Triplet Excited States as a Source of Relevant (Bio)Chemical Information

[EN] The properties of triplet excited states are markedly medium-dependent, which turns this species into valuable tools for investigating the microenvironments existing in protein binding pockets. Monitoring of the triplet excited state behavior of drugs within transport proteins (serum albumins and alpha(1)-acid glycoproteins) by laser flash photolysis constitutes a valuable source of information on the strength of interaction, conformational freedom and protection from oxygen or other external quenchers. With proteins, formation of spatially confined triplet excited states is favored over competitive processes affording ionic species. Remarkably, under aerobic atmosphere, the triplet decay of drug@protein complexes is dramatically longer than in bulk solution. This offers a convenient dynamic range for assignment of different triplet populations or for stereochemical discrimination. In this review, selected examples of the application of the laser flash photolysis technique are described, including drug distribution between the bulk solution and the protein cavities, or between two types of proteins, detection of drug-drug interactions inside proteins, and enzyme-like activity processes mediated by proteins. Finally, protein encapsulation can also modify the photoreactivity of the guest. This is illustrated by presenting an example of retarded photooxidation.Financial support by Spanish Government (CTQ2013-47872-C2-1-P) and Generalitat Valenciana (Prometeo II/2013/005) is gratefully acknowledged.Jiménez Molero, MC.; Miranda Alonso, MÁ. (2014). Triplet Excited States as a Source of Relevant (Bio)Chemical Information. Current Topics in Medicinal Chemistry. 14(23):2734-2742. https://doi.org/10.2174/1568026614666141216100907S27342742142

Regioselectivity in the adiabatic photocleavage of DNA-based oxetanes

[EN] Direct absorption of UVB light by DNA may induce formation of cyclobutane pyrimidine dimers and pyrimidine-pyrimidone (6-4) photoproducts. The latter arise from the rearrangement of unstable oxetane intermediates, which have also been proposed to be the electron acceptor species in the photoenzymatic repair of this type of DNA damage. In the present work, direct photolysis of oxetanes composed of substituted uracil (Ura) or thymine (Thy) derivatives and benzophenone (BP) have been investigated by means of transient absorption spectroscopy from the femtosecond to the microsecond time-scales. The results showed that photoinduced oxetane cleavage takes place through an adiabatic process leading to the triplet excited BP and the ground state nucleobase. This process was markedly affected by the oxetane regiochemistry (head-to-head, HH, vs. head-to-tail, HT) and by the nucleobase substitution; it was nearly quantitative for all investigated HH-oxetanes while it became strongly influenced by the substitution at positions 1 and 5 for the HT-isomers. The obtained results clearly confirm the generality of the adiabatic photoinduced cleavage of BP/Ura or Thy oxetanes, as well as its dependence on the regiochemistry, supporting the involvement of triplet exciplexes. As a matter of fact, when formation of this species was favored by keeping together the Thy and BP units after splitting by means of a linear linker, a transient absorption at similar to 400 nm, ascribed to the exciplex, was detected.Financial support from the Spanish Government (RYC-2015-17737 and CTQ2017-89416-R) and from the Conselleria d'Educacio Cultura i Esport (PROMETEO/2017/075 and GRISOLIAP/2017/005) is gratefully acknowledged.Blasco-Brusola, A.; Vayá Pérez, I.; Miranda Alonso, MÁ. (2020). Regioselectivity in the adiabatic photocleavage of DNA-based oxetanes. Organic & Biomolecular Chemistry. 18(44):9117-9123. https://doi.org/10.1039/D0OB01974GS91179123184

Influence of the linking bridge on the photoreactivity of benzophenone-thymine conjugates

