Model Studies on the Photorepair of (6-4) Dimeric Lesions of DNA

[ES] La radiación ultravioleta está asociada a la formación de ciertas lesiones en el ADN que están en el origen del cáncer de piel. Entre las más relevantes se encuentran los daños que se producen en las bases pirimidínicas: los dímeros ciclobutánicos (CPDs) y fotoproductos (6-4) (6-4PPs). Como protección contra las fotolesiones del ADN, los organismos vivos disponen de enzimas que restauran las lesiones a su forma original, manteniendo así la integridad genética. Algunos organismos manifiestan un proceso de reparación adicional de los CPDs y los 6-4PPs, que corresponde a la foto-rreactivación y que involucra enzimas denominadas fotoliasas CPD y (6-4). En con-creto, actualmente existe una viva discusión sobre el mecanismo de reparación por la fotoliasa (6-4). El objectivo general de esta tesis doctoral ha sido estudiar la ciclorre-versión de los intermedios clave propuestos para la lesión 6-4PP para apoyar uno de los mecanismos propuestos hasta ahora. En primer lugar se ha preparado un modelo de la azetidina intermedia de la le-sión 6-4PP en secuencias TC para investigar su reparación mediante un proceso de donación de electrones a través de fotosensibilizadores con un potencial redox ade-cuado, mimetizando así el cofactor flavina de la fotoliasa (6-4). Los estudios de elec-troquímica, espectroscopía, análisis y química computacional mostraron que la posibi-lidad de inyectar un electrón al anillo de la azetidina conlleva una ciclorreversión de la azetidina bipirimidínica generando las bases timina y 6-azauracilo. También se ha evi-denciado que la transferencia de electrones sólo tiene lugar si el componente timina está presente en el modelo. En segundo lugar, se ha investigado la ciclorreversión de la azetidina mediante un proceso oxidativo en cual el anillo de azetidina dona un electrón al fotosensibilizador. La comparación con un derivado ciclobutánico mostró que la presencia del nitrógeno en el anillo de cuatro miembros disminuye el potencial redox facilitando el proceso de oxidación. En tercer lugar, el paso de ciclorreversión se ha estudiado con dos fotosensibili-zadores intrínsecos, la guanina y el daño oxidativo 8-oxoguanina (OG), unidos cova-lentemente a un CPD o a un oxetano, como modelo del intermedio formado en la reparación del daño (6-4). En conjunto, los datos de espectroscopía y análisis croma-tográfica mostraron la posibilidad de que estos fotosensibilizadores endógenos pueden actuar como dadores de electrones mimetizando, por tanto, la función del cofactor flavina en la fotoliasa. Finalmente, el anillo de azetidina ha sido incorporado en un oligonucleótido para estudiar su ciclorreversión mediante transferencia de electrones. En base a los resulta-dos de los capítulos previos, OG ha sido elegido como un fotorreductor natural. En un primer paso, una metodología ha sido desarrollada para insertar la azetidina dentro de una secuencia de oligonucleótido. Luego, la irradiación en estado estacionario del dúplex que contiene OG y la azetidina ha demostrado que la transferencia de electro-nes tiene lugar y conlleva a la ciclorreversión del heterociclo. Además, experimentos preliminares han sido llevados a cabo para evaluar la reparación del anillo de cuatro miembros, como un análogo del intermedio generado en el caso del fotoproducto (6-4), por las fotoliasas reales CPD y (6-4).