Singlet Molecular Oxygen Reactions with Nucleic Acids, Lipids, and

Review pubs.acs.org/CR

Cite This: Chem. Rev. XXXX, XXX, XXX−XXX

Singlet Molecular Oxygen Reactions with Nucleic Acids, Lipids, and Proteins Paolo Di Mascio,*,† Glaucia R. Martinez,‡ Sayuri Miyamoto,† Graziella E. Ronsein,† Marisa H. G. Medeiros,† and Jean Cadet*,§ †

Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, CP 26077, CEP 05508-000, São Paulo, SP Brazil Departamento de Bioquímica e Biologia Molecular, Setor de Ciências Biológicas, Universidade Federal do Paraná, 81531-990 Curitiba, PR, Brazil § Département de Médecine Nucléaire et Radiobiologie, Faculté de Médecine des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, J1H 5N4 Québec, Canada

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‡

ABSTRACT: Singlet oxygen (1O2) is a biologically relevant reactive oxygen species capable of efficiently reacting with cellular constituents. The resulting oxidatively generated damage to nucleic acids, membrane unsaturated lipids, and protein components has been shown to be implicated in several diseases, including arthritis, cataracts, and skin cancer. Singlet oxygen may be endogenously produced, among various possibilities, by myeloperoxidase, an enzyme implicated in inflammation processes, and also efficiently in skin by the UVA component of solar radiation through photosensitization reactions. Emphasis is placed in this Review on the description of the main oxidation reactions initiated by 1O2 and the resulting modifications within key cellular targets, including guanine for nucleic acids, unsaturated lipids, and targeted amino acids. Most of these reactions give rise to peroxides and dioxetanes, whose formation has been rationalized in terms of [4+2] cycloaddition and 1,2-cycloaddition with dienes + olefins, respectively. The use of [18O]-labeled thermolabile endoperoxides as a source of [18O]-labeled 1O2 has been applied to study mechanistic aspects and preferential targets of 1O2 in biological systems. A relevant major topic deals with the search for the molecular signature of the 1O2 formation in targeted biomolecules within cells. It may be anticipated that [18O]-labeled 1O2 and labeled peroxides in association with sensitive mass spectrometric methods should constitute powerful tools for this purpose.

CONTENTS 1. Introduction 1.1. Chemical Sources of Singlet Oxygen: Focus on Naphthalene Endoperoxides 1.2. Photosensitized Generation of Singlet Oxygen 2. Nucleic Acids 2.1. Reactivity of the Nucleobase Moieties toward Singlet Oxygen 2.2. Oxidation Reactions of Nucleic Acids Model Compounds 2.2.1. Guanine Nucleosides and Nucleotides 2.2.2. Guanine−Amino Acid Cross-Links 2.2.3. 8-Oxo-7,8-dihydroguanine Components 2.2.4. 8-Methoxy-2′-deoxyguanosine 2.2.5. Thiobases 2.3. Isolated Nucleic Acids 2.3.1. DNA 2.3.2. RNA 2.4. Cellular DNA 2.4.1. Oxidation Reactions Triggered by a Chemical Source of Singlet Oxygen 2.4.2. Exogenous Photodynamic Agents as Generators of Singlet Oxygen

© XXXX American Chemical Society

2.4.3. Oxidizing Effects of UVA Radiation 3. Lipids 3.1. Lipid Hydroperoxide Formation 3.1.1. Unsaturated Fatty Acids 3.1.2. Cholesterol 3.1.3. Membrane Phospholipids 3.2. Lipid Hydroperoxide Reactions 3.2.1. Lipid Peroxyl RadicalsLight Emission (Russell Mechanism) 3.2.2. [18O]-Labeled Lipid Hydroperoxides and Singlet Oxygen Generation 3.2.3. Cholesterol and Phospholipid Hydroperoxides 3.2.4. Lipid Hydroperoxides and Reactive Nitrogen Species (Nitro-lipids) 3.2.5. Lipid Hydroperoxides and Hypohalous Species 4. Proteins 4.1. Cysteine 4.2. Methionine 4.3. Histidine 4.4. Tyrosine

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M O O O P R S T T U V W W X X Y AA

Received: September 7, 2018

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DOI: 10.1021/acs.chemrev.8b00554 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews 4.5. Tryptophan 4.6. Reaction with Amino Acids in Proteins 5. Conclusions and Perspectives Author Information Corresponding Authors ORCID Notes Biographies Acknowledgments References

Review

ground-state oxygen, a light-dependent mechanism called type II photosensitization (see below) (Figure 1).4,19,20 A typical reaction involves endogenous photosensitizers that, upon excitation by the UVA component of solar radiation, generate predominantly 1O2 as the main source of cellular biomolecule oxidation. Singlet oxygen is one of the major species responsible for the cytotoxic effects of photodynamic therapy (PDT) of cancerous tissues,21 and it is being implicated in diseases such as porphyria21 and cataracts.22 It is also associated with the defense mechanisms used by phagocytic cells against viruses and bacteria.23,24 In addition, 1O2 can trigger ultraviolet A (UVA)induced biological effects through activation of gene expression and oxidative genotoxicity and is involved in the lipoperoxidation process.25−29 1 O2 is a dienophile that exhibits a high reactivity toward electron-rich organic molecules such as olefins, dienes, and polycyclic aromatic compounds.30−34 Most biomolecules have unsaturated components that are excellent substrates for 1O2. This is the case of guanine for DNA, polyunsaturated fatty acids, cholesterol, and several amino acids including tryptophan, tyrosine, histidine, methionine, and cysteine. Herein, the reactions of 1O2 with these biological targets will be critically surveyed. We start this Review by briefly mentioning chemical and physical (photosensitization reactions) sources of 1O2 that we consider relevant to biological systems. Excellent reviews are available for both topics,35,36 and a more profound description is out of the scope of the present survey. We then continue focusing on the reactions of 1O2 with relevant biological targets: DNA, lipids, and proteins. The main oxidation pathways that are available for each of the three classes of biomolecules are reported, providing a detailed description of oxidation products that is completed by discussion of their mechanism of formation. In addition, strategies for detection of oxidized biomolecules that may be used for their search in biological samples are presented.

AA AC AC AD AD AD AD AD AE AE

1. INTRODUCTION In 1938, Kautsky described the ability of oxygen to quench the fluorescence of numerous dyes through an energy-transfer process, where an “activated” state of oxygen was produced.1 Formation of an excited state of dioxygen in photosensitized reactions was confirmed by Foote and Wexler.2,3 Ground-state oxygen is a triplet species O2 (3Σg−) that can absorb energy from triplet sensitizers, giving rise to an excited form of oxygen in its singlet state (1O2). In its first excited state, singlet oxygen (1Δg) has an energy of 22 kcal above that of the ground state, while the energetically higher singlet state (3Σg+) lies 37 kcal above triplet oxygen.2,4 Due to the fast deactivation of the latter excited oxygen species in aqueous solutions, only the first excited state (1Δg) will be considered in this Review; for simplicity, it will be abbreviated as 1O2 throughout the text. In biological systems, light-dependent and -independent processes (dark reactions) may generate 1O2.5 Examples of dark reactions (chemiexcitation) include reactions catalyzed by peroxidases (myeloperoxidase6) or oxygenases (lipoxygenases7), the reaction of hydrogen peroxide with hypochlorite or peroxynitrite,8−10 the thermodecomposition of dioxetanes,11−14 or the reaction of ozone with biomolecules (Figure 1).15,16 Besides, evidence has been provided from extensive model studies that the recombination of peroxyl radicals derived from biomolecules can lead to the release of 1O2 as the result of decomposition of transient tetroxides according to the concerted Russell mechanism.17,18 1O2 can also be generated in cells through energy transfer from triplet excited molecules to

1.1. Chemical Sources of Singlet Oxygen: Focus on Naphthalene Endoperoxides

Several chemical sources of 1O2 are able to convert, in the dark, molecular oxygen (O2) into 1O2 with almost quantitative yields.31,32,37 Among them one may quote the oxidation of hypochlorite (ClO−) by hydrogen peroxide (H2O2), the disproportionation of H2O2 catalyzed by MoO42−, the reduction of ozone by triphenylphosphite, and the base-catalyzed disproportionation of peracids (Figure 1). Unfortunately, conditions required by biological systems (aqueous environment, neutral pH, moderate temperature) are not compatible with these chemical sources of 1O2. Further, these compounds are also toxic and may have additional oxidizing features. Therefore, suitable 1O2 generators based on the thermolysis of endoperoxides have been widely employed.35,38 In general, endoperoxides of alkyl-substituted naphthalene derivatives are good generators of 1O2 (Scheme 1). Indeed, synthetic naphthalene endoperoxides that are able to release pure 1O2 upon gentle warming, and that can be labeled with stable isotopes (i.e., 18O2), are available for mechanistic studies in both aqueous solution and cells.35,38 The thermolysis of endoperoxides was investigated by Turro and co-workers,39 who showed that two mechanisms are possible: a diradical mechanism, which involves homolytic cleavage of a single C−O bond followed by possible loss of O2 (in a singlet or triplet state), and a mechanism involving the