[EN] Benzophenone (BP) is present in a variety of bioactive molecules. This chromophore is able to photosensitize DNA damage, where one of the most relevant BP/ DNA interactions occurs with thymine (Thy). In view of the complex photoreactivity previously observed for dyads containing BP covalently linked to thymidine, the aim of this work is to investigate whether appropriate changes in the nature of the spacer could modulate the intramolecular BP/Thy photoreactivity, resulting in an enhanced selectivity. Accordingly, the photobehavior of a series of dyads derived from BP and Thy, separated by linear linkers of different length, has been investigated by steady-state photolysis, as well as femtosecond and nanosecond transient absorption spectroscopy. Irradiation of the dyads led to photoproducts arising from formal hydrogen abstraction or Paterno-Buchi (PB) photoreaction, with a chemoselectivity that was clearly dependent on the nature of the linking bridge; moreover, the PB process occurred with complete regio- and stereoselectivity. The overall photoreactivity increased with the length of the spacer and correlated well with the rate constants estimated from the BP triplet lifetimes. A reaction mechanism explaining these results is proposed, where the key features are the strain associated with the reactive conformations and the participation of triplet exciplexes.Financial support from the Spanish Government (RYC-2015-17737 and CTQ2017-89416-R) and from the Conselleria d'Educació Cultura i Esport (PROMETEO/2017/075 and GRISOLIAP/2017/005) is gratefully acknowledged. The authors would like to thank the use of RIAIDT-USC analytical facilities for the X-ray crystallography analysis.Blasco-Brusola, A.; Vayá Pérez, I.; Miranda Alonso, MÁ. (2020). Influence of the linking bridge on the photoreactivity of benzophenone-thymine conjugates. The Journal of Organic Chemistry. 85(21):14068-14076. https://doi.org/10.1021/acs.joc.0c02088S14068140768521Kraemer, K. H. (1997). Sunlight and skin cancer: Another link revealed. Proceedings of the National Academy of Sciences, 94(1), 11-14. doi:10.1073/pnas.94.1.11Cadet, J., Mouret, S., Ravanat, J.-L., & Douki, T. (2012). Photoinduced Damage to Cellular DNA: Direct and Photosensitized Reactions†. Photochemistry and Photobiology, 88(5), 1048-1065. doi:10.1111/j.1751-1097.2012.01200.xRastogi, R. P., Richa, Kumar, A., Tyagi, M. B., & Sinha, R. P. (2010). Molecular Mechanisms of Ultraviolet Radiation-Induced DNA Damage and Repair. Journal of Nucleic Acids, 2010, 1-32. doi:10.4061/2010/592980Sinha, R. P., & Häder, D.-P. (2002). UV-induced DNA damage and repair: a review. Photochemical & Photobiological Sciences, 1(4), 225-236. doi:10.1039/b201230hChatterjee, N., & Walker, G. C. (2017). Mechanisms of DNA damage, repair, and mutagenesis. Environmental and Molecular Mutagenesis, 58(5), 235-263. doi:10.1002/em.22087Brash, D. E., & Haseltine, W. A. (1982). UV-induced mutation hotspots occur at DNA damage hotspots. Nature, 298(5870), 189-192. doi:10.1038/298189a0Taylor, J. S., & Cohrs, M. P. (1987). DNA, light, and Dewar pyrimidinones: the structure and biological significance to TpT3. Journal of the American Chemical Society, 109(9), 2834-2835. doi:10.1021/ja00243a052Taylor, J. S., Garrett, D. S., & Cohrs, M. P. (1988). Solution-state structure of the Dewar pyrimidinone photoproduct of thymidylyl-(3’ .fwdarw. 