A Sunscreen-Based Photocage for Carbonyl Groups

This is the peer reviewed version of the following article: M. Lineros-Rosa, M. A. Miranda, V. Lhiaubet-Vallet, Chem. Eur. J. 2020, 26, 7205, which has been published in final form at https://doi.org/10.1002/chem.202000123. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.[EN] Photolabile protecting groups (PPGs) have been exploited in a wide range of chemical and biological applications, due to their ability to provide spatial and temporal control over light-triggered activation. In this work, we explore the concept of a new photocage compound based on the commercial UVA/UVB filter oxybenzone (OB; 2-hydroxy-4-methoxybenzophenone) for photoprotection and controlled release of carbonyl groups. The point here is that oxybenzone not only acts as a mere PPG, but also provides, once released, UV photoprotection to the carbonyl derivative. This design points to a possible therapeutic approach to reduce the severe photoadverse effects of drugs containing a carbonyl chromophore.This work was supported by the Spanish Government (project PGC2018-096684-B-I00) and the Universitat Politecnica de Valencia (FPI grant to M.L.-R.). Carmen Clemente Martínez is acknowledged for her technical help during the UPLC-HRMS experiments.Lineros-Rosa, M.; Miranda Alonso, MÁ.; Lhiaubet, VL. (2020). A Sunscreen-Based Photocage for Carbonyl Groups. Chemistry - A European Journal. 26(32):7205-7211. https://doi.org/10.1002/chem.202000123S720572112632Silva, J. M., Silva, E., & Reis, R. L. (2019). Light-triggered release of photocaged therapeutics - Where are we now? Journal of Controlled Release, 298, 154-176. doi:10.1016/j.jconrel.2019.02.006Klausen, M., Dubois, V., Verlhac, J., & Blanchard‐Desce, M. (2019). Tandem Systems for Two‐Photon Uncaging of Bioactive Molecules. 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Angewandte Chemie, 119(31), 5938-5967. doi:10.1002/ange.200700264Wang, P. (2017). Developing photolabile protecting groups based on the excited state meta effect. Journal of Photochemistry and Photobiology A: Chemistry, 335, 300-310. doi:10.1016/j.jphotochem.2016.11.031Griesbeck, A., Kropf, C., Porschen, B., Landes, A., Hinze, O., Huchel, U., & Gerke, T. (2016). Photocaged Hydrocarbons, Aldehydes, Ketones, Enones, and Carboxylic Acids and Esters that Release by the Norrish II Cleavage Protocol and Beyond: Controlled Photoinduced Fragrance Release. Synthesis, 49(03), 539-553. doi:10.1055/s-0036-1588645Herrmann, A. (2012). Using photolabile protecting groups for the controlled release of bioactive volatiles. Photochem. Photobiol. Sci., 11(3), 446-459. doi:10.1039/c1pp05231dFalvey, D. E., & Sundararajan, C. (2004). Photoremovable protecting groups based on electron transfer chemistry. Photochemical & Photobiological Sciences, 3(9), 831. doi:10.1039/b406866aHébert, J., & Gravel, D. (1974). o-Nitrophenylethylene Glycol: a Photosensitive Protecting Group for Aldehydes and Ketones. Canadian Journal of Chemistry, 52(1), 187-189. doi:10.1139/v74-030Gravel, D., Hebert, J., & Thoraval, D. (1983). o-Nitrophenylethylene glycol as photoremovable protective group for aldehydes and ketones: syntheses, scope, and limitations. Canadian Journal of Chemistry, 61(2), 400-410. doi:10.1139/v83-072Wang, P., Hu, H., & Wang, Y. (2007). Application of the Excited State Meta Effect in Photolabile Protecting