Figure 1. Possible sources of 1O2. B


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Scheme 1. Formation of 1O2 upon Heating of Naphthalene Endoperoxides and Subsequent Trapping by Anthracene Derivatives Used as Probes for 1O2 Detection

Another important point is the optimization of the molecular properties of such naphthalene-based carriers for the controlled release of 1O2. For this purpose, Posavec et al.44 designed the synthesis of two novel, functionalized naphthalene derivatives with different polarity using 1,4-dimethylnaphthalene as the starting molecule. The introduction of hydrogen-bonding motifs in the periphery of the compounds has been shown to influence the endoperoxide decay kinetics. Utilization of endoperoxide derivatives for photomedical applications has gained increased attention over the years.45,46 The use of the corresponding [18O]-labeled naphthalene endoperoxide coupled to mass spectrometry analysis of oxidized targets is suitable for the elucidation of 1O2 oxidation reaction mechanisms in biological media.38 This is a relevant tool for investigations that require the specific identification of the 1O2mediated oxidation products. In order to synthesize [18O]-labeled naphthalene endoperoxides, a primary source of [18O]-labeled 1O2 is necessary. This could be achieved using a type II photosensitizer and [18O]labeled O2. Until now, only the synthesis of the labeled endoperoxide from the naphthalene derivative DHPN has been reported.38 In contrast to thermolabile naphthalene endoperoxide derivatives, the anthracene endoperoxides are stable are room temperature and therefore can be used as probes (chemical traps) for the detection of 1O2 in biological samples. These probes react with [18O]-labeled 1O2, yielding the corresponding labeled endoperoxides that can be specifically detected by mass spectrometry47,48(Scheme 1). Chemical trapping of 1O2 is usually carried out with either lipo-soluble or water-soluble anthracene derivatives. For instance, when using [18O]-labeled lipid hydroperoxides as sources of 1O2, the specific detection and quantification of generated [18O]-labeled 1O2 was achieved using either 9,10-diphenylanthracene (DPA) or the watersoluble disodium salt of anthracene-9,10-diyldiethane-2,1diyldisulfate (EAS) as the chemical trap.49−52 The formation of the corresponding DPA or EAS endoperoxides that contain labeled oxygen (EAS18O18O or DPA18O18O) was monitored and quantified by HPLC-MS/MS measurements50,51 (Scheme 1). An important issue concerning labeling experiments is that 1 O2 is able to transfer energy to molecular oxygen in the ground state (3Σg−) with subsequent conversion into the singlet state (1Δg) in aqueous solution.53 Support for the occurrence of this reaction was provided by experiments performed using DHPN18O2, a chemical generator of 18O2 (1Δg), and the water-soluble disodium salt of EAS as a chemical trap of 1O2. The products of the reaction were analyzed by mass spectrometry measurement after HPLC purification of the oxidized probe. These data contributed to explain previous reported results where the formation of unlabeled products was detected (around 40−50%) despite DHPN18O2 generator showing an isotopic labeling close to 95%.

concerted cleavage of both C−O bonds. The primary yield of 1 O2 is relatively low in the diradical mechanism and is nearly quantitative in the concerted mechanism. The researchers also showed that the structure of the endoperoxide may favor one pathway or the other. The formation of endoperoxides involves a [4+2] cycloaddition of 1O2 to the electron-rich atoms of the naphthalene ring. The stability of the endoperoxides strongly depends on their structure and the temperature. In general, the main structural effects that determine endoperoxide stability are the number of fused rings and the presence of electron-rich substituents on the aromatic system, which increase stability and steric effects40 (Scheme 1, green arrows). The ideal condition is achieved when the compound may be formed and stored at low temperature and then used at the desired temperature upon heating. The naphthalene itself does not react with 1O2, and the direct binding of electron-attractive groups to the aromatic core further decreases its reactivity. Therefore, electron-donating groups must be present on the 1 and 4 positions to enhance the [4+2] cycloaddition of 1O2 and to stabilize the endoperoxide thus formed.41 For biological purposes, the water solubility of endoperoxides is essential, and hydrophilic substituents must be introduced on the 1,4-dimethylnaphthalene backbone. Examples of suitable naphthalene derivatives are the sodium 3,3′-(1,4naphthylidene)dipropanoate (NDP) and N,N′-di(2,3-dihydroxypropyl)-3,3′-(1,4-naphthylidene)dipropanamide (DHPN) (Scheme 1). Interestingly, these naphthalene derivatives did not show any cellular toxicity at the concentration employed to generate enough 1O2 to produce a biological response.42,43 Another key parameter is the cell penetration of the bulky endoperoxides across the cellular membrane. In that respect, only DHPNO2 was found to be able to enter human skin fibroblast cells and release 1O2 in the intracellular milieu.26

1.2. Photosensitized Generation of Singlet Oxygen

Absorption of light by a photosensitizer in the ground state (S) leads to its excitation in the singlet state (1S*) (Figure 2). This short-lived state is rapidly converted through intersystem crossing into a more stable, longer lifetime species, the triplet excited state (3S*). The photosensitizer in its triplet excited state is able to trigger two distinct photosensitized oxidation pathways, called type I and type II reactions. The type I and type II mechanisms were originally defined by Foote4 and have C


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cell membrane photo-peroxidation depends on factors such as the lipophilicity of the photosensitizer61 and the concentration of O2 and lipid substrate (RH) with which 3S will get in contact.62 These parameters will critically affect the ability of the sensitizer to interact with the membrane and the rate by which it will react with O2 or the substrate. In type II-mediated oxidation, 1O2 reaction with olefins can proceed by three types of mechanisms63,64 (Scheme 2). The first Scheme 2. 1O2 Reaction with Olefins

Figure 2. Photosensitized oxidation reactions involving the type I and type II mechanisms.

been subsequently revisited.20,54 Here we will only briefly summarize the two processes, indicating the main reactive species responsible for biomolecule oxidation. More detailed information on photosensitized production of 1O2 and its photophysical properties can be found in other excellent reviews.3,55−57 In type I processes, 3S* may participate in electron transfer or, less frequently, in hydrogen atom abstraction reactions with nearby suitable molecules or solvent, producing radicals or radical ions.4 These primary radicals are often involved in subsequent electron-transfer and hydrogen-atom-transfer reactions. One reported reaction is the generation of superoxide anion radical (O2•−) by electron transfer from the sensitizer radical anion to molecular oxygen.4 Further, the neutral carboncentered radicals directly formed by hydrogen atom abstraction or after deprotonation of the initially generated radical cation can subsequently react either with oxygen or, less frequently, with superoxide anion radical (O2•−) to produce oxygenated products (peroxyl radicals, peroxides).20 Peroxyl radicals produced in type I reactions can, for instance, initiate the oxidation of biomolecules by promoting hydrogen atom abstraction. In type II reactions, 3S* transfers its excitation energy to ground-state molecular oxygen with subsequent generation of 1 O2. Energy transfer from triplet sensitizer to triplet oxygen is a spin-allowed process, and for most triplet-state sensitizers the reaction occurs with a rate constant in the order of 1 × 109−3 × 109 M−1 s−1.19 Therefore, this process is rather favorable under conditions where oxygen is available, being responsible for the efficient photosensitized generation of 1O2.3,58 As described above, 1O2 has two metastable states with the notations 1Σg+ (37 kcal) and 1Δg (22 kcal). Early photochemical studies detected the production of both species. However, only the lowest singlet 1 Δg is considered as the major excited species responsible for biomolecule oxidations.4 No evidence was found for organic molecule oxygenation involving the excited sigma state (1Σg+).59,60 Both the free radical intermediates issued from type I reactions and 1O2 generated by energy transfer through a type II mechanism can be involved in the oxidation of biomolecules. The generation of hydroperoxides (ROOH) exemplifies these photosensitized oxidation reactions (Figure 2). For example, the photosensitized oxidation of membrane lipids is one of the primary events that can occur in photodynamic induced cell death. The relative importance of type I vs type II reactions in