[CA] La radiació ultravioleta està associada a la formació de certes lesions en l'ADN que podrien concluir al càncer de pell. Entre les més rellevants es troben els danys que es produïxen en les bases pirimidínicas: els dímers ciclobutánics (CPDs) i els fotopro-ductes (6-4) (6-4PPs) . Per a protegir-se de les fotolesions al l'ADN, els organismes vius disposen d'enzims que restauren les lesions a la seua forma original, mantenint així la integritat genètica. En alguns organismes els CPDs i els 6-4PPs manifesten un procés de reparació addicional, que correspon a la fotorreactivació on están involu-crats enzims denominades fotoliases CPD i (6-4) . En concret, actualment hi ha una viva discussió sobre el mecanisme de reparació per la fotoliasa (6-4) . L'objectiv gene-ral d'esta tesi doctoral ha sigut estudiar la ciclorreversió dels intermedis clau proposats per a la lesió 6-4PP com a recolzament d' un dels mecanismes proposats fins ara. En primer lloc s'ha preparat un model de l'azetidina intermèdia de la lesió 6-4PP en seqüències TC per a investigar la seua reparació per mitjà d'un procés de donació d'electrons per fotosensibilizadors amb un potencial redox adequat, mimetitzant així el cofactor flavina de la fotoliasa (6-4) . Els estudis d'electroquímica, espectroscòpia, anàlisi cromatogràfica i química computacional van mostrar que la possibilitat d'injec-tar un electró a l'anell de l'azetidina comporta una ciclorreversió de l'azetidina bipiri-midínica a les bases de timina i 6-azauracil. També s'ha evidenciat que la transferència d'electrons només té lloc si la base timina està present en el model. En segon lloc, s'ha investigat la ciclorreversión de l'azetidina mitjacant procés oxidatiu en que l'anell d'azetidina dóna un electró cap al fotosensibilizador. La compa-ració amb un derivat ciclobutánic va mostrar que la presència del nitrògen en el anell de quatre membres disminuïx el potencial redox facilitant el procés d'oxidació. En tercer lloc, el pas de ciclorreversió s'ha estudiat amb dos fotosensibilizadors intrínsecs, guanina i el dany oxidatiu 8-oxoguanina (OG) , units covalentment a un CPD o a un oxetano, com a intermedi del dany (6-4) . En conjunt, les dades d'espec-troscòpia i anàlisi cromatogràfica van mostrar la possibilitat que estos fotosensibiliza-dors endògens poden actuar com a donadors d'electrons mimetitzant, per tant, la fun-ció del cofactor flavina en la fotoliasa. Finalment, l'anell d'azetidina ha sigut incorporat en un oligonucleotid per a estu-diar la seua ciclorreversió per mitjà de una transferència electrònica. Basant-se en els resultats dels capítols previs, OG ha sigut triat com un fotorreductor natural. En un primer pas, una metodologia ha sigut desenvolupada per a inserir l'azetidina dins d'una seqüència d'oligonucleòtid. Després, la irradiació en estat estacionari del dúplex que conté OG i l'azetidina ha demostrat que la transferència d'electrons té lloc i comporta a la ciclorreversió de l'heterocicle. A més, experiments preliminars han sigut duts a terme per a avaluar la reparació de l'anell de quatre membres, com un anàleg del in-termedi en la reparació del fotoproducte (6-4) , per les fotoliases reals CPD i (6-4).[EN] Ultraviolet radiation is associated with the formation of certain lesions in the DNA that are at the origin of skin cancer. Among the most relevant are the damages that occur at pyrimidine bases: cyclobutane dimers (CPDs) and (6-4) photoproducts (6-4) (6-4PPs). To obtain protection from DNA photolesions, living organisms have enzymes that restore the lesions to their original form, thus maintaining genetic integ-rity. In some organisms, CPDs and 6-4PPs show an additional repair process, which corresponds to photoreactivation and involves enzymes called CPD and (6-4) photol-yases. In particular, there is currently a lively discussion about the mechanism of repair by (6-4) photolyase. The general objective of this doctoral thesis has been to study the cycloreversion of the proposed intermediate of 6-4PP lesions as a key to support one of the mechanisms proposed so far. In a first place, a model of the intermediate azetidine of the 6-4PP lesion for TC sequences was prepared to investigate its repair by means of electron donation by photosensitizers with suitable redox potential, mimicking the flavin cofactor of the (6-4) photolyase. Electrochemical, spectroscopic, analytical measurements as well as computational studies showed that the injection of an electron into the azetidine ring leads to a cycloreversion of the bipyrimidine azetidine to the thymine and 6-azauracil bases. It has also been shown that electron transfer only takes place if the thymine component is present in the model. Secondly, the cycloreversion of azetidine has been investigated by means of an oxidative process in which the azetidine ring donates an electron to the photosensitiz-er. The comparison with a cyclobutane derivative showed that the presence of the nitrogen in the four-membered ring decreases the redox potential, facilitating thus the oxidation process. Third, the cycloversion step has been studied with two intrinsic photosensitizers, guanine and the oxidatively generated damage 8-oxoguanine (OG), covalently bound to a CPD or to an oxetane, as a model for the intermediate of 6-4PP repair. Altogeth-er, the spectroscopic and analytical data showed that these endogenous photosensitiz-ers can act as electron donors mimicking, thus, the function of the flavin cofactor in photolyase. Finally, azetidine ring has been incorporated in an oligonucleotide to study its cy-cloreversion by electron transfer. Based on the results of the previous chapter, OG has been chosen as a natural photoreductant. In a first step, a methodology has been developed to insert the azetidine within the oligonucleotide sequence. Then, steady-state irradiation of the duplex containing OG and the azetidine has demonstrated that the electron transfer takes place and leads to the cycloreversion of the heterocycle. In addition, preliminary experiments have been carried out to evaluate the repair of this four-membered ring, as an analog to the (6-4) photoproduct intermediate, by real CPD and (6-4) photolyases.Fraga Timiraos, AB. (2019). Model Studies on the Photorepair of (6-4) Dimeric Lesions of DNA [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/117610TESI

Rehabilitación de vivienda rural

El objeto del presente proyecto es la rehabilitación de una vivienda rural, para su mismo uso. Se pretende renovar todo el interior de la vivienda, que se encuentra en mal estado, así como adecuar la envolvente.Traballo fin de grao (UDC.EUAT). Arquitectura técnica. Curso 2014/2015

Stereoselective Fluorescence Quenching in the Electron Transfer Photooxidation of Nucleobase-Related Azetidines by Cyanoaromatics

[EN] Electron transfer involving nucleic acids and their derivatives is an important field in bioorganic chemistry, specifically in connection with its role in the photo-driven DNA damage and repair. Four-membered ring heterocyclic oxetanes and azetidines have been claimed to be the intermediates involved in the repair of DNA (6-4) photoproduct by photolyase. In this context, we examine here the redox properties of the two azetidine isomers obtained from photocycloaddition between 6-aza-1,3-dimethyluracil and cyclohexene. Steady-state and time-resolved fluorescence experiments using a series of photoreductants and photooxidants have been run to evaluate the efficiency of the electron transfer process. Analysis of the obtained quenching kinetics shows that the azetidine compounds can act as electron donors. Additionally, it appears that the cis isomer is more easily oxidized than its trans counterpart. This result is in agreement with electrochemical studies performed on both azetidine derivatives.Spanish Government (CTQ2015-70164-P, RIRAAF RETICS RD12/0013/0009, Red de Fotoquimica Biologica CTQ2015-71896-REDT, Severo Ochoa program/SEV-2012-0267 and SVP-2013-068057 for A. B. F.-R. grant) and Generalitat Valenciana (Prometeo II/2013/005) are gratefully acknowledged.Fraga-Timiraos, AB.; Rodríguez Muñiz, GM.; Peiro-Penalba, V.; Miranda Alonso, MÁ.; Lhiaubet, VL. (2016). Stereoselective Fluorescence Quenching in the Electron Transfer Photooxidation of Nucleobase-Related Azetidines by Cyanoaromatics. Molecules. 