasa y la EA. Sin embargo, el mecanismo que les relaciona mantiene sin esclarecerse. La memantina (MEM) es un antagonista del receptor de NMDA que actualmente se utiliza para la EA. El objetivo de este estudio es esclarecer los efectos de este fármaco, administrado durante 2 meses, en ratones APP/PS1 de 6 meses de edad exacerbados con la ingesta de dieta rica en grasa, además de intentar determinar los posibles mecanismos moleculares que conectan la EA y DMT2. Los resultados obtenidos mostraron la mejora significativa de los parámetros periféricos en los animales tratados con MEM y alimentados con dieta rica en grasa. Además, se demostró una disminución de la neuroinflamación, pérdida cognitiva, deposición de placas beta amiloide y resistencia a la insulina en el hipocampo. A su vez, los animales tratados presentaron la activación de moléculas involucradas en la vía de la insulina en el hígado, sin embargo, curiosamente, no se detectaron niveles proteicos ni expresión del receptor de NMDA en el tejido hepático. Por consiguiente, además de demostrar el papel fundamental del beta amiloide en los desórdenes metabólicos, este estudio sugiere la posible aplicación de la MEM en los desórdenes metabólicos como es el caso de la DMT2
Common scaffolds for the enantioselective synthesis of marine, plant, and amphibian cis-decahydroquinoline alkaloids by Alexandre Miguel Gregório Pinto( Book )

2 editions published in 2017 in English and held by 2 WorldCat member libraries worldwide

Chiral amino alcohol derived lactams are a valuable scaffold for the enantioselective synthesis of alkaloids. In the present thesis the potential of this methodology was expanded and to demonstrate the synthetic utility of chiral tricyclic lactams obtainedthe enantioselective total synthesis complex cis-decahydroquinoline alkaloids was carried out. The alkaloids that were targeted for synthesis using the developed methodology were the lepadin alkaloids (marine alkaloids) and tricyclic cis-decahydroquinoline alkaloids such as cermizine B (Lycopodium alkaloids). To accomplish these objectives further studies on the functionalization of the decahydroquinoline system were required in order to install the appropriate substituents and functionalities for the synthesis of each target. During the present PhD thesis it was possible to complete the total synthesis of (+)-gephyrotoxin 287C, (−)-cermizine B, (−)-lepadin B and (+)-lepadin D and the formal total synthesis of (−)-lepadins A and C
Synthesis of 2-Vinyl sphingolipids as S1PL inhibitors by Raquel Calderón i Almendro( Book )

2 editions published in 2017 in English and held by 2 WorldCat member libraries worldwide

Novel multi-target directed ligands as drug candidates against Alzheimer's disease by Francisco Javier Pérez Areales( Book )

2 editions published in 2017 in English and held by 2 WorldCat member libraries worldwide

Characterization of epigenetic and transcriptional changes in aging and Alzheimer's disease by Marta Cosín Tomàs( Book )

2 editions published in 2017 in English and held by 2 WorldCat member libraries worldwide

Chloroacetamides as Valuable Synthetic Tools to Access Nitrogen-Containing Heterocycles Using Both Radical and Non-Radical Processes by Juan Andrés Montiel Achong( Book )

2 editions published between 2016 and 2017 in English and held by 2 WorldCat member libraries worldwide