5’)-thymidine. Biochemistry, 27(19), 7206-7215. doi:10.1021/bi00419a007Kim, S. T., Malhotra, K., Smith, C. A., Taylor, J. S., & Sancar, A. (1994). Characterization of (6-4) photoproduct DNA photolyase. Journal of Biological Chemistry, 269(11), 8535-8540. doi:10.1016/s0021-9258(17)37228-9Li, J., Liu, Z., Tan, C., Guo, X., Wang, L., Sancar, A., & Zhong, D. (2010). Dynamics and mechanism of repair of ultraviolet-induced (6–4) photoproduct by photolyase. Nature, 466(7308), 887-890. doi:10.1038/nature09192Todo, T., Ryo, H., Yamamoto, K., Toh, H., Inui, T., Ayaki, H., … Ikenaga, M. (1996). Similarity Among the Drosophila (6-4)Photolyase, a Human Photolyase Homolog, and the DNA Photolyase-Blue-Light Photoreceptor Family. Science, 272(5258), 109-112. doi:10.1126/science.272.5258.109Todo, T., Takemori, H., Ryo, H., lhara, M., Matsunaga, T., Nikaido, O., … Nomura, T. (1993). A new photoreactivating enzyme that specifically repairs ultraviolet light-induced (6-4)photoproducts. Nature, 361(6410), 371-374. doi:10.1038/361371a0Todo, T., Tsuji, H., Otoshi, E., Hitomi, K., Sang-Tae Kim, & Ikenaga, M. (1997). Characterization of a human homolog of (6-4)photolyase. Mutation Research/DNA Repair, 384(3), 195-204. doi:10.1016/s0921-8777(97)00032-3Epe, B., Pflaum, M., & Boiteux, S. (1993). DNA damage induced by photosensitizers in cellular and cell-free systems. Mutation Research/Genetic Toxicology, 299(3-4), 135-145. doi:10.1016/0165-1218(93)90091-qMichaud, S., Hajj, V., Latapie, L., Noirot, A., Sartor, V., Fabre, P.-L., & Chouini-Lalanne, N. (2012). Correlations between electrochemical behaviors and DNA photooxidative properties of non-steroïdal anti-inflammatory drugs and their photoproducts. Journal of Photochemistry and Photobiology B: Biology, 110, 34-42. doi:10.1016/j.jphotobiol.2012.02.007Marguery, M. C., Chouini-Lalanne, N., Ader, J. C., & Paillous, N. (1998). Comparison of the DNA Damage Photoinduced by Fenofibrate and Ketoprofen, Two Phototoxic Drugs of Parent Structure. Photochemistry and Photobiology, 68(5), 679-684. doi:10.1111/j.1751-1097.1998.tb02529.xVinette, A. L., McNamee, J. P., Bellier, P. V., McLean, J. R. N., & Scaiano, J. C. (2003). Prompt and Delayed Nonsteroidal Anti-inflammatory Drug–photoinduced DNA Damage in Peripheral Blood Mononuclear Cells Measured with the Comet Assay¶. Photochemistry and Photobiology, 77(4), 390. doi:10.1562/0031-8655(2003)0772.0.co;2Lhiaubet, V., Gutierrez, F., Penaud–Berruyer, F., Amouyal, E., Daudey, J.-P., Poteau, R., … Paillous, N. (2000). Spectroscopic and theoretical studies of the excited states of fenofibric acid and ketoprofen in relation with their photosensitizing properties. New Journal of Chemistry, 24(6), 403-410. doi:10.1039/a909539jLhiaubet, V., Paillous, N., & Chouini-Lalanne, N. (2001). Comparison of DNA Damage Photoinduced by Ketoprofen, Fenofibric Acid and Benzophenone via Electron and Energy Transfer¶. Photochemistry and Photobiology, 74(5), 670. doi:10.1562/0031-8655(2001)0742.0.co;2Cuquerella, M. C., Lhiaubet-Vallet, V., Cadet, J., & Miranda, M. A. (2012). Benzophenone Photosensitized DNA Damage. Accounts of Chemical Research, 45(9), 1558-1570. doi:10.1021/ar300054eBignon, E., Marazzi, M., Besancenot, V., Gattuso, H., Drouot, G., Morell, C., … Monari, A. (2017). Ibuprofen and ketoprofen potentiate UVA-induced cell death by a photosensitization process. Scientific Reports, 7(1). doi:10.1038/s41598-017-09406-8Boscá, F., & Miranda, M. A. (1998). New Trends in Photobiology (Invited Review) Photosensitizing drugs containing the benzophenone chromophore. Journal of Photochemistry and Photobiology B: Biology, 43(1), 1-26. doi:10.1016/s1011-1344(98)00062-1Rogers, J. E., & Kelly, L. A. (1999). Nucleic Acid Oxidation Mediated by Naphthalene