21(12). https://doi.org/10.3390/molecules21121683S2112Arnold, A. R., Grodick, M. A., & Barton, J. K. (2016). DNA Charge Transport: from Chemical Principles to the Cell. Cell Chemical Biology, 23(1), 183-197. doi:10.1016/j.chembiol.2015.11.010Jia, C., Ma, B., Xin, N., & Guo, X. (2015). Carbon Electrode–Molecule Junctions: A Reliable Platform for Molecular Electronics. 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Science, 283(5400), 375-381. doi:10.1126/science.283.5400.375Breeger, S., von Meltzer, M., Hennecke, U., & Carell, T. (2006). Investigation of the Pathways of Excess Electron Transfer in DNA with Flavin-Donor and Oxetane-Acceptor Modified DNA Hairpins. Chemistry - A European Journal, 12(25), 6469-6477. doi:10.1002/chem.200600074Boussicault, F., & Robert, M. (2008). Electron Transfer in DNA and in DNA-Related Biological Processes. Electrochemical Insights. Chemical Reviews, 108(7), 2622-2645. doi:10.1021/cr0680787The Nobel Prize in Chemistry 2015—Advanced Informationhttp://www.nobelprize.org/nobel_prizes/chemistry/laureates/2015/advanced.htmlBrettel, K., & Byrdin, M. (2010). Reaction mechanisms of DNA photolyase. Current Opinion in Structural Biology, 20(6), 693-701. doi:10.1016/j.sbi.2010.07.003Dandliker, P. J. (1997). Oxidative Thymine Dimer Repair in the DNA Helix. Science, 275(5305), 1465-1468. doi:10.1126/science.275.5305.1465Vicic, D. A., Odom, D. T., Núñez, M. E., Gianolio, D. A., McLaughlin, L. W., & Barton, J. K. (2000). Oxidative Repair of a Thymine Dimer in DNA from a Distance by a Covalently Linked Organic Intercalator. Journal of the American Chemical Society, 122(36), 8603-8611. doi:10.1021/ja000280iHartman, T., & Cibulka, R. (2016). Photocatalytic Systems with Flavinium Salts: From Photolyase Models to Synthetic Tool for Cyclobutane Ring Opening. Organic Letters, 18(15), 3710-3713. doi:10.1021/acs.orglett.6b01743Scannell, M. P., Fenick, D. J., Yeh, S.-R., & Falvey, D. E. (1997). Model Studies of DNA Photorepair:  Reduction Potentials of Thymine and Cytosine Cyclobutane Dimers Measured by Fluorescence Quenching. Journal of the American Chemical Society, 119(8), 1971-1977. doi:10.1021/ja963360oPérez-Ruiz, R., Jiménez, M. C., & Miranda, M. A. (2014). Hetero-cycloreversions Mediated by Photoinduced Electron Transfer. Accounts of Chemical Research, 47(4), 1359-1368. doi:10.1021/ar4003224Boussicault, F., & Robert, M. (2006). Electrochemical Approach to the Repair of Oxetanes Mimicking DNA (6−4) Photoproducts. The Journal of Physical Chemistry B, 110(43), 21987-21993. doi:10.1021/jp062425zPrakash, G., & Falvey, D. E. (1995). Model studies of the (6-4) photoproduct DNA photolyase: Synthesis and photosensitized splitting of a thymine-5,6-oxetane. Journal of the American Chemical Society, 117(45), 11375-11376. doi:10.1021/ja00150a050Friedel, M. G., Cichon, M. K., & Carell, T. (2005). Model compounds for (6–4) photolyases: a comparative flavin induced cleavage study of oxetanes and thietanes. Organic & Biomolecular Chemistry, 3(10), 1937. doi:10.1039/b503205aFraga-Timiraos, A. B., Lhiaubet-Vallet, V., & Miranda, M. A. (2016). Repair of a Dimeric Azetidine Related to the Thymine-Cytosine (6- 4) Photoproduct by Electron Transfer Photoreduction. Angewandte Chemie International Edition, 55(20), 6037-6040. doi:10.1002/anie.201601475Andreu, I., Delgado, J., Espinós, A., Pérez-Ruiz, R., Jiménez, M. C., & Miranda, M. A. (2008). Cycloreversion of Azetidines via Oxidative Electron Transfer. Steady-State and Time-Resolved Studies. Organic Letters, 10(22), 5207-5210. doi:10.1021/ol802181uPac, C., Ohtsuki, T., Shiota, Y., Yanagida, S., & Sakurai, H. (1986). Photochemical Reactions of Aromatic Compounds. XLII. Photosensitized Reactions of Some Selected Diarylcyclobutanes by Aromatic Nitriles and