Durante este trabajo de tesis doctoral se ha demostrado que las cloroacetamidas son intermedios de gran utilidad para la síntesis de heterociclos nitrogenados a través de procesos radicalarios o no radicalarios. En este trabajo, hemos descrito por primera vez la espirociclación desaromatizante en bencenos no activados utilizando ciclación radicalaria con transferencia de átomo, a partir de benciltricloroacetamidas por tratamiento con CuCl en acetonitrilo y activación por microondas. Mientras que las N-(#xF061;-metilbencil)tricloroacetamidas sometidas a condiciones radicalarias tenía dos rutas principales, la formación de morfanos y la generación de normorfanos a través de una transferencia 1,4 de hidrógeno y ciclación radicalaria con inversión de configuración en el centro bencílico y con memoria de quiralidad. Asimismo, como resultado de una investigación enfocada a la preparación de enaminas, a partir de 4-tricloroacetamidociclohexanona y pirrolidina, hemos descrito una nueva ruta para la síntesis de 6-azabiciclo[3.2.1]octanos (normorfanos). La reacción se llevó a cabo en 5 minutos ya sea sin disolvente o bien en tolueno y bajo activación por microondas. El proceso de #xF061;#xF02D;carbamoilación o reacción tipo haloformo intramolecular a partir de cetonas no tenía precedentes en la literatura. Esta metodología fue aplicada a la síntesis del sistema tricíclico presente en el producto natural cephalocyclidin A. Los resultados anteriormente obtenidos con las tricloroacetamidas propiciaron el uso de dicloroacetamidas en su lugar para conseguir el proceso radicalario. De este modo, se logró desarrollar una nueva ruta de síntesis de 2-azabiciclo[3.3.1]nonanos a través de la ciclación radicalaria de cetonas enlazadas a dicloroacetamidas en presencia de pirrolidina, AIBN y TTMSS bajo activación por microondas durante cinco minutos. Esta metodología fue aplicada con éxito a la síntesis del núcleo tricíclico del inmunosupresor FR901483. Asimismo, se investigó la síntesis de pirrolidinonas y piperidinonas funcionalizadas a partir de dicloro- y monocloroacetamidas lineales utilizando química no radicalaria. Estas cloroacetamidas fueron fácilmente preparadas por reacción de las aminas correspondientes con metilvinilcetona y posterior tratamiento con cloruro de dicloro- o cloroacetilo en un proceso one-pot. Mientras que el derivado con el ter-butilo sobre el nitrógeno experimenta una ciclación espontánea, la ciclación de las cloroacetamidas lineales fue lograda a través de una condensación de Darzens
New polycyclic small molecules as ion channel modulators by Marta Barniol Xicota( Book )

2 editions published in 2017 in English and held by 2 WorldCat member libraries worldwide

L'objectiu de la present tesi doctoral consisteix en desenvolupar molècules policícliques de baix pes molecular que tinguin com a diana tres canals iònics específics: la viroporina A/M2 del virus de la grip, el receptor purinèrgic dependent de lligand P2X7 i el receptor glutamatèrgic dependent de lligand N-metil-D-Aspartat, per tal de modular-los d'una manera tal que n'evitin o millorin el desenvolupament dels processos patogènics associats a aquestes proteïnes i/o que permetin ser emprades com a eines de recerca. En el capítol 1 es presenta una introducció general del paper dels canals iònics, així com una descripció més específica de cadascun dels 3 canals objecte d'estudi en aquesta Tesi. Els objectius d'aquest treball es detallen en el capítol 2, després del qual, en el capítol 3 es presenten un seguit d'anàlegs per contracció d'anell del fàrmac comercial Amantadina, resultant-ne els primers inhibidors duals del canal M2 del virus de la Influenza A descrits en la bibliografia, actius sobre la soca salvatge (wt) i sobre el mutant resistent a fàrmacs V27A (Rey-Carrizo, M. et al. J. Med. Chem. 2013, 56, 9265). Seguidament en la part A del capítol 4 es gràcies a estudis in silico, s'observa com un dels inhibidors triples presenta un mode d'unió diferent sobre els canals wt i V27A, que podria estar directament relacionat amb el mecanisme de resistència a fàrmacs del mutant V27A (Rey-Carrizo, M., et al. J. Med. Chem. 2014, 57(13), 5738). En el capítol 5 es completa el treball presentant per primera vegada la proba experimental d'una possible explicació del mecanisme de resistència a fàrmacs del mutant V27A. (Barniol-Xicota, M., et al. manuscrit acceptat al J. Med. Chem.). Com a continuació en el capítol 6 s'explora una diana diferent de la viroporina M2: l'hemaglutinina (HA) (Leiva, R., et al. manuscrit pendent d'enviar a J. Med. Chem.). El capítol 7 representa el primer treball que marca l'inici de la línia de recerca d'antagonistes del receptor P2X7 en el grup. (Barniol-Xicota, M., et al. manuscrit en revisió al Bioorg. Med. Chem. Lett.). Finalment, en el capítol 8, es presenten els primers exemples descrits a la bibliografia de multi-target directed ligands (MTDL) amb els receptors NMDA i P2X7 com a dianes. (Karou, O., et al. manuscrit pendent d'enviar a ACS Med. Chem. Lett.). Deixant de banda la recerca de compostos bioactius en la part B del capítol 4 es descriu un estudi teòric i experimental d'un alquè altament piramidalitzat, derivat de l'estructura d'un compost bioactiu detallat en la part A del mateix capítol. (Rey-Carrizo, M. et al. Angew. Chem. Int. Ed. 2014, 53, 8195)
Efectes metabòlics, vasculars i cognitius del consum de sucres simples en rates femella by Gemma Sangüesa Puigventós( )