and Benzophenone Imide and Diimide Derivatives:  Consequences for DNA Redox Chemistry. Journal of the American Chemical Society, 121(16), 3854-3861. doi:10.1021/ja9841299Surana, K., Chaudhary, B., Diwaker, M., & Sharma, S. (2018). Benzophenone: a ubiquitous scaffold in medicinal chemistry. MedChemComm, 9(11), 1803-1817. doi:10.1039/c8md00300aCuquerella, M. C., Lhiaubet-Vallet, V., Bosca, F., & Miranda, M. A. (2011). Photosensitised pyrimidine dimerisation in DNA. Chemical Science, 2(7), 1219. doi:10.1039/c1sc00088hBlasco-Brusola, A., Navarrete-Miguel, M., Giussani, A., Roca-Sanjuán, D., Vayá, I., & Miranda, M. A. (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. doi:10.1039/d0cp03084hBurrows, C. J., & Muller, J. G. (1998). Oxidative Nucleobase Modifications Leading to Strand Scission. Chemical Reviews, 98(3), 1109-1152. doi:10.1021/cr960421sBelmadoui, N., Climent, M. J., & Miranda, M. A. (2006). Photochemistry of a naphthalene–thymine dyad in the presence of acetone. Tetrahedron, 62(7), 1372-1377. doi:10.1016/j.tet.2005.11.035Bonancía, P., Vayá, I., Climent, M. J., Gustavsson, T., Markovitsi, D., Jiménez, M. C., & Miranda, M. A. (2012). Excited-State Interactions in Diastereomeric Flurbiprofen–Thymine Dyads. The Journal of Physical Chemistry A, 116(35), 8807-8814. doi:10.1021/jp3063838Encinas, S., Climent, M. J., Gil, S., Abrahamsson, U. O., Davidsson, J., & Miranda, M. A. (2004). Singlet Excited-State Interactions in Naphthalene-Thymine Dyads. ChemPhysChem, 5(11), 1704-1709. doi:10.1002/cphc.200400262Belmadoui, N., Encinas, S., Climent, M. J., Gil, S., & Miranda, M. A. (2006). Intramolecular Interactions in the Triplet Excited States of Benzophenone–Thymine Dyads. Chemistry - A European Journal, 12(2), 553-561. doi:10.1002/chem.200500345Dumont, E., Wibowo, M., Roca-Sanjuán, D., Garavelli, M., Assfeld, X., & Monari, A. (2015). Resolving the Benzophenone DNA-Photosensitization Mechanism at QM/MM Level. The Journal of Physical Chemistry Letters, 6(4), 576-580. doi:10.1021/jz502562dDelatour, T., Douki, T., D’Ham, C., & Cadet, J. (1998). Photosensitization of thymine nucleobase by benzophenone through energy transfer, hydrogen abstraction and one-electron oxidation. Journal of Photochemistry and Photobiology B: Biology, 44(3), 191-198. doi:10.1016/s1011-1344(98)00142-0Tamai, N., Asahi, T., & Masuhara, H. (1992). Intersystem crossing of benzophenone by femtosecond transient grating spectroscopy. Chemical Physics Letters, 198(3-4), 413-418. doi:10.1016/0009-2614(92)85074-kGut, I. G., Wood, P. D., & Redmond, R. W. (1996). Interaction of Triplet Photosensitizers with Nucleotides and DNA in Aqueous Solution at Room Temperature. Journal of the American Chemical Society, 118(10), 2366-2373. doi:10.1021/ja9519344Miro, P., Gomez‐Mendoza, M., Sastre, G., Cuquerella, M. C., Miranda, M. A., & Marin, M. L. (2019). Generation of the Thymine Triplet State by Through‐Bond Energy Transfer. Chemistry – A European Journal, 25(28), 7004-7011. doi:10.1002/chem.201900830Joseph, A., Prakash, G., & Falvey, D. E. (2000). 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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. 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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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Organic Letters, 14(7), 1788-1791. doi:10.1021/ol3003805Görner, H. (2008). Photoinduced Oxygen Uptake of Diphenylamines in Solution and Their Ring Closure Revisited. The Journal of Physical Chemistry A, 112(6), 1245-1250. doi:10.1021/jp076788