Chloranil. Implications of Charge-Transfer Contributions on Exciplex Reactivities. Bulletin of the Chemical Society of Japan, 59(4), 1133-1139. doi:10.1246/bcsj.59.1133Swenton, J. S., & Hyatt, J. A. (1974). Photosensitized cycloadditions to 1,3-dimethyl-6-azauracil and 1,3-dimethyl-6-azathymine. Imine linkage unusually reactive toward photocycloaddition. Journal of the American Chemical Society, 96(15), 4879-4885. doi:10.1021/ja00822a027Scannell, M. P., Prakash, G., & Falvey, D. E. (1997). Photoinduced Electron Transfer to Pyrimidines and 5,6-Dihydropyrimidine Derivatives:  Reduction Potentials Determined by Fluorescence Quenching Kinetics. The Journal of Physical Chemistry A, 101(24), 4332-4337. doi:10.1021/jp970164aPavlishchuk, V. V., & Addison, A. W. (2000). Conversion constants for redox potentials measured versus different reference electrodes in acetonitrile solutions at 25°C. Inorganica Chimica Acta, 298(1), 97-102. doi:10.1016/s0020-1693(99)00407-

Experimental and Theoretical Study on the Cycloreversion of a Nucleobase-Derived Azetidine by Photoinduced Electron Transfer

[EN] Azetidines are interesting compounds in medicine and chemistry as bioactive scaffolds and synthetic intermediates. However, photochemical processes involved in the generation and fate of azetidine-derived radical ions have scarcely been reported. In this context, the photoreduction of this four-membered heterocycle might be relevant in connection with the DNA (6-4) photoproduct obtained from photolyase. Herein, a stable azabipyrimidinic azetidine (AZT(m)), obtained from cycloaddition between thymine and 6-azauracil units, is considered to be an interesting model of the proposed azetidine-like intermediate. Hence, its photoreduction and photo-oxidation are thoroughly investigated through a multifaceted approach, including spectroscopic, analytical, and electrochemical studies, complemented by CASPT2 and DFT calculations. Both injection and removal of an electron result in the formation of radical ions, which evolve towards repaired thymine and azauracil units. Whereas photoreduction energetics are similar to those of the cyclobutane thymine dimers, photo-oxidation is clearly more favorable in the azetidine. Ring opening occurs with relatively low activation barriers (< 13 kcal mol(-1)) and the process is clearly exergonic for photoreduction. In general, a good correlation has been observed between the experimental results and theoretical calculations, which has allowed a synergic understanding of the phenomenon.The Spanish Government (CTQ2015-70164-P, CTQ2017-87054-C2-2-P, SVP-2013-068057 grants to A.B.F.-R. and RYC-2015-19234 grant to D.R.-S.) and the Valencia Regional Government (Prometeo/2017/075) are acknowledged for financial support. A.F.-M. is grateful to the Region Grand Est government (France) and the Universite de Lorraine for their financial support.Fraga-Timiraos, AB.; Francés-Monerris, A.; Rodríguez Muñiz, GM.; Navarrete-Miguel, M.; Miranda Alonso, MÁ.; Roca Sanjuan, D.; Lhiaubet, VL. (2018). 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Regiochemical memory in the adiabatic photolysis of thymine-derived oxetanes. A combined ultrafast spectroscopic and CASSCF/CASPT2 computational study

[EN] The photoinduced cycloreversion of oxetanes has been thoroughly investigated in connection with the photorepair of the well-known DNA (6-4) photoproducts. In the present work, the direct photolysis of the two regioisomers arising from the irradiation of benzophenone (BP) and 1,3-dimethylthymine (DMT), namely the head-to-head (HH-1) and head-to-tail (HT-1) oxetane adducts, has been investigated by combining ultrafast spectroscopy and theoretical multiconfigurational quantum chemistry analysis. Both the experimental and computational results agree with the involvement of an excited triplet exciplex(3)[BPMIDLINE HORIZONTAL ELLIPSISDMT]* for