type is 1,2-cycloaddition ([2+2] cycloaddition) to a double bond to generate 1,2-dioxetanes (Scheme 2).65 This kind of reaction occurs preferentially with electron-rich or sterically hindered olefins, such as enol ethers, enamines, ketenes, and thioketenes. The cyclic peroxide (1,2-dioxetane) is quite unstable, cleaving into two carbonyl fragments, one of which is in the excited state.13,14,66 The second type, known as an “ene”-type reaction, was described initially by Schenck in 1953.67 Olefins containing allylic hydrogen react with 1O2 to form allylic hydroperoxides in which the double bond is shifted to the adjacent carbon.68 Singlet oxygen attack to the double bond proceeds stereospecifically in a suprafacial manner with respect to the unsaturated bond such that hydrogen removal occurs on the same side of 1O2 approach.64 It has been suggested that this reaction occurs through a stepwise process involving a perepoxide intermediate69 (Scheme 2). However, Singleton, Foote, and Hook proposed a “two-step no-intermediate” mechanism for the 1O2 addition to simple alkenes (e.g., cis-2butene, tetramethylene) on the basis of several theoretical calculations and experimental data on 13C and 2H isotope effects.70 The proposed mechanism involves a two-adjacent transition state without intermediate, and the reaction proceeds mostly like a “concerted” reaction. Nonetheless, more recent theoretical calculations and experimental studies still discuss the plausible involvement of perepoxide intermediate in some few cases.69,71 The third type of mechanism of reaction is the [4+2] cycloaddition to produce endoperoxides (Scheme 2).72 This reaction is analogous to a Diels−Alder reaction in which 1O2 acts as a dienophile. A singlet oxygen reaction involving simple openchain or cyclic dienes is expected to proceed via a stepwise path involving a polarized diradical intermediate, while reaction with aromatic dienes is predicted to proceed through concerted mechanisms.71,73 D


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It should be noted that the detailed mechanisms by which these three types of reactions can occur have been extensively investigated and are still under debate.30,64 Here, only the overall features of the three types of 1O2 reactions are summarized. There are several mechanistic studies discussing the concerted versus non-concerted reactions that can occur with the intermediacy of biradical, zwitterion, perepoxide, or a chargetransfer complex,63,69,74,75 and those topics have not been completely covered in this section.

Scheme 3. Main Oxidative Degradation Pathways of 2′Deoxyguanosine Induced by 1O2, •OH, and One-Electron Oxidants

2. NUCLEIC ACIDS The nucleobases and the sugar moiety of nucleic acids including either 2-deoxyribose for DNA or ribose for RNA are potential targets of oxidative reactions mediated by several reactive oxygen species (ROS) and one-electron oxidants.76−80 Among ROS, the highly reactive hydroxyl radical (•OH) and the predominant selective singlet oxygen molecule in the 1Δg state are the most damaging oxidants of cellular DNA.81,82 It is worth mentioning that 1O2 is the main contributor to oxidatively generated damage to DNA in cells and human skin upon exposure to the UVA component of solar radiation.83,84 This explains the major interest that has been devoted during the past 40 years to the elucidation of the oxidation reactions triggered by 1 O2 with emphasis on the identification and mechanistic aspects of final degradation products. Available data are critically reviewed in this section, thus allowing proposal of comprehensible oxidative degradation pathways that are applied, with some differences, to model compounds, isolated DNA, and, more recently, cells and skin.17,85−88

Table 1. Total Rate Constants for Quenching of 1O2 by Nucleic Acid Components in Organic Solvents and Aqueous Solutions solvent

kr + kq, M−1 s−1

Freon 113 − − − − acetone-d6 methylene chlorided2 benzene-d6 H2O

(3.0 ± 0.2) × 106 (1.8 ± 0.1) × 104 (5.8 ± 0.1) × 104 (1.1 ± 0.1) × 104 (6.9 ± 0.3) × 103 6.33 × 106 1.42 × 106

nucleic acid component 89

guanosine adenosine89 cytidine89 uridine89 thymidine89 guanosine89,90 guanosine91

2.1. Reactivity of the Nucleobase Moieties toward Singlet Oxygen

Relevant information on the reactivity of nucleic acid components toward 1O2 was gained from both their ability to chemically quench this ROS and their susceptibility to undergo oxidative degradation. All the published data support the conclusion that guanine is the preferential target among the canonical pyrimidine and purine bases of 1O2-mediated oxidation reactions, with notable differences with respect to other oxidizing agents, including •OH and one-electron oxidants29 (Scheme 3). Preliminary reactivity data were provided from the consideration of the total quenching rate constant (kt), the sum of chemical quenching (kr) and physical quenching (kq) that were determined by the measurement of the decay rate of 1O2 nearinfrared (NIR) luminescence at 1270 nm in both organic solvents and aqueous solutions (Table 1). The reactivity of the base moiety of suitably sugar derivatized nucleosides in Freon 113 (1,1,2-trichlorotrifluorethane) toward 1 O2 was found to decrease in the order guanine ≫ cytosine > adenine > uracil > thymine,89 as observed using more direct methods (vide inf ra). The total quenching rate constant of 1O2 for guanosine (Guo), the most reactive ribonucleoside, was shown to depend on the organic solvent with values varying from 1.42 × 106 M−1 s−1 in methylene chloride-d2 up to 6.33 × 106 M−1 s−1 in acetone-d6 (Table 1).89−91 Similar kt values around 5.3 × 106 M−1 s−1 were obtained for 2′-deoxyguanosine (dGuo) and 2′-deoxyguanosine 5′-monophosphate (dGMP) in aqueous solutions92,93 with photodynamic dyes operating through the predominant type II photosensitization mechanism20 as the sources of 1O2. Interestingly, an almost identical kt value was obtained (Table 1) with a pure source of 1O2 that was released from the thermally unstable 3,3′-(naphthylidene)

guanosine91 2′-deoxyguanosine 5′phosphate92 2′-deoxyguanosine93 2′-deoxyguanosine85

H2O H2O

1.75 × 106 5.3 × 106 ∼5 × 106 5.2 × 106

dipropionate endoperoxide (NDPO2).94 It may be noted that the chemical quenching rate constant of 1O2 by Guo (kr = 1.36 × 105 M−1 s−1), one of the most reactive nucleic acid components, was determined in acetone-d6 using a competition reaction with tetramethylethylene as the specific chemical quencher of 1 O2.90,91 Chemical quenching appears to contribute as a minor process (2%) of total quenching. The first experiment assessing the reactivity of nucleic acids components toward 1O2 was based on the susceptibility for purine and pyrimidine nucleotides to be decomposed in aqueous solutions upon exposure to UVA-excited methylene blue (MB).95 This photosensitizer predominantly generates 1 O2, although it also acts as a type I photosensitizer through oneelectron oxidation.96−98 The guanine base of dGMP was found to be the preferential target of the 1O2-mediated degradation over thymidine 5′-monophosphate (dTMP), whereas uridine 5′-monophosphate (UMP), 2′-deoxycytidine 5′-monophosphate (dCMP), and 2′-deoxyadenosine 5′-monophosphate (dAMP) were found to be unaffected.95 A similar trend was observed when DNA from Bacillus natto, Pseudomonas aeruginosa, or Bacillus subtilis was photo-oxidized by MB.95 It was also shown that denaturation of DNA increases the E


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Scheme 4. 1O2 Oxidation Products of the Base Moiety of Free 2′-Deoxyguanosine

susceptibility of the bases95,99 that however is not influenced by the nature of the sugar moieties.100 Similar data emphasizing the high reactivity of guanine components in DNA or isolated nucleosides toward 1O2 were gained from photooxidation experiments involving either lumichrome101−103 or acridine orange104 as the photodynamic dyes. Subsequently, attempts were made by using chemical sources of 1O2 to confirm that the conclusion of photodynamic studies on the guanine reactivity toward 1O2 may be partly affected by the occurrence of side oxidation reactions involving type I photosensitization mechanism. Thus, exposure of nucleic acid components to chemically generated 1O2 by the reaction of sodium hypochlorite (NaOCl) with hydrogen peroxide (H2O2)4 was indicative of the preferential degradation of guanine nucleosides and nucleotides, whereas related thymine and uracil derivatives were only slightly decomposed.105 These data received further support from reactivity studies that involved the generation of 1O2 by microwave discharge on a stream of molecular oxygen (O2).106,107 However, the unexpected relatively high oxidation susceptibility that was observed for pyrimidine components could be explained by the side formation of ozone, which has been shown to react efficiently with thymidine and 2′deoxycytidine.108,109 Another chemical source of 1O2 that is produced by the thermal decomposition of solid potassium peroxochromate (K3CrO8) in aqueous solutions has been used to investigate the susceptibility of pyrimidine and purine nucleobases and nucleosides to this oxidant. Surprisingly, it was found that the extent of modifications was similar for guanine, thymine, and cytosine,110 in contrast to previous studies showing that guanine (G) is the preferential target of 1 O2. This unexpected observation was rationalized in terms of significant generation, in addition to 1O2, of highly reactive • OH111 that efficiently reacts with all nucleic acid components. Therefore, it is a requisite to add a scavenger of •OH such as methanol to the aqueous solutions of K3CrO8 in order to investigate 1O2 reactions with this oxidizing system. A relevant alternative for generating a clean source of 1O2 as already discussed involves the thermal decomposition of naphthalene endoperoxides.35,112 Exposure of isolated DNA to naphthalene endoperoxides led to the exclusive formation of 8-oxo-7,8dihydroguanine (8-oxoG),113 thus indirectly confirming that

guanine (Scheme 3) is the exclusive target of 1O2 reaction with DNA components. This was further supported by recent theoretical studies that showed that only guanine is able to react among DNA canonical bases with 1O2.114−116 2.2. Oxidation Reactions of Nucleic Acids Model Compounds