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.

Type I vs Type II photodegradation of pollutants

[EN] Rose Bengal (RB) is a widely used photocatalyst due to its high quantum yield of singlet oxygen (O-1(2)) formation. Hence, when RB has been employed for wastewater remediation, the observed photodegradation has been attributed to reaction between the pollutants and the O-1(2) formed (Type II mechanism). However, RB could also react, in principle, via electron transfer (Type I mechanism). Herein, competition between Type I vs Type II oxidation has been investigated for RB in the photodegradation of emerging pollutants such as diclofenac (DCF) and acetaminophen (ACP). In parallel, the photocatalyst perinaphthenone (PN) has also been evaluated for comparison. The degree of removal achieved for both pollutants in aerated/deaerated aqueous solutions irrespective of the employed photocatalyst does not support the involvement of O-1(2) as the main species responsible for removal of the pollutants. Photophysical experiments showed that the triplet excited states of RB and PN are efficiently quenched by both DCF and ACP. Moreover, O-1(2) emission was also quenched by DCF and ACP. Thus the contribution of Type I versus Type II in the photodegradation has been evaluated from the experimentally determined rate constants. Nevertheless, at the upper limit for the typical concentration of emerging pollutants (10(-5) M) photodegradation proceeds mainly via Type I mechanism.Financial support from Spanish Government (Grants SEV-2016-0683 and CTQ2012-38754-C03-03) and Generalitat Valenciana (Prometeo Program) is gratefully acknowledged. We also thank support from VLC/Campus. R. Martinez-Haya thanks financial support from Spanish Government (Grant SEV-2012-0267).Martínez-Haya, R.; Miranda Alonso, MÁ.; Marín García, ML. (2018). Type I vs Type II photodegradation of pollutants. Catalysis Today. 313:161-166. https://doi.org/10.1016/j.cattod.2017.10.034S16116631

Triplet excited states as chiral reporter for the binding of drugs to transport proteins

[EN] The triplet excited state of flurbiprofen methyl ester (FBPMe) has been used as a chiral reporter for the two binding sites of human serum albumin (HSA). The occupation level of the binding sites has been estimated from regression analysis of the triplet decays at several [FBPMe]/[HSA] ratios. The data agree with two high affinity binding sites (I and II) that are populated to a different extent. A remarkable stereodifferentiation has been found in the drug triplet lifetimes within the protein microenvironment.The UPV (Grant PI 2003-0522 and fellowship to I.V.), the MEC (Grant CTQ2004-03811), and Generalitat Valenciana (Grant GV2004-0536 and Grupos03/082) are gratefully acknowledged for financial support.Jiménez Molero, MC.; Miranda Alonso, MÁ.; Vayá Pérez, I. (2005). Triplet excited states as chiral reporter for the binding of drugs to transport proteins. Journal of the American Chemical Society. 127(29):10134-10135. https://doi.org/10.1021/ja0514489S10134101351272

Transient UV-vis absorption spectroscopic characterisation of 2 '-methoxyacetophenone as a DNA photosensitiser