Group Design. Organic Letters, 9(15), 2831-2833. doi:10.1021/ol071085cWang, P., Hu, H., & Wang, Y. (2007). Novel Photolabile Protecting Group for Carbonyl Compounds. Organic Letters, 9(8), 1533-1535. doi:10.1021/ol070346fYang, H., Zhang, X., Zhou, L., & Wang, P. (2011). Development of a Photolabile Carbonyl-Protecting Group Toolbox. The Journal of Organic Chemistry, 76(7), 2040-2048. doi:10.1021/jo102429gKostikov, A. P., Malashikhina, N., & Popik, V. V. (2009). Caging of Carbonyl Compounds as Photolabile (2,5-Dihydroxyphenyl)ethylene Glycol Acetals. The Journal of Organic Chemistry, 74(4), 1802-1804. doi:10.1021/jo802612fBlanc, A., & Bochet, C. G. (2002). Bis(o-nitrophenyl)ethanediol:  A Practical Photolabile Protecting Group for Ketones and Aldehydes. The Journal of Organic Chemistry, 68(3), 1138-1141. doi:10.1021/jo026347xYu, J., Tang, W.-J., Wang, H.-B., & Song, Q.-H. (2007). Anthraquinon-2-ylethyl-1′,2′-diol (Aqe-diol) as a new photolabile protecting group for aldehydes and ketones. Journal of Photochemistry and Photobiology A: Chemistry, 185(1), 101-105. doi:10.1016/j.jphotochem.2006.05.010Lu, M., Fedoryak, O. D., Moister, B. R., & Dore, T. M. (2003). Bhc-diol as a Photolabile Protecting Group for Aldehydes and Ketones. Organic Letters, 5(12), 2119-2122. doi:10.1021/ol034536bLevrand, B., & Herrmann, A. (2006). Light-induced controlled release of fragrance aldehydes from 1-alkoxy-9,10-anthraquinones for applications in functional perfumery. Flavour and Fragrance Journal, 21(3), 400-409. doi:10.1002/ffj.1728Levrand, B., & Herrmann, A. (2007). Controlled Light-Induced Release of Volatile Aldehydes and Ketones by Photofragmentation of 2-Oxo-(2-phenyl)acetates. CHIMIA International Journal for Chemistry, 61(10), 661-664. doi:10.2533/chimia.2007.661Griesbeck, A. G., Hinze, O., Görner, H., Huchel, U., Kropf, C., Sundermeier, U., & Gerke, T. (2012). Aromatic aldols and 1,5-diketones as optimized fragrance photocages. Photochemical & Photobiological Sciences, 11(3), 587. doi:10.1039/c2pp05286eBrinson, R. G., & Jones, P. B. (2004). Caged trans-4-Hydroxy-2-nonenal. Organic Letters, 6(21), 3767-3770. doi:10.1021/ol048478lBrinson, R. G., Hubbard, S. C., Zuidema, D. R., & Jones, P. B. (2005). Two new anthraquinone photoreactions. Journal of Photochemistry and Photobiology A: Chemistry, 175(2-3), 118-128. doi:10.1016/j.jphotochem.2005.03.027Blankespoor, R. L., DeVries, T., Hansen, E., Kallemeyn, J. M., Klooster, A. M., Mulder, J. A., … Vander Griend, D. A. (2002). Photochemical Synthesis of Aldehydes in the Solid Phase. The Journal of Organic Chemistry, 67(8), 2677-2681. doi:10.1021/jo025508uMcHale, W. A., & Kutateladze, A. G. (1998). An Efficient Photo-SET-Induced Cleavage of Dithiane−Carbonyl Adducts and Its Relevance to the Development of Photoremovable Protecting Groups for Ketones and Aldehydes. The Journal of Organic Chemistry, 63(26), 9924-9931. doi:10.1021/jo981697yLi, Z., Wan, Y., & Kutateladze, A. G. (2003). Dithiane-Based Photolabile Amphiphiles:  Toward Photolabile Liposomes1,2. Langmuir, 19(16), 6381-6391. doi:10.1021/la034188mMajjigapu, J. R. R., Kurchan, A. N., Kottani, R., Gustafson, T. P., & Kutateladze, A. G. (2005). 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Model Studies on the Photoreduction of the 5-Hydroxy-5,6-dihydrothymine and 5-Methyl-2-pyrimidone Moieties of (6-4) Photoproducts by Photolyase