Among pyrimidine and purine DNA bases, guanine, which possesses conjugated double bonds rich in electrons, is the specific target for the dienophile 1O2, with the exception of a few thiopurine components, 8-methoxyguanine and 8-oxo-7,8dihydroguanine (8-oxoG) derivatives, as discussed further below. The reactivity of 1O2 toward guanine is increased at alkaline pH values that favor the formation of a more reactive [G−H]− intermediate.117 It may be pointed out that studies aimed at characterizing the guanine oxidation products were hampered, until the beginning of the 1980s, by the low solubility of guanine in water. Furthermore, the high polarity of guanine oxidation products made their separation a challenging analytical issue that was partly overcome with the advent of high-performance liquid chromatography (HPLC) separation techniques. Another major difficulty concerns the poor structural information that may be inferred from 1H NMR measurements of the modified bases of oxidized guanine components, since in most cases they have lost the unique non-exchangeable H8-proton. This was overcome using 15N NMR and two-dimensional 1H and 13C NMR techniques that allowed the assignment of the two main dGuo oxidation products as 2, 2-di amino-4-[(2-deoxy- β- D -eryth ropentofuranosyl)amino]-5-(2H)-oxazolone (dOz) and 2amino-5-[(2-deoxy-β-D-erythro-pentofuranosyl)amino]-4Himidazol-4-one (dIz).118,119 Relevant structural information could also be gained from electrospray ionization−tandem mass spectrometry (ESI-MS/MS) analysis.120 It may be remembered that the three main identified reactions of 1O2 with olefins are [4+2] Diels−Alder cycloaddition, [2+2] cycloaddition, and the ene reaction that lead to endoperoxides, dioxetanes, and allylic hydroperoxides, respectively.3,70,86 In the case of nucleic acids, the most evidence has been provided for the occurrence of the first two reactions, which are further discussed in the subsequent sections. F


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2.2.1. Guanine Nucleosides and Nucleotides. Most of the mechanistic studies have been established from the characterization of transient and final oxidation products of model compounds including guanine (Scheme 4), related nucleosides, and guanine-containing dinucleoside monophosphates before receiving confirmation from recent theoretical studies.114−117 2.2.1.1. Identification of the Oxidation Products. Initial attempts to characterize 1O2 oxidation products of guanine involved tedious and poorly resolved paper chromatographic separations that allowed isolation of secondary oxidation products arising from extensive degradation of the purine moiety. Thus, exposure of [14C]-labeled guanine at different positions to visible-light-excited lumichrome in aerated aqueous solutions (pH 7) gave rise to radioactive parabanic acid, guanidine, and CO2.103 Parabanic acid, which has been shown to be a secondary 1O2 oxidation product of transiently generated 8oxoG in a single-stranded 15-mer oligonucleotide,38 was found to be easily converted into oxaluric acid under alkaline conditions of paper chromatography analysis.103 In a subsequent study urea, N-(β-D-erythro-pentofuranosyl)urea, free ribose, and guanidine were identified among the oxidation products of guanosine upon MB photosensitization.121 The lability of the N-glycosidic bond of N-(β-D-erythropentofuranosyl)urea is likely to explain the release of urea with concomitant formation of free ribose. The presence of guanidine is accounted for by the generation of Oz as a secondary 1O2 oxidation product of 8-oxo-7,8-dihydroguanosine (8-oxoGuo)120 and its subsequent degradation under mild alkaline conditions119 as those used for the photosensitized experiments. N-(2-Deoxy-β-D-erythro-pentofuranosyl)cyanuric acid, another 1 O2 oxidation product of 8-oxodGuo,122 was isolated by twodimensional thin-layer chromatography (TLC) upon exposure of dGuo in aerated aqueous solutions to either photoexcited MB or 1O2 produced by the NaOCl−H2O2 mixture or radiofrequency discharge.77,122 The first evidence showing that 8-oxoG is a relevant primary 1 O2 oxidation product of guanine was obtained using thiazin dyes as the photosensitizers and isolated DNA and not model compounds as the target.123−125 Thus, the guanine oxidation product that was detected in an independent study as a formamidopyrimidine DNA N-glycosylase-sensitive site126 was identified as 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodGuo) after suitable enzymatic digestion of oxidized DNA.123−125 This was achieved using a sensitive method that associates HPLC separation with an amperometric detector operating in the oxidative mode at the output of the column.127 This also resulted in the discovery of 8-oxodGuo as the main radical oxidation product of dGuo upon exposure to Udenfriend’s reagent,128 which consists of ascorbic acid, ferrous ion, ethylenediaminetetraacetic acid (EDTA), and O2. It may be added that 8-oxodGuo, which appears to be a ubiquitous DNA oxidation product, was a few years later identified as one of the main guanine products of one-electron oxidants.129,130 It was rapidly confirmed that 8-oxodGuo is also generated, however, in relatively low yields, reaching a plateau that is about 1% of dGuo upon exposure of the guanine nucleosides to either a clean source of 1O2 or UVA-excited phthalocyanines and naphthalocyanine131 as type II photosensitizers. Unambiguous characterization of 8-oxodGuo- and 8-oxoG-containing dinucleotide formed upon 1O2-mediated oxidation of dGuo131−133 and thymidylyl (3′,5′)-2′-deoxyguanosine (d(TpG)),134 respectively, was accomplished using a wide array of analyses,

including fast atom bombardment mass spectrometry measurements. The two main primary 1O2 oxidation products of dGuo that were formed upon exposure to excited MB were initially isolated as two diastereomeric 3′,5′-di-O-acetylated derivatives135 and subsequently as part of modified dTpG136 and non-derivatized nucleosides.131−133 The two main dGuo oxidation products that were purified by HPLC on a polar amino-substituted silica gel column137 were tentatively assigned on the basis of 13C NMR and mass spectrometry features as the 4R* and 4S* diastereomers of 4-hydroxy-8-oxo-4,8-dihydro-2′-deoxyguanosine (4-OH-8-oxodGuo)138 following earlier proposals that stem from the transient formation of diastereomeric 4,8endoperoxides as the initial 1O2 cycloadducts within the imidazole ring.92,135,139,140 The two overoxidized dGuo products were reassigned as the diastereomeric pair of N-(2deoxy-β- D -erythro-pentofuranosyl)spiroiminodihydantoin (dSp).141 This was achieved indirectly by showing that the two main MB UVA-sensitized photooxidation products of Guo141 were identical to the main one-electron oxidation products of 8oxoGuo in neutral and slightly alkaline aqueous solutions. It was concluded that the oxidized guanine nucleosides were the 4R* and 4S* diastereomers of N-(β-D-erythro-pentofuranosyl)spiroiminodihydantoin.142,143 This also rules out another earlier suggestion128 implicating unstable 5-hydroxy-8-oxo-4,8-dihydroguanosine (5-OH-8-oxoGuo) that is, in fact, the precursor of dSp. The reassignment was mostly made by considering similar rearrangement reactions of 5-hydroxyurate144 and an oxidation product of C8-arylamine of guanine145 that give rise respectively to related spiroiminodihydantoin compounds. The presence of a spirocyclic connectivity in dSp diastereomers was further established on the basis of unambiguous SELINQUATE 13C NMR measurements.146 Evidence that most of the dSp products arise from a direct 1O2-mediated oxidation pathway at the early stage of the degradation of dGuo was provided by the use of [18O]-labeled 1O 2 (Scheme 4) and HPLC-ESI-MS/MS measurements of the oxidized 2′-deoxyribonucleosides.147,148 The absolute configuration of the 4R and 4S diastereomers of dSp, that was initially assigned by considering NOE measurements,149 was recently confirmed by detailed biochemical, spectroscopic, and computational studies.150 It should be pointed out that the ribonucleoside derivatives of guanidinohydantoin (Gh) are preferentially formed at the expense of Sp in acidic aqueous solution of Guo exposed to 1O2.151,152 In agreement with earlier postulates,92,135,139,140 it was confirmed on the basis of HPLC-MS/MS measurements that the 4R* and 4S* diastereomers of 4-OH-8-oxodGuo are formed by 1O2 oxidation of dGuo, however with a low efficiency.153 Additionally, another minor product was identified as 2,5-diimino-4-[(2deoxy-β-D-erythro-pentofuranosyl)amino]-2H,5H-imidazole (dD) among the degradation products of dGuo upon MB photosensitization.154 However, it remains to assess whether dD is formed through 1O2-mediated degradation pathway and not from one-electron oxidation reaction of the 8-oxoG moiety, since MB is known to also operate according to the type I photosensitization mechanism. 2.2.1.2. Mechanisms of Singlet Oxygen Oxidation Products of Guanine Nucleoside and Nucleotide Constituents. Most of the primary oxidation products of the components of the nucleic acid guanine have been isolated and characterized through extensive spectroscopic measurements, as discussed above. This allowed, in agreement with the known 1O2 reactions with alkenes and dienes, comprehensive mechanistic pathways to be G