[EN] 2'-Methoxyacetophenone (2M) presents improved UVA absorption as compared with other acetophenone derivatives. On the basis of transient infrared spectroscopy it has been previously claimed that 2M is an interesting photosensitiser for cyclobutane pyrimidine dimers (CPDs) formation. In the present paper, a complete UV-Vis transient absorption spectroscopic characterisation of this compound is provided, including triplet-triplet spectra, triplet lifetimes and rate constants for quenching of 2M by a dimeric thymine derivative. Furthermore, generation of singlet oxygen has been proven by time-resolved near IR phosphorescence measurements. Overall, the obtained results confirm the potential of 2M as a DNA photosensitiser, not only for CPDs formation, but also for oxidative damage.Financial support by the Spanish Government (O.R-A., FPU14/05294 and CTQ2015-70164-P) and Generalitat Valenciana (PROMETEO/2017/075) is gratefully acknowledged.Rodriguez-Alzueta, O.; Cuquerella Alabort, MC.; Miranda Alonso, MÁ. (2019). Transient UV-vis absorption spectroscopic characterisation of 2 '-methoxyacetophenone as a DNA photosensitiser. Spectrochimica Acta Part A Molecular and Biomolecular Spectroscopy. 218:191-195. https://doi.org/10.1016/j.saa.2019.04.007S19119521

Stereodifferentiation in the fluorescence of naproxen-arginine salts in the solid state

[EN] Three stereoisomeric salts of naproxen (NPX) with arginine (Arg), namely (S)-NPX/(S)-Arg, (R)-NPX/(S)-Arg and (S)NPX/(R)-Arg, have been prepared, and their fluorescence spectra recorded in solution and in the solid state. While the emission properties in solution did not show significant differences with lambda(max) = 355 nm, tau(F) (MeOH) ca. 11.5 ns and tau(F) (H2O) ca. 9 ns (as NPX/Na), the (R)-NPX/(S)-Arg and (S)-NPX/(R)-Arg solid salts displayed red-shifted fluorescence spectra With maxima at 375 mn and tau(F) = 1.1 ns. By contrast, the behaviour of solid (S)-NPX/(S)-Arg was similar to that of NPX/Na With; ax = 355 nm and tau(F) ca. 5.5 ns. These results are explained based on the X-ray crystal structures and attributed to formation of NPX excimers emitting at longer wavelengths. Accordingly, such excimer emission was also observed in the fluorescence spectrum of a model NPX dyad in solution.The UPV (PI 2003-0522 and predoctoral fellowship to I.V.), the MYCT (Grant CTQ2004-03811) the Generalitat Valenciana (Grupos03/082 and GV04B-468) are gratefully acknowledged for financial support. We also thank our colleague Dr. M. L. Marin for providing a gift of (2-methoxynaphthalen-6-yl)acetic acid and Dr. A. Llamas (Unidade de Raios X de la Universidade de Santiago de Compostela) for the X-ray measurements.Vayá Pérez, I.; Jiménez Molero, MC.; Miranda Alonso, MÁ. (2005). Stereodifferentiation in the fluorescence of naproxen-arginine salts in the solid state. Tetrahedron Asymmetry. 16(12):2167-2171. https://doi.org/10.1016/j.tetasy.2005.05.018S21672171161

A comprehensive mechanistic study on the visible light photocatalytic reductive dehalogenation of haloaromatics mediated by Ru(bpy)3Cl2