This is the peer reviewed version of the following article: Rodríguez-Muñiz, G. M., Miranda, M. A., & Lhiaubet-Vallet, V. (2022). Model Studies on the Photoreduction of the 5-Hydroxy-5, 6-dihydrothymine and 5-Methyl-2-pyrimidone Moieties of (6-4) Photoproducts by Photolyase. Photochemistry and Photobiology, 98(3), 671-677, which has been published in final form at https://doi.org/10.1111/php.13592. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.[EN] Photorepair mechanism of (6-4) photoproducts (6-4PP) by photolyase has been the subject of active debate over the years. The initial rationalization based on electron transfer to an oxetane or azetidine intermediate formed upon binding to the enzyme has been questioned, and there is now a more general consensus that the lesion is directly reduced from the excited flavin cofactor. However, the accepting moiety, i.e. the 5-methyl-2-pyrimidone or 5-hydroxy-5,6-dihydrothymine, has not been fully identified yet. In this work, spectroscopic experiments have been run to determine which of the 5 '- or 3 '-base of 6-4PP is more prone to be reduced. For this aim, the two building blocks of 6-4PP were synthesized and used as electron acceptors. Instead of the short-lived photolyase cofactor, which does not provide a time window compatible with diffusion-controlled intermolecular processes, carbazole, 2-methoxynaphthalene and phenanthrene have been selected as electron donors due to their appropriate singlet lifetimes and reduction potentials. Steady-state and time-resolved fluorescence revealed that, in solution, the pyrimidone chromophore is the most easily reduced moiety. This was confirmed by transient absorption experiments consisting of quenching of the solvated electron by the two moieties of 6-4PP.This work has been supported in part by the project PGC2018-096684-B-I00 funded by Spanish Government MCIN/AEI/10.13039/501100011033/ and FEDER "Una manera de hacer Europa" and the Generalitat Valenciana (Prometeo/2017/075).Rodríguez Muñiz, GM.; Miranda Alonso, MÁ.; Lhiaubet, VL. (2022). Model Studies on the Photoreduction of the 5-Hydroxy-5,6-dihydrothymine and 5-Methyl-2-pyrimidone Moieties of (6-4) Photoproducts by Photolyase. Photochemistry and Photobiology. 98(3):671-677. https://doi.org/10.1111/php.1359267167798