Chemical Reviews

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Scheme 5. Secondary 1O2 Oxidation Products of 8-Oxo-7,8-dihydroguanine-Containing Oligonucleotide

conditions or guanidinohydantoin (Gh) through hydration at C6 and subsequent decarboxylation at acidic pHs.148,151,156 Competitive reduction of the 8-peroxo intermediate was found experimentally to occur as a minor process in a relative 1:1 ratio with respect to dehydration for the nucleosides. The resulting 8enol guanine tautomer is in dynamic equilibrium with predominant 8-oxodGuo, the more stable 6,8-diketo tautomer.161,162 It was found that the presence of thiols25 or Fe2+ ions156 in the aqueous solutions dGuo exposed to 1O2 led to a substantial increase in the formation of 8-oxodGuo, likely at the expense of dSp, thus providing further support to the transient formation of reducible 8-hydroperoxyguanine intermediate. The less favored decomposition pathway of guanine endoperoxides is the cleavage of the O−O bond that leads to minor amounts of 4-hydroxy-8-oxo-4,8-dihydroguanine (4-OH-8-oxoG) after protonation of an anionic intermediate.116 It should be pointed out that secondary formation of dSp occurs as soon as the level of 8oxodG reaches 0.6−0.8% as the result of preferential 1O2 oxidation of the latter substrate, as further discussed in a subsequent section. 2.2.2. Guanine−Amino Acid Cross-Links. Evidence has been provided for the 1O2-mediated formation of adducts between Guo as the free nucleoside or when inserted into oligonucleotides and several amino acids, including lysine, histidine, and arginine.163 Interestingly, amino-substituted dSp adducts are formed upon rose bengal (RB) photosensitization of dGuo in aerated aqueous solutions of NH4Cl.164 The main addition products were identified as C5-substituted spiroiminodihydantoin adducts, whose formation is rationalized in terms of nucleophilic addition. For example, addition of lysine through one of its two amino groups to the highly reactive electrophilic quinonoid intermediate arising from dehydration of rearranged 8-hydroperoxyguanosine was shown to occur. This was confirmed by computational studies showing that addition of lysine, which occurs more efficiently than that of water, is barrierless.116 However, the formation of guanine−protein cross-links upon 1O2 exposure does not appear to be an efficient process in double-stranded DNA, since the generation of the reactive quinonoid intermediate is prevented while reduction of 8-hydroperoxyguanine is favored.76,82,116,164 As a further support for this lack of reaction, the expected tris(hydroxymethyl)aminomethane−guanine cross-links,165 the likely 5-substituted spiroiminodihydantoin compounds, formed in aerated solutions of guanine nucleosides or nucleotides upon

proposed for the formation of the main guanine oxidation products, but these were recently challenged by detailed theoretical calculations.114−117,155 Thus, the generation of the three main 1O2 oxidation products of dGuo as a free nucleoside or when part of a dinucleoside monophosphate was rationalized in terms of initial Diels−Alder [4+2] cycloaddition that involves the 7,8- and 4,5-ethylenic bonds of the imidazole ring, giving rise to a mixture of two diastereomeric 4,8-endoperoxides.156 Interestingly, characterization of related intermediates was achieved by 13C NMR measurements performed on aerated CD2Cl2 solutions of 2′,3′,5′-O-tert-butyldimethylsilyl)-8-methylguanosine that were subjected to type II photosensitization at low temperature (−80 °C).140 Further support for the 1O2mediated formation of guanine 4,8-endoperoxides that, however, were not detected among the sensitized photooxidation products of 2′,3′,5′-O-tert-butyldimethylsilyl)[8-13C]-guanosine in CBr2F2 at low temperature (−100 °C)157 by 2,9,16,23-tetra-tert-butyl-19H,31H-phthalocyanine was provided by detailed computational studies.114−117,155 However, evidence for the 1O2-mediated formation of transient guanine 4,8-endoperoxide in the gas phase was provided by guided-ion-beam mass spectrometry measurements.158 As an alternative to the concerted 1O2 [4+2] photocycloaddition that has been found for benzene and anthracene,73,159 a two-step pathway initiated by the formation of a zwitterionic peroxyl intermediate according to a barrier-less reaction profile was proposed on the basis of either closed-shell reference calculations114,115,155 or open-shell density functional theory (DFT) computations.116 The stepwise syn addition of 1O2 to C8 of the imidazole ring of G, followed by cyclization and subsequent formation of the guanine endoperoxides, appears to be the more favorable pathway.109 A different mechanism that involved, in the initial step, the formation of an 8-peroxide was proposed from computational studies for the deprotonated form of guanine [G−H]− 117 and 9-methylguanine.160 A common decomposition route to the main primary stable G oxidation products involves a rearrangement of the unstable 4,8endoperoxides with the loss of H8 proton and the concomitant formation of an 8-peroxyguanine cation. Subsequent dehydration, which is the main pathway for isolated nucleosides, gives rise to a highly reactive quinonoid that, in the presence of water, generates transient 5-OH-8-oxoG. The latter intermediate is known to rearrange into either spiroiminodihydantoin (Sp) via an acyl shift under neutral and slightly alkaline H


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Scheme 6. 1O2 Oxidation of 8-Methoxy-2′-deoxyguanosine

exposure to 1O2, are not generated in double-stranded DNA. It is worth mentioning that other DNA cross-links have been shown to be formed upon one-electron oxidation of guanine. The amino group of lysine embedded into a tripeptide or polyamines has been found to efficiently react by nucleophilic addition to the C8 position of guanine radical cation, thus giving rise to 8substituted guanine adducts.166,167 Confirmation of the mechanism of guanine−lysine cross-link formation initiated by one-electron oxidation of guanine was recently provided by theoretical studies.168 2.2.3. 8-Oxo-7,8-dihydroguanine Components. The high susceptibility of 8-oxoGuo components to 1O2, that has been estimated to be about 2 orders of magnitude higher than that of Guo,90 explains the efficient consumption of 8-oxodGuo as soon it is produced by type II photosensitizers in aerated aqueous solutions of dGuo.133 This was inferred from the measurement of the rate of the chemical quenching (kr = 1.92 × 107 M−1 s−1) by 1O2 with 2′,3′,5′-tris(tert-butyldimethylsilyloxy)-8-oxo-7,8-dihydroguanosine in acetone-d 6 using 5,10,15,20-tetraphenyl-21H,23H-porphine as the type II photosensitizer.90 2.2.3.1. 8-Oxo-7,8-dihydro-2′-deoxyguanosine. The first comprehensive study aimed at identifying the 1O2 oxidation degradation products of 8-oxodGuo using MB as the photosensitizer has allowed the isolation of four main oxidized guanine nucleosides (Scheme 5):169 (5R)- and (5S)-dSp, 2,2-diamino-4[2-deoxy-β-D-erythro-pentofuranosyl)amino]-5-(2H)-oxazolone (dOz), and 2-amino-5-[(2-deoxy-β- D -erythropentofuranosyl)amino]-4H-imidazol-4-one (dIz), its hydrolytically unstable precursor.119 In a subsequent study, N-(2-deoxyβ-D-erythro-pentofuranosyl)-cyanuric acid and 1,3,5-triazine1(2H)-carboximidamide, 3-(2-deoxy-β-D-erythro-pentofurano-