1 edition published in 2017 in Catalan and held by 1 WorldCat member library worldwide

Multi-functionalization of micro- and nanoparticles for cancer theranostics by Ezhil Amirthalingam( )

1 edition published in 2018 in English and held by 1 WorldCat member library worldwide

This thesis has its main focus on developing multi-functional nanomaterials, that we called nano- and microtools through two different approaches, top-down to provide support and bottom up to give functionality to prepare nanomaterials for diagnosis and therapy in cancer cells (theranostics). It includes functionalization of inorganic and or metallic nano- and microparticles with natural and synthetic receptors capable of acting as sensors to monitor different cellular parameters in living cells and deliverers specifically for diagnosis and therapy in cancer cells (theranostics). For this purpose, we used micro- and nanoparticles as substrates, made up of polysilicon or polysilicon-gold and gold nanoparticles, and functionalized them with (bio)molecules. The first objective was to develop a novel microtool for cell adhesion. For this purpose specially designed polysilicon microparticles of different shapes and sizes were chemically modified, to sense carbohydrates present on tumour cell membranes. An optimized protocol for bio-functionalization of polysilicon microparticles with lectins (WGA and Con A), both on surfaces and in suspension, was developed. Influence of different shapes in bio-functionalization of the microparticles was also observed. The final yield of the number of bio-functionalized microparticles was between 12-21 % with a major loss of approximately 50 % of microparticles during the activation step. These bio-functionalized microparticles in suspension were stable for three consecutive weeks, stored in PBS at room temperature. In vitro experiments were carried out which showed, Con A bio-functionalized Batch 2 microparticles adhered to the membrane of the Dictyostelium discoideum (Dicty) whereas, WGA bio-functionalized microparticles did not adhere to the cell membrane of Dicty or HeLa cells. Therefore, a synthetic lectin called Boronic Acids (BAs) was used and an optimized protocol for functionalization of polysilicon microparticles with 4-formylphenylboronic acid (PBA), through stable secondary amine bonds was developed. Interaction of BA functionalized surfaces with carbohydrate, N-acetylglucosamine (GlcNAc) was also studied on surfaces using ARS, which indicates stronger interaction between BA and GlcNAc. Polysilicon microparticles of different sizes functionalized using BA showed adhesion to the cell membranes of Dicty and HeLa cells. In the second objective, the primary goal is to sense intracellular pH in living cells using bi-functional microparticles (polysilicon-gold), in order to differentiate between cancer cells and normal cells. The immobilization of pH dependent fluorophores, Oregon green, pHrodo, SNARF and Alexa fluor on to polysilicon surfaces was achieved successfully. An optimized protocol for the bi-functionalization of two pH dependent fluorophores, Oregon green (on polysilicon) and pHrodo (on gold) on to a hexahedral bi-functional microparticle was achieved for pH sensing. The third objective was the generation and sensing of Reactive oxygen species (ROS) using a bio-photosensitizer for photodynamic therapy. The selected bio-photosensitizer, Cytochrome c (Cyt c) showed generation of ROS in solution. BODIPY was able to sense the production of ROS from the Cyt c in solution. An optimized protocol for immobilizing Cyt c on to the polysilicon surfaces and BODIPY on gold surfaces and microparticles was achieved. Protocol for bi-functionalization of ROS generator: Cyt c and ROS sensor: BODIPY on bi-functional microparticles was also developed for ROS sensing. The fourth objective is to deliver anionic drugs using gold nanoparticles synthesized using imidazolium based macrocycles. The ability of these gold nanoparticles to extract and incorporate ibuprofenate from an aqueous phase was calculated to be ca 85 %. The release of ibuprofenate from the gold nanoparticles system follows Fickian diffusion, which could be potentially used for local drug delivery applications
 
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Universitat de Barcelona. Departament de Farmacologia, Toxicologia i Química

Universitat de Barcelona. Departamento de Farmacología, Toxicología y Química Terapéutica

Universitat de Barcelona. Facultat de Farmàcia i Ciències de l'Alimentació. Departament de Farmacologia, Toxicologia i Química Terapèutica

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