Sunscreen-Based Photocages for Topical Drugs: A Photophysical and Photochemical Study of A Diclofenac-Avobenzone Dyad

[EN] Photosensitization by drugs is a problem of increasing importance in modern life. This phenomenon occurs when a chemical substance in the skin is exposed to sunlight. Photosensitizing drugs are reported to cause severe skin dermatitis, and indeed, it is generally advised to avoid sunbathing and to apply sunscreen. In this context, the nonsteroidal anti-inflammatory drug (NSAID) diclofenac is a photosensitive drug, especially when administered in topical form. In this work, efforts have been made to design and study an innovative pro-drug/pro-filter system containing diclofenac and the UVA filter avobenzone in order to develop a safer use of this topical drug. The design is based on the presence of a well-established photoremovable phenacyl group in the avobenzone structure. Steady-state photolysis of the dyad in hydrogen-donor solvents, monitored by UV-Vis spectrophotometry and HPLC, confirms the simultaneous photorelease of diclofenac and avobenzone. Laser flash photolysis and phosphorescence emission experiments allow us to gain insight into the photoactive triplet excited-state properties of the dyad. Finally, it is shown that avobenzone provides partial photoprotection to diclofenac from photocyclization to carbazole derivatives.The present work was supported by the Spanish Government (CTQ2015-70164-P, BES-2013-066566), Generalitat Valenciana (Prometeo/2017/075).Aparici-Espert, MI.; Miranda Alonso, MÁ.; Lhiaubet, VL. (2018). Sunscreen-Based Photocages for Topical Drugs: A Photophysical and Photochemical Study of A Diclofenac-Avobenzone Dyad. Molecules. 23(3):1-11. https://doi.org/10.3390/molecules23030673S111233Siegel, R. L., Miller, K. D., & Jemal, A. (2018). Cancer statistics, 2018. CA: A Cancer Journal for Clinicians, 68(1), 7-30. doi:10.3322/caac.21442Curtius, K., Wright, N. A., & Graham, T. A. (2017). An evolutionary perspective on field cancerization. Nature Reviews Cancer, 18(1), 19-32. doi:10.1038/nrc.2017.102Brem, R., Guven, M., & Karran, P. (2017). Oxidatively-generated damage to DNA and proteins mediated by photosensitized UVA. Free Radical Biology and Medicine, 107, 101-109. doi:10.1016/j.freeradbiomed.2016.10.488Epe, B. (2012). DNA damage spectra induced by photosensitization. Photochem. Photobiol. Sci., 11(1), 98-106. doi:10.1039/c1pp05190cKarran, P., & Brem, R. (2016). Protein oxidation, UVA and human DNA repair. DNA Repair, 44, 178-185. doi:10.1016/j.dnarep.2016.05.024Montoro, J., Rodriguez, M., Diaz, M., & Bertomeu, F. (2003). Photoallergic contact dermatitis due to diclofenac. Contact Dermatitis, 48(2), 115-115. doi:10.1034/j.1600-0536.2003.480212_1.xFernández-Jorge, B., Goday-Buján, J. J., Murga, M., Molina, F. P., Pérez-Varela, L., & Fonseca, E. (2009). Photoallergic contact dermatitis due to diclofenac with cross-reaction to aceclofenac: two case reports. Contact Dermatitis, 61(4), 236-237. doi:10.1111/j.1600-0536.2009.01596.xMonteiro, A. F., Rato, M., & Martins, C. (2016). Drug-induced photosensitivity: Photoallergic and phototoxic reactions. Clinics in Dermatology, 34(5), 571-581. doi:10.1016/j.clindermatol.2016.05.006Akat, P. (2013). Severe photosensitivity reaction induced by topical diclofenac. Indian Journal of Pharmacology, 45(4), 408. doi:10.4103/0253-7613.114999Kowalzick, L., & Ziegler, H. (2006). Photoallergic contact dermatitis from topical diclofenac in SolarazeR gel. Contact Dermatitis, 54(6), 348-349. doi:10.1111/j.0105-1873.2006.0645f.xEncinas, S., Boscá, F., & Miranda, M. A. (1998). Photochemistry of 2,6-Dichlorodiphenylamine and 1-Chlorocarbazole, the Photoactive Chromophores of Diclofenac, Meclofenamic Acid and Their Major Photoproducts. Photochemistry and Photobiology, 68(5), 640. doi:10.1562/0031-8655(1998)0682.3.co;2Encinas, S., Bosca, F., & Miranda, M. A. (1998). Phototoxicity Associated with Diclofenac:  A Photophysical, Photochemical, and Photobiological Study on the Drug and Its Photoproducts. Chemical Research in Toxicology, 11(8), 946-952. doi:10.1021/tx9800708Moore, D. E., Roberts-Thomson, S., Zhen, D., & Duke, C. C. (1990). PHOTOCHEMICAL STUDIES ON THE ANTIINFLAMMATORY DRUG DICLOFENAC. Photochemistry and Photobiology, 52(4), 685-690. doi:10.1111/j.1751-1097.1990.tb08667.xIoele, G., De Luca, M., Tavano, L., & Ragno, G. (2014). The difficulties for a photolabile drug in topical formulations: The case of diclofenac. International Journal of Pharmaceutics, 465(1-2), 284-290. doi:10.1016/j.ijpharm.2014.01.030Ioele, G., Tavano, L., De Luca, M., Ragno, G., Picci, N., & Muzzalupo, R. (2015). Photostability and ex-vivo permeation studies on diclofenac in topical niosomal formulations. International Journal of Pharmaceutics, 494(1), 490-497. doi:10.1016/j.ijpharm.2015.08.053Aparici-Espert, I., Cuquerella, M. C., Paris, C., Lhiaubet-Vallet, V., & Miranda, M. A. (2016). Photocages for protection and controlled release of bioactive compounds. Chemical Communications, 52(99), 14215-14218. doi:10.1039/c6cc08175dKlán, P., Šolomek, T., Bochet, C. G., Blanc, A., Givens, R., Rubina, M., … Wirz, J. (2012). Photoremovable Protecting Groups in Chemistry and Biology: Reaction Mechanisms and Efficacy. Chemical Reviews, 113(1), 119-191. doi:10.1021/cr300177kŠolomek, T., Wirz, J., & Klán, P. (2015). Searching for Improved Photoreleasing Abilities of Organic Molecules. Accounts of Chemical Research, 48(12), 3064-3072. doi:10.1021/acs.accounts.5b00400Young, D. D., & Deiters, A. (2007). Photochemical control of biological processes. Org. Biomol. Chem., 5(7), 999-1005. doi:10.1039/b616410mYu, H., Li, J., Wu, D., Qiu, Z., & Zhang, Y. (2010). Chemistry and biological applications of photo-labile organic molecules. Chem. Soc. Rev., 39(2), 464-473. doi:10.1039/b901255aPravst, I., Zupan, M., & Stavber, S. (2006). Solvent-free bromination of 1,3-diketones and β-keto esters with NBS. Green Chem., 8(11), 1001-1005. doi:10.1039/b608446jParis, C., Lhiaubet-Vallet, V., Jiménez, O., Trullas, C., & Miranda, M. Á. (2009). A Blocked Diketo Form of Avobenzone: Photostability, Photosensitizing Properties and Triplet Quenching by a Triazine-derived UVB-filter. Photochemistry and Photobiology, 85(1), 178-184. doi:10.1111/j.1751-1097.2008.00414.