syl)-tetrahydro-2,4,6-trioxo- were identified through extensive H, 13C NMR, and FAB-MS measurements as additional 1O2mediated degradation products of 8-oxodGuo.122 However, the formation of the two latter, heavily modified 2′-deoxyribonucleosides was not confirmed when DNPNO2 or its related [18O]-labeled chemical source of 1O238 was used to oxidize 8oxodGuo (Scheme 5).147,148,156 This difference in the pattern of oxidation products may be explained by the fact that excited MB is not a pure generator of 1O2 but also acts as a one-electron oxidant of 8-oxodGuo through the type I mechanism.96,139 The latter reaction is likely to generate purine radical intermediates and also O2•− that may lead to additional oxidation products besides those induced by pure 1O2. It may be added that oxidized guanidinohydantoin 2′-deoxyribonucleoside (dGhox) has been characterized as an 1O2 oxidation product of 8oxodGuo, however with a low efficiency.147 A plausible mechanism for the formation of dSp, dOz, dZ, and dGhox involves, in the initial step, 1O2 addition across the 4,5-double bond of 8-oxodGuo, giving rise to an unstable dioxetane.147,148 as recently confirmed by theoretical studies.170 Subsequent cleavage of the O−O bond is expected to lead to the formation of transient 5-hydroperoxy-8-oxo-5,7-dihydro-2′-deoxyguanosine (5-OOH-8-oxodGuo), which may be reduced into 5hydroxy-8-oxo-5,7-dihydro-2′-deoxyguanosine (5-OH-8-oxodGuo). This is followed by purine rearrangement, involving an acyl shift of 5-OH-8-oxodGuo that leads subsequently to 5(R)- and 5(S)-dSp. The proposed oxidation pathway received further support from the characterization of initial 4,5endoperoxides171 and subsequently 5-OOH-8-oxodGuo172 by 13 C NMR and 2-D HMBC measurements that were performed at low temperatures in organic solvent solutions of the photosensitized TBDMS derivative of 8-oxoGuo. It may also 1

I


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Scheme 7. 1O2 Oxidation of 6-Thiouracil

mechanism of formation of the main oxidation products was rationalized in terms of initial generation of diastereomeric dioxetanes through initial [2+2] photocycloaddition of 1O2 across the 4,5-ethylenic bond of 8-MedGuo (Scheme 6). It was found that the 8-methoxy-substituted derivative of urea arises from the hydrolytic decomposition of O-MedSp. Additional experiments have shown that 1O2 oxidation of OMedGuo when inserted into a trinucleotide with thymidine residues at both the 3′ and 5′ ends leads to a more specific degradation pattern, with the predominant formation of both dOz and dIz. It is worth mentioning that similar oxidation product distribution was observed upon exposure of the trinucleotide to photoexcited riboflavin, a predominant type I photosensitizer operating through preferential one-electron oxidation of the guanine. This is in agreement with a previous study that showed that one-electron oxidation of O-MedGuo gave rise to the exclusive formation of dOz and Idz.176 2.2.5. Thiobases. The reactivity of photoexcited sulfursubstituted derivatives of nucleobases has received wide attention since these nucleic acid derivatives are potent generators of 1O2 and some of them are suitable substrates for oxidation reactions triggered by the latter ROS thus generated. Interestingly, the replacement of an oxygen atom of a carbonyl group of uracil by a sulfur atom leads to a significant redshift in the absorption spectrum, with a major change in the photophysical properties. These include an efficient population of the reactive long-lived triplet excited state with a yield close to unity as the result of a very fast intersystem crossing process.177 2.2.5.1. Thiopyrimidines. UVA irradiation of 4-thiouracil (4TU), a non-canonical base of tRNA molecules,178,179 has been shown to sensitize the efficient formation of 1O2178,179 as the result of O2 quenching of the triplet excited state, with a 90% quantum yield efficiency.180 1O2 thus generated is able to readily react with 4-TU (Scheme 7), giving rise predominantly to fluorescent uracil-6-sulfonate (USO3) together with uracil (U), however in lower amounts.181 Insights into the two competitive 1 O2 oxidation pathways of 4-TU were gained from time-resolved IR spectroscopy measurements and time dependent-density functional theory (TD-DFT) calculations at the B3LYP/6311+G(d,p) level.181 It was proposed that the formation of USO3 involves two successive 1O2 oxidation reactions. In the initial step, 1O2 addition to 4-TU gives rise to a peroxyl intermediate (USOOH) that efficiently rearranges into uracil-4-sulfinate (USO2) with a rate-limiting step showing a low energy barrier of only 1.9 kcal mol−1.180 Subsequent addition of 1O2 to USO2 generates the peroxy intermediate USO4 that is subjected to abstraction of an

emphasized that 5-OH-8-oxodGuo, which was obtained by mild dimethyl sulfide reduction of the hydroperoxide precursor at −40 °C, was unambiguously characterized by extensive NMR.172 2.2.3.2. 8-Oxo-7,8-dihydroguanine Containing 15-mer Oligodeoxynucleotide. Endoperoxide DHPNO2-mediated 1 O2 oxidation of the unique 8-oxo-7,8-dihydroguanine target that was site-specifically inserted as a nucleotide in a 15-mer oligodeoxynucleotide lacking guanine bases leads to the formation of overwhelming oxaluric acid at the exclusion of spiroiminodihydantoin (Scheme 5).38 This contrasts with the predominant generation of dSp diastereomers with lower amounts of dOz when isolated 8-oxodGuo was oxidized by a chemical source of 1O2.96 Despite this almost completely different pattern of final oxidation products, the initial oxidation pathway of the 8-oxoGcontaining oligomer that involves the formation of transient diastereomeric 4,5-dioxetanes is identical to that reported for 8oxodGuo.147,148 This applies as well to the subsequent cleavage of the endoperoxide bond that gives rise to 5-OOH-8-oxodGuo. At this stage, however, a major change takes place in the degradation path: the 5-hydroperoxide intermediate that is reduced into 5-OH-8-oxodGuo for the free nucleoside147 is converted into oxaluric acid (Oxa) in the 15-mer.38 This was rationalized in terms of C5−C6 bond opening of the pyrimidine ring consecutively to α-ketohydroperoxide cleavage and subsequent decarboxylation that gives rise to relatively stable dGhox (Scheme 5) that was unambiguously characterized as a metal−oxo porphyrin oxidation product of the guanine moiety of the dinucleoside monophosphate d(GpT).173 Hydration of the unsaturated C4N bond of the Schiff base and subsequent hydrolysis, accompanied by the release of guanidine, yielded parabanic acid (Pa). Further hydrolysis of poorly stable Pa gave rise to linear oxaluric acid (Oxa)38 upon cleavage of the C4−N9 bond, as further confirmed by detailed 1H NMR and mass spectrometry measurements.174 2.2.4. 8-Methoxy-2′-deoxyguanosine. 8-Methoxy-2′deoxyguanosine (O-MedGuo), which may be considered as the 8-methoxy-substituted derivative of the minor 8-enol tautomer of 8-oxodGuo, has been subjected to 1O2 oxidation upon thermal decomposition of either DHPNO2 or its [18O]labeled derivative.175 The main oxidation products that were detected by HPLC-ESI-MS/MS include predominantly dOz and its precursor dIz together with 8-methoxy-substituted nucleoside derivatives of spiroiminodihydantoin (O-MedSp) and oxidized iminoallantoin (O-MedIaox) and urea.175 The J


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Scheme 8. 1O2 Oxidation of 6-Thioguanine

formation of (GSO)193,194 was further supported by the fast rate constant (k = 4.9 × 109 M−1 s−1) of the reaction of 1O2 with 6TG, leading to GSO3.195 It may be added that the competitive generation of guanine occurs as a minor process in agreement with the unfavorable energy profile of the reaction.195 The generation of 1O2 by thiobases is expected to give rise to 8-oxodGuo in DNA. In addition, the formation of several other lesions, including tentatively DNA−protein and interstrand cross-links, has been proposed to occur upon exposure of 6-TGcontaining oligodeoxynucleotides to UVA radiation.196 However, no mechanisms are available so far to rationalize the generation of this complex DNA damage, the characterization of which awaits further experiments.

