Structures of (5′S)-8,5′-Cyclo-2′-deoxyguanosine Mismatched with dA or dT

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Benzophenone photosensitized DNA damage

[EN] A lthough the carcinogenic potential of ultraviolet radiation is well-known, UV light may interact with DNA by direct absorption or through photosensitization by endogenous or exogenous chromophores. These chromophores can extend the ¿active¿ fraction of the solar spectrum to the UVA region and beyond, which means that photosensitizers increase the probability of developing skin cancer upon exposure to sunlight. Therefore researchers would like to understand the mechanisms involved in photosensitized DNA damage both to anticipate possible photobiological risks and to design tailor-made photoprotection strategies. In this context, photosensitized DNA damage can occur through a variety of processes including electron transfer, hydrogen abstraction, triplet triplet energy transfer, or generation of reactive oxygen species. In this Account, we have chosen benzophenone (BP) as a classical and paradigmatic chromophore to illustrate the different lesions that photosensitization may prompt in nucleosides, in oligonucleotides, or in DNA. Thus, we discuss in detail the accumulated mechanistic evidence of the BP-photosensitized reactions of DNA or its building blocks obtained by our group and others. We also include ketoprofen (KP), a BP-derivative that possesses a chiral center, to highlight the stereodifferentiation in the key photochemical events, revealed through the dynamics of the reactive triplet excited state (3KP*). Our results show that irradiation of the BP chromophore in the presence of DNA or its components leads to nucleobase oxidations, cyclobutane pyrimidine dimer formation, single strand breaks, DNA protein cross-links, or abasic sites. We attribute the manifold photoreactivity of BP to its well established photophysical properties: (i) it absorbs UV light, up to 360 nm; (ii) its intersystem crossing quantum yield (OISC) is almost 1; (iii) the energy of its n¿* lowest triplet excited state (ET) is ca. 290 kJ mol 1; (iv) it produces singlet oxygen (1O2)with a quantum yield (¿¿) of ca. 0.3. For electron transfer and singlet oxygen reactions, we focused on guanine, the nucleobase with the lowest oxidation potential. Among the possible oxidative processes, electron transfer predominates. Conversely, triplet triplet energy transfer occurs mainly from 3BP* to thymine, the base with the lowest lying triplet state in DNA. This process results in the formation of cyclobutane pyrimidine dimers, but it also competes with the Patern o B¿uchi reaction in nucleobases or nucleosides, giving rise to oxetanes as a result of crossed cycloadditions. Interestingly, we have found significant stereodifferentiation in the quenching of the KP triplet excited state by both 20-deoxyguanosine and thymidine. Based on these results, this chromophore shows potential as a (chiral) probe for the investigation of electron and triplet energy transport in DNA.We thank our co-workers who contributed to this research whose names appear in the references. Financial support from the Spanish Government (Grant CTQ2009-13699, JAE Doc fellowship for M.C.C, and Ramon y Cajal contract for V.L.-V.) is gratefully acknowledged.Cuquerella Alabort, MC.; Lhiaubet ., VL.; Cadet, J.; Miranda Alonso, MÁ. (2012). Benzophenone photosensitized DNA damage. Accounts of Chemical Research. 45(9):1558-1570. https://doi.org/10.1021/ar300054eS1558157045

Characterization of the Chemical Reactivity and Selectivity of DNA Bases Through the Use of DFT-Based Descriptors

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