Photosensitised pyrimidine dimerisation in DNA

Triplet-mediated pyrimidine (Pyr) dimerisation is a key process in photochemical damage to DNA. It may occur in the presence of a photosensitiser, provided that a number of requirements are fulfilled, such as favourable intersystem crossing quantum yield and high triplet energy. The attention has been mainly focused on cyclobutane pyrimidine dimers, as they are by far the most relevant Pyr photoproducts obtained by sensitisation. The present perspective deals with the involved chemistry, not only in DNA but also in its simple building blocks. It also includes the photophysical characterisation of the Pyr triplet excited states, as well as a brief discussion of the theoretical aspects.Financial support from the Spanish Government (CTQ2009-13699, CTQ2009-14196, JAE Doc fellowship for M. C. C. and Ramon y Cajal contract for V. L.-V.) and EU (CM0603) is gratefully acknowledged.Bosca Mayans, F.; Lhiaubet, VL.; Cuquerella Alabort, MC.; Miranda Alonso, MÁ. (2011). 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Nucleic Acids Research, 31(11), 2786-2794. doi:10.1093/nar/gkg402Mitchell, D. L., Fernandez, A. A., Nairn, R. S., Garcia, R., Paniker, L., Trono, D., … Gimenez-Conti, I. (2010). Ultraviolet A does not induce melanomas in a Xiphophorus hybrid fish model. Proceedings of the National Academy of Sciences, 107(20), 9329-9334. doi:10.1073/pnas.1000324107Douki, T., Reynaud-Angelin, A., Cadet, J., & Sage, E. (2003). Bipyrimidine Photoproducts Rather than Oxidative Lesions Are the Main Type of DNA Damage Involved in the Genotoxic Effect of Solar UVA Radiation†. Biochemistry, 42(30), 9221-9226. doi:10.1021/bi034593cYoung, A. R., Potten, C. S., Nikaido, O., Parsons, P. G., Boenders, J., Ramsden, J. M., & Chadwick, C. A. (1998). Human Melanocytes and Keratinocytes Exposed to UVB or UVA In Vivo Show Comparable Levels of Thymine Dimers. Journal of Investigative Dermatology, 111(6), 936-940. doi:10.1046/j.1523-1747.1998.00435.xCooke, M. S., Evans, M. D., Patel, K., Barnard, A., Lunec, J., Burd, R. M., & Hutchinson, P. E. (2001). Induction and Excretion of Ultraviolet-Induced 8-Oxo-2′-deoxyguanosine and Thymine Dimers In Vivo: Implications for PUVA. Journal of Investigative Dermatology, 116(2), 281-285. doi:10.1046/j.1523-1747.2001.01251.xMouret, S., Philippe, C., Gracia-Chantegrel, J., Banyasz, A., Karpati, S., Markovitsi, D., & Douki, T. (2010). UVA-induced cyclobutane pyrimidine dimers in DNA: a direct photochemical mechanism? Organic & Biomolecular Chemistry, 8(7), 1706. doi:10.1039/b924712bJiang, Y., Rabbi, M., Kim, M., Ke, C., Lee, W., Clark, R. L., … Marszalek, P. E. (2009). UVA Generates Pyrimidine Dimers in DNA Directly. Biophysical Journal, 96(3), 1151-1158. doi:10.1016/j.bpj.2008.10.030Tyrrell, R. M., & Keyse, S. M. (1990). New trends in photobiology the interaction of UVA radiation with cultured cells. Journal of Photochemistry and Photobiology B: Biology, 4(4), 349-361. doi:10.1016/1011-1344(90)85014-nBesaratinia, A., Synold, T. 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Photoinduced intersystem crossing in DNA oxidative lesions and epigenetic intermediates