oxygen atom by a water molecule in a hydrogen-bond complex, thus giving rise to USO3 together with H2O2.181 The competitive formation of U was rationalized in terms of initial [2+2] cycloaddition of 1O2 across the CS bond of 4-TU. This leads to the formation of a dioxetane with a labile CS bond that, through rearrangement, gives rise to U and the release of SO.181 Other mono- and disulfur-substituted pyrimidine derivatives, including 2-thiouracil, 2,4-dithiouracil,182 2-thiothymine, 4thiothymine, 2,4-dithiothymine,183,184 and 2-thiocytosine,177,185 have been shown to be efficient 1O2 generators, an interesting feature for potentially photochemotherapeutic agents. However, so far, no evidence for a significant reactivity of these thiobases toward 1O2 has been provided. 2.2.5.2. 6-Thioguanine. Metabolization of several thiopurine derivatives, including azathioprine, 6-mercaptopurine, and 6thioguanine (6-TG), used as anti-cancer, immunosuppressive, and anti-inflammatory agents,186 leads to the incorporation of strongly UVA-absorbing 6-TG into nuclear DNA.187,188 Photophysical and photochemical studies have shown that 6-TG is an efficient type II photosensitization generator of 1O2189−191 through triplet−triplet energy transfer from the long-lived excited thionucleobase toward molecular oxygen.177,189,192 The 1 O2 quantum yield (ΦΔ = 0.24 ± 0.02) that was measured for UVA-excited 6-thio-2′-deoxyguanosine (6-TdGuo) in aerated aqueous solution189 was about 2-fold lower than that estimated in previous measurements.190 The difference was explained189 by the use of an empirical correction parameter close to 2 in the earlier study.190 The presence of 2-deoxyribose at the N9 position of 6-TdGuo leads to a decrease in the lifetime of the triplet manifold that is accompanied by a 2-fold reduction in the 1 O2 quantum yield.189 UVA irradiation of 6-TG either as the free nucleobase or embedded into short oligonucleotides gave rise to three photoproducts that were identified as guanine-6-sulfinate (GSO2),193 highly fluorescent guanine-6-sulfonate (GSO3),193−195 and guanine (Scheme 8).195 Mechanistic insights into the formation of GSO2 and GSO3 that implicates two 1O2 molecules were gained from extensive TD-DFT calculations. Similarly to the 1O2 oxidation of 4-TU, a peroxy intermediate (GSOOH) is initially generated before rearranging to GSO2 that is then converted into GSO3 after further reaction with a second 1O2 molecule (Scheme 8). This involves the transient formation of an unstable peroxy guanine compound (GSO4) that generates GSO3, likely through an interaction with a water molecule.195 The validity of the overall mechanism that is characterized by a low energy barrier reaction and the exclusion of putative transient

2.3. Isolated Nucleic Acids

Most of the measurements of 1O2-mediated oxidation products in nucleic acids have been performed by chromatographic methods involving HPLC analysis coupled with either electrochemical detection (HPLC-ECD) or electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). It may be emphasized that the majority of studies were devoted to the characterization and detection of base oxidation products generated in DNA with, however, a few reports on RNA. 2.3.1. DNA. Early attempts to identify 1O2-mediated oxidation products of bases that mostly concerned the guanine moiety were based on the use of MB123,125 and other thiazine dyes124 including azure A, azure B, toluidine blue, and thionine as the photosensitizers. In addition, low amounts of DNA strand breaks that are likely to occur as the result of the lability of secondary 1O2 oxidation products of 8-oxodGuo such as dOz were also quantified.123,125 In a subsequent study, the presence of dSp diastereomers was detected in a very low yield, about 1% of 8-oxodGuo, in calf thymus DNA upon MB photosensitization.138 The predominant formation of 8-oxodGuo was also observed in isolated DNA that was exposed to either mesotetra(4-N-methylpyridyl)porphyrin (p-TMPyP) or nonbinding meso-tetra(4-sulfatophenyl)porphyrin (TSPP), two type II photosensitization agents.197 The reactivity of 1O2 toward double-stranded DNA upon exposure to UVA excited RB is strongly reduced by comparison with the single-stranded form.88,162 Interestingly, the four guanine motifs in the G4 quadruplex structure of telomeres show a similar susceptibility to 1O2 oxidation, which is much higher with respect to that of duplex DNA.88 The main oxidation products in the overoxidized G4 quadruplex folds were identified as the diastereomeric pair of dSp together with dZ, K


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Scheme 9. 1O2 Oxidation of the Guanine Moiety of Isolated and Cellular DNA

dOz, and low amounts of 8-oxodGuo.88,162 This is explained by the formation of the latter secondary oxidation products at the result of efficient continuous consumption of initially generated 8-oxodGuo. In contrast, moderate oxidation of isolated DNA using DHPNO2 as a clean source of 1O2 led to the almost exclusive formation of 8-oxodGuo (Scheme 9). Under these conditions, the overall amount of damage that was measured by sensitive HPLC-ESI-MS/MS analysis was lower than 40 lesions per 106 normal bases.113 This is in agreement with recent HPLC-ESIMS/MS measurements of dSp and dOz, whose relative frequencies with respect to 8-oxodGuo were less than 10−2 in calf thymus DNA upon RB photosensitization.152 It may be pointed out that the level of dGh is barely detectable, being 10fold lower than those of dSp and dOz. These data further confirm that the dehydration pathway of 8-OOHdGuo, giving rise to reactive quinonoid intermediate, previously observed in isolated nucleoside, does not take place, at least in detectable amounts, upon 1O2 oxidation of native DNA. Therefore, the overwhelming formation of 8-oxodGuo under conditions of moderate exposure to 1O2 is accounted for by the predominant reduction of transient 8-OOHdGuo, the rearrangement product of initially generated guanine 4,8-endoperoxides. The lack of quinonoid formation is also expected to prevent the generation of DNA−protein as well. It may also be pointed out that the formation of 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG), that was proposed to be a 1O2 oxidation product of DNA,198 has been ruled out, in agreement with the wellestablished 1O2-mediated oxidative degradation pathways of guanine.113 A characteristic feature of 1O2 oxidation of the guanine bases in DNA is the total lack of sequence specificity. This was illustrated using [32P]-labeled DNA fragments obtained from p53 tumor suppressor gene and the human c-Ha-ras-1 protooncogene. The modifications, including secondary single-strand breaks (SSBs), were located and quantified by high-resolution polyacrylamide gel electrophoresis (PAGE) analysis that provides relevant information at the nucleotide level. Base lesions including 8-oxoG and its secondary oxidation products were visualized as additional strand breaks upon Fpg-enzymatic digestion and hot piperidine treatment, respectively.199 UVAexcited lomefloxacin, a synthetic fluoroquinolone antibiotic, was shown to generate Fpg-sensitive sites on most guanines in duplex DNA without sequence specificity.200,201 The level of base damage was significantly enhanced when the photosensitization experiments were performed in D2O, which is known to increase the lifetime of 1O2. These two observations are strongly suggestive of the implication of 1O2 in the guanine photo-oxidation reactions implicating the type II photosensitization mechanism. In contrast, UVA-sensitized oxidation of double-stranded DNA fragments by riboflavin202 and nalidixic acid,201 another fluoroquinolone, that mainly operate through type I mechanism led to the preferential formation of Fpg-sensitive sites at the 5′-guanine in GG doublets. This

specific 8-oxoG pattern formation is characteristic of oneelectron oxidation of guanines that is followed by migration of the radical cations thus generated along the DNA duplex. The hole transfer occurs over several base-pairs before the hole is preferential trapped by guanines that exhibit the lowest ionization potential, as in the case of 5′G in 5′-GG3′ sequences.203,204 Predominant formation of 8-oxodGuo was observed upon incubation of calf thymus DNA to H2O2 in the presence of either free Cu2+ ions or Cu2+/o-phenanthroline mixture.205 The relatively low level of FapyG that arises from the transient formation of 8-hydroxy-7,8-dihydroguanyl radical, a common precursor of 8-oxoG, would exclude a significant contribution of • OH and one-electron processes in the oxidation of the guanine moieties. This is suggestive of the implication of 1O2 as the main ROS, as further supported by the almost 6-fold increase in the formation of 8-oxoG when the oxidation reactions are performed in D2O solution.205 Complexation of Cu2+ to DNA has been proposed in the presence of H2O2 to trigger the formation of 1O2 through a Cu-hydroperoxo complex.206,207 2.3.2. RNA. Only limited information is available on oxidation reactions to RNA mediated by 1O2. In that respect the reported photosensitized formation of 8-oxoGuo that was detected in isolated RNA following calf exposure to excited MB (MB) and RB constitutes two relevant examples.208 In another investigation, a comparative study of the formation of 8-oxoG was performed in single-stranded DNA, native DNA, and RNA upon photosensitization by MB, TMPyP, and TSPP.197 It was found that RNA and ssDNA showed a 5-fold higher susceptibility to 1O2 oxidation when TSSP was used as the photosensitizer.197 8-OxoGuo has been also shown to be generated in the RNA of Qβ bacteriophage upon photosensitization by either RB208 or MB.208−210 2.4. Cellular DNA