the photoinduced oxetane cleavage to generate(3)BP* and DMT through an adiabatic photochemical reaction. The experimental signature of(3)[BPMIDLINE HORIZONTAL ELLIPSISDMT]* is the appearance of an absorption band atca.400 nm, detected by femtosecond transient absorption spectroscopy. Its formation is markedly regioselective, as it is more efficient and proceeds faster for HH-1 (similar to 2.8 ps) than for HT-1 (similar to 6.3 ps). This is in line with the theoretical analysis, which predicts an energy barrier to reach the triplet exciplex for HT-1, in contrast with a less hindered profile for HH-1. Finally, the more favorable adiabatic cycloreversion of HH-1 compared to that of HT-1 is explained by its lower probability to reach the intersystem crossing with the ground state, which would induce a radiationless deactivation process leading either to a starting adduct or to a dissociated BP and DMT.Financial support from the Spanish Government (RYC-2015-17737, CTQ2017-89416-R, RYC-2015-19234, CTQ2017-87054-C2-2-P, and MDM-2015-0538), from the Conselleria d'Educacio, Investigacio, Cultura i Esport (PROMETEO/2017/075 and GRISOLiAP/2017/005) and from the Universitat de Valencia (postdoctoral grant within the "Atraccio de Talent 2019" Program for A. G.) is gratefully acknowledged. This work was also supported by a 2019 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation. The Foundation takes no responsibility for the opinions, statements, and contents of this project, which are entirely the responsibility of its authors.Blasco-Brusola, A.; Navarrete-Miguel, M.; Giussani, A.; Roca-Sanjuan, D.; Vayá Pérez, I.; Miranda Alonso, MÁ. (2020). Regiochemical memory in the adiabatic photolysis of thymine-derived oxetanes. A combined ultrafast spectroscopic and CASSCF/CASPT2 computational study. Physical Chemistry Chemical Physics. 22(35):20037-20042. https://doi.org/10.1039/d0cp03084hS2003720042223

Oral Anticoagulation and Risk of Symptomatic Hemorrhagic Transformation in Stroke Patients Treated With Mechanical Thrombectomy: Data From the Nordictus Registry

Introduction: We aimed to evaluate if prior oral anticoagulation (OAC) and its type determines a greater risk of symptomatic hemorrhagic transformation in patients with acute ischemic stroke (AIS) subjected to mechanical thrombectomy. Materials and Methods: Consecutive patients with AIS included in the prospective reperfusion registry NORDICTUS, a network of tertiary stroke centers in Northern Spain, from January 2017 to December 2019 were included. Prior use of oral anticoagulants, baseline variables, and international normalized ratio (INR) on admission were recorded. Symptomatic intracranial hemorrhage (sICH) was the primary outcome measure. Secondary outcome was the relation between INR and sICH, and we evaluated mortality and functional outcome at 3 months by modified Rankin scale. We compared patients with and without previous OAC and also considered the type of oral anticoagulants. Results: About 1.455 AIS patients were included, of whom 274 (19%) were on OAC, 193 (70%) on vitamin K antagonists (VKA), and 81 (30%) on direct oral anticoagulants (DOACs). Anticoagulated patients were older and had more comorbidities. Eighty-one (5.6%) developed sICH, which was more frequent in the VKA group, but not in DOAC group. OAC with VKA emerged as a predictor of sICH in a multivariate regression model (OR, 1.89 [95% CI, 1.01–3.51], p = 0.04) and was not related to INR level on admission. Prior VKA use was not associated with worse outcome in the multivariate regression model nor with mortality at 3 months. Conclusions: OAC with VKA, but not with DOACs, was an independent predictor of sICH after mechanical thrombectomy. This excess risk was associated neither with INR value by the time thrombectomy was performed, nor with a worse functional outcome or mortality at 3 months