[EN] The propensity of 5-formyluracil and 5-formylcytosine, i.e. oxidative lesions and epigenetic intermediates, in acting as intrinsic DNA photosensitizers is unraveled by using a combination of molecular modeling, simulation and spectroscopy. Exploration of potential energy surfaces and non-adiabatic dynamics confirm a higher intersystem crossing rate for 5-formyluracil, whereas the kinetic models evidence different equilibria in the excited states for both compounds.Support from the Universite de Lorraine, CNRS and Spanish Government (PGC2018-096684-B-I00) is kindly acknowledged. A. F.-M. is grateful to Generalitat Valenciana (CTQ2017-87054-C2-2-P) and the European Social Fund for a postdoctoral contract (APOSTD/2019/149), M. L.-R. acknowledges the Universitat Politecnica de Valencia for the FPI grant. Calculations have been performed on the local LPCT computer center and on the Explor regional center in the framework of the project "Dancing under the light''.Francés-Monerris, A.; Lineros-Rosa, M.; Miranda Alonso, MÁ.; Lhiaubet, VL.; Monari, A. (2020). Photoinduced intersystem crossing in DNA oxidative lesions and epigenetic intermediates. Chemical Communications. 56(32):4404-4407. https://doi.org/10.1039/d0cc01132kS440444075632Madabhushi, R., Pan, L., & Tsai, L.-H. (2014). DNA Damage and Its Links to Neurodegeneration. Neuron, 83(2), 266-282. doi:10.1016/j.neuron.2014.06.034Sage, E. (1993). DISTRIBUTION AND REPAIR OF PHOTOLESIONS IN DNA: GENETIC CONSEQUENCES AND THE ROLE OF SEQUENCE CONTEXT. Photochemistry and Photobiology, 57(1), 163-174. doi:10.1111/j.1751-1097.1993.tb02273.xCadet, J., Sage, E., & Douki, T. (2005). Ultraviolet radiation-mediated damage to cellular DNA. 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Experimental and theoretical studies on thymine photodimerization mediated by oxidatively generated DNA lesions and epigenetic intermediates

[EN] Interaction of nucleic acids with light is a scientific question of paramount relevance not only in the understanding of life functioning and evolution, but also in the insurgence of diseases such as malignant skin cancer and in the development of biomarkers and novel light-assisted therapeutic tools. This work shows that the UVA portion of sunlight, not absorbed by canonical DNA nucleobases, can be absorbed by 5-formyluracil (ForU) and 5-formylcytosine (ForC), two ubiquitous oxidatively generated lesions and epigenetic intermediates present in living beings in natural conditions. We measure the strong propensity of these molecules to populate triplet excited states able to transfer the excitation energy to thymine-thymine dyads, inducing the formation of cyclobutane pyrimidine dimers (CPDs). By using steady-state and transient absorption spectroscopy, NMR, HPLC, and theoretical calculations, we quantify the differences in the triplet-triplet energy transfer mediated by ForU and ForC, revealing that the former is much more efficient in delivering the excitation energy and producing the CPD photoproduct. Although significantly slower than ForU, ForC is also able to harm DNA nucleobases and therefore this process has to be taken into account as a viable photosensitization mechanism. The present findings evidence a rich photochemistry crucial to understand DNA damage photobehavior.Support from the Universite de Lorraine, CNRS, regional (Prometeo/2017/075) and Spanish Government (PGC2018-096684-B-I00, CTQ2017-87054-C2-2-P) is kindly acknowledged. A. F.-M. is grateful to Generalitat Valenciana and the European Social Fund (postdoctoral contract APOSTD/2019/149 and project GV/2020/226) for financial support. M. 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Theoretical Study on the Photo-Oxidation and Photoreduction of an Azetidine Derivative as a Model of DNA Repair

