A mechanistic study on the phototoxicity of atorvastatin: singlet oxygen generation by a phenanthrene-like photoproduct

Atorvastatin calcium (ATV) is one of the most frequently prescribed drugs worldwide. Among the adverse effects observed for this lipid-lowering agent, clinical cases of cutaneous adverse reactions have been reported and associated with photosensitivity disorders. Previous work dealing with ATV photochemistry has shown that exposure to natural sunlight in aqueous solution leads to photoproducts resulting from oxidation of the pyrrole ring and from cyclization to a phenanthrene derivative. Laser flash photolysis of ATV, at both 266 and 308 nm, led to a transient spectrum with two maxima at λ ) 360 and λ ) 580 nm (τ ) 41 μs), which was assigned to the primary intermediate of the stilbene-like photocyclization. On the basis of the absence of a triplet-triplet absorption, the role of the parent drug as singlet oxygen photosensitizer can be discarded. By contrast, a stable phenanthrene-like photoproduct would be a good candidate to play this role. Laser flash photolysis of this compound showed a triplet-triplet transient absorption at λmax ) 460 nm with a lifetime of 26 μs, which was efficiently quenched by oxygen (kq ) 3 ((0.2) × 109 M-1 s-1). Its potential to photosensitize formation of singlet oxygen was confirmed by spin trapping experiments, through conversion of TEMP to the stable free radical TEMPO. The photoreactivity of the phenanthrene-like photoproduct was investigated using Trp as a marker. The disappearance of the amino acid fluorescence (λmax ) 340 nm) after increasing irradiation times at 355 nm was taken as a measurement of photodynamic oxidation. To confirm the involvement of a type II mechanism, the same experiment was also performed in D2O; this resulted in a significant enhancement of the reaction rate. On the basis of the obtained photophysical and photochemical results, the phototoxicity of atorvastatin can be attributed to singlet oxygen formation with the phenanthrene-like photoproduct as a photosensitizer

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

Seeking to shed some light on the binding of fluoroquinolones to albumins

Interactions between serum albumins (HSA, human, and BSA, bovine) and fluoroquinolones (FQs), such as enoxacin, norfloxacin, ciprofloxacin, and ofloxacin, have been studied using the laser flash photolysis technique. Lifetimes and quantum yields of FQs triplet excited states ((3)FQs) are not affected by the presence of albumins, however, the quenching of (3)FQs by tryptophan and tyrosine and the subsequent generation of FQs. radical anions and tyrosyl or tryptophanyl radicals were detected. These results, besides agreeing with association constants (K-a) for FQs binding to albumins lower than 6 x 10(2) M-1, are highly relevant to understanding the process of photohapten formation, the first event in the onset of photoallergy. The emission of tryptophan within albumin is not affected by the presence of FQs when the inner filter effects (IFE) of these drugs are taken into account, which explains the discrepancies reported in the literature about K-a of FQs with albumins.Financial support from Spanish government (CTQ2010-19909) is gratefully acknowledged.Bosca Mayans, F. (2012). Seeking to shed some light on the binding of fluoroquinolones to albumins. Journal of Physical Chemistry B. 116(11):3504-3511. https://doi.org/10.1021/jp208930qS350435111161

Photoreactivity of fluoroquinolones: nature of aryl cations generated in water

The nature of stabilized aryl cations generated from photodehalogenations of fluoroquinolones in aqueous media has been studied by comparing the photophysical and photochemical behavior of lomefloxacin (LFX) and its N(40)-acetylated form (ALFX). Photoproduct studies, laser flash photolysis, and emission measurements have shown that this small peripheral modification produces important changes in the properties of the singlet aryl cations generated. Also, in basic medium, a new photodehalogenation pathway for 6,8-dihalogenated fluoroquinolones has been observed.Financial support from Spanish government (CTQ2010-19909) and the Generalitat Valenciana (PROMETEO program, ref 2008/090) is gratefully acknowledged.Soldevila Serrano, S.; Bosca Mayans, F. (2012). Photoreactivity of fluoroquinolones: nature of aryl cations generated in water. Organic letters. 14(15):3940-3943. https://doi.org/10.1021/ol301694pS39403943141