[EN] Visible light photoredox catalysis is emerging as a versatile technique for a great variety of chemical transformations. Specifically,Ru(bpy)(3)(2+) has been widely used as a transition metal-based photocatalyst; however, little if any attention has been paid to the thermodynamic analysis of the photoredox processes that occur in the photocatalytic cycle of the studied reactions or, even more interestingly, to the examination of the kinetic feasibility of the involved processes. In addition, only a few studies on the progress of the reaction have been performed. Organic halides constitute a major concern for environmental remediation since they are reluctant towards aerobic oxidation. Therefore, p-halonitrobenzene (X-NB) derivatives have been selected in the present work as the model compounds to obtain a deeper understanding of their photocatalytic reduction using visible light and RuRu(bpy)(3)(2+). Thermodynamic estimations were made on the basis of the experimentally determined energy of the LUMO of RuRu(bpy)(3)(2+), which was determined to be 54.5 kcal mol(-1) from the cross-point of the normalized emission and excitation spectra, and redox potentials of X-NB and several sacrificial amines. As anticipated from chemical intuition, the feasibility of the global photoredox process increased upon going down in the group of halogens regardless of the participation of the oxidative or reductive quenching cycles. To unequivocally demonstrate the direct participation of the excited state of RuRu(bpy)(3)(2) in the photoreduction, steady-state and time-resolved experiments were carried out upon increasing X-NB or amine concentration; this allowed determining the quenching rate constants for the electron transfer processes, which were found to be in the range of 108 M-1 s(-1) for the X-NB and 106 M-1 s(-1) for the amines. Therefore, the main role of the oxidative quenching cycle has been demonstrated under the experimental conditions employed. A good correlation was found between the thermodynamic and kinetic parameters, in agreement with the expectations from Marcus theory. Upon optimization of the reaction conditions, reductive dehalogenation was found to occur leading to the parent nitrobenzene.Generous support from the Ministerio de Economia y Competitividad (Project CTQ2012-38754-C03-03 and SEV-2016-0683) and from the Generalitat Valenciana (Prometeo Program) is gratefully acknowledged.Marin Melchor, M.; Miranda Alonso, MÁ.; Marín García, ML. (2017). A comprehensive mechanistic study on the visible light photocatalytic reductive dehalogenation of haloaromatics mediated by Ru(bpy)3Cl2. Catalysis Science & Technology. 7(20):4852-4858. https://doi.org/10.1039/c7cy01231dS48524858720Ravelli, D., Dondi, D., Fagnoni, M., & Albini, A. (2009). Photocatalysis. A multi-faceted concept for green chemistry. Chemical Society Reviews, 38(7), 1999. doi:10.1039/b714786bPalmisano, G., Augugliaro, V., Pagliaro, M., & Palmisano, L. (2007). Photocatalysis: a promising route for 21st century organic chemistry. Chemical Communications, (33), 3425. doi:10.1039/b700395cMarin, M. L., Santos-Juanes, L., Arques, A., Amat, A. M., & Miranda, M. A. (2011). Organic Photocatalysts for the Oxidation of Pollutants and Model Compounds. Chemical Reviews, 112(3), 1710-1750. doi:10.1021/cr2000543Martinez-Haya, R., Barecka, M. H., Miro, P., Marin, M. L., & Miranda, M. A. (2015). Photocatalytic Treatment of Cork Wastewater Pollutants. Degradation of Gallic Acid and Trichloroanisole using Triphenyl(thia)pyrylium salts. Applied Catalysis B: Environmental, 179, 433-438. doi:10.1016/j.apcatb.2015.05.039Miró, P., Arques, A., Amat, A. M., Marin, M. L., & Miranda, M. A. (2013). A mechanistic study on the oxidative photodegradation of 2,6-dichlorodiphenylamine-derived drugs: Photo-Fenton versus photocatalysis with a triphenylpyrylium salt. Applied Catalysis B: Environmental, 140-141, 412-418. doi:10.1016/j.apcatb.2013.04.042Huang, L., Shen, Y., Dong, W., Zhang, R., Zhang, J., & Hou, H. (2008). A novel method to decompose two potent greenhouse gases: Photoreduction of SF6 and SF5CF3 in the presence of propene. Journal of Hazardous Materials, 151(2-3), 323-330. doi:10.1016/j.jhazmat.2007.05.080Tucker, J. W., & Stephenson, C. R. J. (2012). Shining Light on Photoredox Catalysis: Theory and Synthetic Applications. The Journal of Organic Chemistry, 77(4), 1617-1622. doi:10.1021/jo202538xPrier, C. K., Rankic, D. A., & MacMillan, D. W. C. (2013). Visible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis. Chemical Reviews, 113(7), 5322-5363. doi:10.1021/cr300503rNarayanam, J. M. R., & Stephenson, C. R. J. (2011). 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