Benzophenone Photosensitized DNA Damage

Abstract

Although 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 ((3)KP*). 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 (ϕ(ISC)) is almost 1; (iii) the energy of its nπ* lowest triplet excited state (E(T)) is ca. 290 kJ mol(-1); (iv) it produces singlet oxygen ((1)O(2)) with a quantum yield (ϕ(Δ)) 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 (3)BP* 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 Paternò-Büchi 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 2'-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.

Photoinduced Damage to Cellular DNA: Direct and Photosensitized Reactions†

“…Evidence has been provided for the occurrence of several UVA-sensitized reactions in both isolated and cellular DNA that are triggered by exogenous compounds, mostly drugs that are used for therapeutic purposes (7,(131)(132)(133). We may distinguish photosensitizers which operate in an oxygenindependent manner through mainly triplet energy transfer and photoaddition reactions.…”

Blocking cyclobutane pyrimidine dimer formation by steric hindrance

“…2,[7][8][9][10] In this context, the aim of the present work is to determine the influence of steric hindrance on the photosensitized dimerization that leads to CPDs. With this purpose, the tert-butyl substituted uracil derivative 1 and its thymine analog 2, have been selected to investigate their photosensitization with BP (E T = 290 kJ mol -1 ) and acetone (E T = 332 kJ mol -1 ) looking at the kinetic aspects and also at the photoproducts distribution.…”

Photostability evaluation of five UV-filters, trans-resveratrol and beta-carotene in sunscreens

“…As a consequence of sunlight exposure some compounds may undergo photochemical reactions giving rise to ROS such as singlet oxygen and superoxide (Cuquerella et al, 2012;Epe, 2012), which can trigger photodamage processes (Nichols and Katiyar, 2010). UVA radiation is involved in changes of chemical stability in sunscreens, since UV-filter degradation occurs mainly in this region (Hojerová et al, 2011).…”