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

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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