[EN] Photocycloreversion plays a central role in the study of the repair of DNA lesions, reverting them into the original pyrimidine nucleobases. Particularly, among the proposed mechanisms for the repair of DNA (6-4) photoproducts by photolyases, it has been suggested that it takes place through an intermediate characterized by a four-membered heterocyclic oxetane or azetidine ring, whose opening requires the reduction of the fused nucleobases. The specific role of this electron transfer step and its impact on the ring opening energetics remain to be understood. These processes are studied herein by means of quantum-chemical calculations on the two azetidine stereoisomers obtained from photocycloaddition between 6-azauracil and cyclohexene. First, we analyze the efficiency of the electron-transfer processes by computing the redox properties of the azetidine isomers as well as those of a series of aromatic photosensitizers acting as photoreductants and photo-oxidants. We find certain stereodifferentiation favoring oxidation of the cis-isomer, in agreement with previous experimental data. Second, we determine the reaction profiles of the ring-opening mechanism of the cationic, neutral, and anionic systems and assess their feasibility based on their energy barrier heights and the stability of the reactants and products. Results show that oxidation largely decreases the ring-opening energy barrier for both stereoisomers, even though the process is forecast as too slow to be competitive. Conversely, one-electron reduction dramatically facilitates the ring opening of the azetidine heterocycle. Considering the overall quantum-chemistry findings, N,N-dimethylaniline is proposed as an efficient photosensitizer to trigger the photoinduced cycloreversion of the DNA lesion model.This work has been funded by the Generalitat Valenciana and the European Social Fund through the postdoctoral contract APOSTD/2019/149 and the project GV/2020/226. It also was funded by the Spanish Ministerio de Ciencia e Innovacion (MICINN), projects CTQ2017-87054-C2-2-P and PGC2018-096684-B-I00, and 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. D.R.-S. is grateful to the Spanish MICINN for the "Ramon y Cajal" grant (Ref. RYC-2015-19234). M.N.-M. acknowledges the Generalitat Valenciana for the predoctoral grant (Ref. ACIF/2020/075).Navarrete-Miguel, M.; Francés-Monerris, A.; Miranda Alonso, MÁ.; Lhiaubet, VL.; Roca-Sanjuan, D. (2021). Theoretical Study on the Photo-Oxidation and Photoreduction of an Azetidine Derivative as a Model of DNA Repair. Molecules. 26(10):1-14. https://doi.org/10.3390/molecules26102911S114261

Oxidatively Generated Lesions as Internal Photosensitizers for Pyrimidine Dimerization in DNA

[EN] In this work, the attention is focused on UVA-photosensitized reactions triggered by a DNA chromophore-containing lesion, namely 5-formyluracil. This is a major oxidatively generated lesion that exhibits an enhanced light absorption in the UVB-UVA region. The mechanistic study combining photochemical and photobiological techniques shows that irradiation of S-formyluracil leads to a triplet excited state capable of sensitizing formation of cyclobutane pyrimidine dimers in DNA via a triplet-triplet energy transfer. This demonstrates for the first time that oxidatively generated DNA damage can behave as an intrinsic sensitizer and result in an important extension of the active fraction of the solar spectrum with photocarcinogenic potential. Overall, this raises the question of an aggravated photomutagenicity of the 5-formyluracil lesion.The present work was supported by Spanish Government (CTQ2015-70164-P, Severo Ochoa program/SEV-2012-0267, BES-2013-066566, CSIC 2016801007), Instituto de Salud Carlos III (RD16/0006/0030, FIS PI16/01877), Generalitat Valenciana (Prometeo/2017/075).Aparici-Espert, MI.; García-Laínez, G.; Andreu Ros, MI.; Miranda Alonso, MÁ.; Lhiaubet, VL. (2018). Oxidatively Generated Lesions as Internal Photosensitizers for Pyrimidine Dimerization in DNA. ACS Chemical Biology. 13(3):542-547. https://doi.org/10.1021/acschembio.7b01097S54254713

Photophysics and photochemistry of the beta-lapachone derived diphenyldihydrodioxin: generation and characterization of its cation radical

[EN] The photophysics and photochemistry of the beta-lapachone derived diphenyldihydrodioxin 3 were investigated using steady-state and time resolved techniques. Laser excitation of 3 leads to the formation of its cation radical 4 (absorption maxima at 410 and 450 nm and a lifetime of 10 mu s), which was confirmed by its thermal generation employing tris(2,4-dibromophenyl)-aminium hexachloroantimonate (BAHA) as the electron acceptor. The cation radical 4 was also formed via the triplet excited state of 3 through a triplet sensitized process using benzophenone (E-T = 69 kcal mol(-1)) as the sensitizer.Financial support by the Spanish Government (grant CTQ2012-32621) is gratefully acknowledged. We thank Prof. Julia Pérez-Prieto for making available the laser flash photolysis facilities at the University of Valencia. BB thanks Coordena- ção de Aperfeiçoamento do Pessoal do Ensino Superior (CAPES-Brazil) for a graduate fellowship. JCN-F thanks Generalitàt Valenciana for a Visiting Professor fellowship.Netto Ferreira, JC.; Lhiaubet ., VL.; Bernades, B.; Ferreira, ABB.; Miranda Alonso, MÁ. (2014). Photophysics and photochemistry of the beta-lapachone derived diphenyldihydrodioxin: generation and characterization of its cation radical. Photochemical & Photobiological Sciences. 13(12):1655-1660. https://doi.org/10.1039/C4PP00231HS16551660131

Photosensitivity to Triflusal: Formation of a Photoadduct with Ubiquitin Demonstrated by Photophysical and Proteomic Techniques

[EN] Triflusal is a platelet aggregation inhibitor chemically related to acetylsalicylic acid, which is used for the prevention and/or treatment of vascular thromboembolisms, which acts as a prodrug. Actually, after oral administration it is absorbed primarily in the small intestine, binds to plasma proteins (99%) and is rapidly biotransformed in the liver into its deacetylated active metabolite 2-hydroxy-4-trifluoromethylbenzoic acid (HTB). In healthy humans, the half-life of triflusal is ca. 0.5 h, whereas for HTB it is ca. 35 h. From a pharmacological point of view, it is interesting to note that HTB is itself highly active as a platelet anti-aggregant agent. Indeed, studies on the clinical profile of both drug and metabolite have shown no significant differences between them. It has been evidenced that HTB displays ability to induce photoallergy in humans. This phenomenon involves a cell-mediated immune response, which is initiated by covalent binding of a light-activated photosensitizer (or a species derived therefrom) to a protein. In this context, small proteins like ubiquitin could be appropriate models for investigating covalent binding by means of MS/MS and peptide fingerprint analysis. In previous work, it was shown that HTB forms covalent photoadducts with isolated lysine. Interestingly, ubiquitin contains seven lysine residues that could be modified by a similar reaction. With this background, the aim of the present work is to explore adduct formation between the triflusal metabolite and ubiquitin as model protein upon sunlight irradiation, combining proteomic and photophysical (fluorescence and laser flash photolysis) techniques. Photophysical and proteomic analysis demonstrates monoadduct formation as the major outcome of the reaction. Interestingly, addition can take place at any of the E-amino groups of the lysine residues of the protein and involves replacement of the trifluoromethyl moiety with a new amide function. This process can in principle occur with other trifluoroaromatic compounds and may be responsible for the appearance of undesired photoallergic side effects.Financial support from the Generalitat Valenciana (Prometeo Program), the Spanish Government (MINECO CTQ2015-70164-P to VL-V and SAF2012-36519 to DP-S) and the Carlos III Institute of Health (Grant RIRAAF, RETICS program, RD12/0013/0009 to MM and RD12/0013/0008 to DP-S, and Miguel Servet Contract CP11/00154 for IA) is gratefully acknowledged.Nuin Pla, NE.; Pérez-Sala, D.; Lhiaubet-Vallet, VL.; Andreu Ros, MI.; Miranda Alonso, MÁ. (2016). Photosensitivity to Triflusal: Formation of a Photoadduct with Ubiquitin Demonstrated by Photophysical and Proteomic Techniques. Frontiers in Pharmacology. 7(277). https://doi.org/10.3389/fphar.2016.00277S727