Numerous attempts were made during the past two decades for measuring oxidatively generated damage in cellular DNA under various oxidative conditions where 1O2 was at least partly involved. A critical parameter that plays a major role concerning the efficiency of the oxidation reactions mediated by 1O2 to nuclear DNA is the intracellular lifetime of this ROS in the cellular environment. This value, estimated to be within the range of a few μs, is dependent on the site of 1O2 generation and shortened by both physical quenching and chemical reactions in a selective way with a few molecules, including unsaturated lipids and a limited number of amino acids.56,211−213 It was concluded that the intracellular diffusion distance of 1O2 is within the range of 150−220 nm that has to be compared with the 10−30 μm diameter of most mammalian cells.211,212 This is much higher than the diffusion distance of highly reactive •OH76,82,214 that reacts with proximate molecules at the site where it is generated. However, 1O2 should be produced in the vicinity of the nucleus in order to allow DNA oxidation. Three main issues are addressed in this section. The careful delineation of the oxidative L


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embryonic fibroblasts, MCF-7 breast cancer cells, and primary human fibroblast cells upon incubation with the Ro19-8022 photosensitizer and subsequent UVA irradiation.223,224 The oxidative degradation pattern revealed using the modified alkaline elution technique analysis225,226 showed an almost complete lack of DNA strand breaks/alkaline labile sites and oxidized pyrimidine bases with respect to overwhelming Fpgsensitive sites.224 This is highly suggestive of the predominant contribution of 1O2 oxidation to DNA damage as the result of type II photosensitization reactions. Pre-treatment of murine leukemia P388D1 cells with Δaminolevulinic acid (ALA) led to its metabolization and subsequent conversion into porphyrins. This has been shown to induce the formation of 8-oxodGuo upon UVA irradiation of the cells.227 In an independent study, it was reported that ALAderived protoporphyrin IX (PPIX), mostly diffusely localized in the cytoplasm, is a poor 8-oxodGuo generator.228 Recent studies have further emphasized the deleterious effects of UVA-excited 6-TG, including an increased risk of squamous cell skin carcinoma in patients and rats following its incorporation into cellular DNA upon incubation with various thiopurines.196,229,230 These include 6-TG, a predominant type II photosensitizer, the poorly photoreactive azathioprine, and its metabolite, 6-mercaptopurine.231 UVA irradiation of mammalian cells pre-treated with 1 μM azathioprine to a dose of 10 kJ/ m2 leads to a significant increase in the frequency of human 8oxoguanine glycosylase (hOGG1)-sensitive sites that mostly consist of 8-oxodGuo.232 The photosensitized formation of oxidatively generated guanine lesions was more efficient in proliferative GM5399 primary human fibroblasts than in the corresponding quiescent cells.232 It may also be pointed out that the urinary release of 8-oxodGuo measured by HPLC-ESI-MS/ MS was significant higher in patients treated by azathioprine with respect to control subjects.233 In a more recent study, it was confirmed that the combined 6-TG and UVA treatment of mouse fibroblast (MEFs) triggers the photosensitized formation of 8-oxodGuo, as revealed by accurate HPLC-ECD measurements.229 The Mutyh-null cells, in which the gene of the mismatch repair enzyme MUTYH was knocked out, showed a higher accumulation of 8-oxodGuo with respect to wild-type MEF cells.229 A similar increase in the level of 8-oxodGuo was observed in the UVA-irradiated skin of wild-type and Mutyh−/− mice treated by azathioprine. Interestingly, no increase in 8oxodGuo was observed in the DNA of internal organs, including liver and spleen.229 However, at the current stage of knowledge, it is not possible to conclude that the UVA-induced formation of 8-oxoGuo in cells and animals treated by 6-TG and azathioprine, respectively, arises from the predominant or exclusive photosensitized generation of 1O2. In particular, the additional formation of strand breaks and/or alkali-labile cells in cells229,232,234,235 raised the question of the implication of other oxidants that may include •OH. 2.4.3. Oxidizing Effects of UVA Radiation. UVA radiation through the photosensitized generation of 1O2 is known to induce several biological effects, including cellular toxicity and inactivation.22,236−238 2.4.3.1. Formation of 8-oxodGuo. Early experiments showed, on the basis of HPLC-ECD measurements, that 8oxodGuo was generated in the DNA of UVA-irradiated mammalian cell lines.239−243 In addition, relevant mechanistic information was gained from the predominant formation of Fpgsensitive sites, revealed as strand breaks using either the alkaline elution technique 225,226,244,245 or the alkaline comet

pathways induced by a clean source of 1O2 to cellular DNA is first reported. Examples of photodynamic effects provided by exogenous photosensitizers are then critically surveyed before delineating the role of 1O2 in the UVA- and visible-lightsensitized oxidation of cellular DNA. 2.4.1. Oxidation Reactions Triggered by a Chemical Source of Singlet Oxygen. Relevant insights into oxidation reactions mediated by 1O2 on nuclear DNA have been gained by incubating THP1 monocytes with DHPNO2 used as a clean source of 1O2.43 Thus, the release of 1O2 from the thermolabile naphthalene endoperoxide within the cells at 37 °C gave rise to the exclusive formation of 8-oxodG that was unambiguously measured in the extracted DNA using the accurate HPLC-ESIMS/MS method operating in the multiple reaction monitoring (MRM) mode.43 Confirmation that 8-oxodGuo was formed by 1 O2 oxidation and not by an induced oxidative stress was provided by incubation of the cells with [18O2]-labeled DHPNO2.43 It was found that the increase in 8-oxodGuo concerns only the [18O]-labeled oxidized 2′-deoxyribonucleoside, thus excluding the contribution of endogenous oxidation reactions that may result as a cellular response to the incubation of the cells with the latter endoperoxide. Another relevant piece of information concerning the reactivity of 1O2 toward cellular DNA was gained from incubation of human monocytes with DHPNO2.215 It was also unambiguously demonstrated, in agreement with results of model studies, that exposure of cells to 1 O2 did not lead to a significant increase in the frequencies of DNA strand breaks and/or alkali-labile sites215 that were measured using the sensitive alkaline comet assay.216 The possibility of specifically generating about 12 000 [18O]labeled 8-oxodGuo residues in cellular DNA has found a relevant application for assessing the suitability of DNA extraction protocols. This has allowed, through the use of [18O]-8-oxodGuo as an internal standard, the selection of the most suitable method that minimizes the occurrence of spurious radical oxidation of the guanine moieties during DNA extraction and subsequent workup.217 2.4.2. Exogenous Photodynamic Agents as Generators of Singlet Oxygen. The ability for several exogenous photosensitizers to induce the formation of 8-oxodGuo in nuclear DNA upon UVA irradiation is well documented, as outlined in previous review articles.86,87,218 The first generation of fluoroquinolones received wide attention since these efficient antibacterial agents exhibit a strong genotoxicity upon exposure to UVA radiation. Thus, excited lomefloxacin has shown its ability to sensitize the formation of 8-oxodGuo measured by HPLC-ECD in the DNA of cultured rat liver cells.219,220 In contrast, UVA-sensitized formation of 8-oxodGuo in THP-1 cells that was assessed using the accurate HPLC-ESI-MS/MS method is rather inefficient.221 Furthermore, the presence of 5(hydroxymethyl)-2′-deoxyuridine that is likely to arise from deprotonation of initially generated thymine radical cation76,82 is strongly indicative of a type I photosensitization pathway,20 as further supported by mechanistic studies.221 Other fluoroquinolones, including enoxacin and, to a lesser extent, norfloxacin, are better generators of 8-oxodGuo through mostly 1O2 oxidation.221 However, the main photosensitized reaction mediated by the three fluoroquinolones is oxygen independent, giving rise to cyclobutane thymine dimers through a triplet− triplet energy-transfer mechanism222 particularly efficient for enoxacin and norfloxacin.221 Predominant formation of 8-oxodGuo was detected by HPLC-ECD in the DNA of AS52 Chinese ovary cells, mouse M


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assay.216,246,247 The preferential oxidation of guanine bases was confirmed by accurate measurements of overwhelming 8oxodGuo using HPLC associated with either ECD or tandem mass spectrometry detection in the DNA of UVA-irradiated cells248,249 and also Drosophila larva.250 In addition, the formation of 8-oxodGuo was detected in the nuclear DNA of several corneal layers, including epithelium, stroma, and endothelium, upon exposure of enucleated eyes from nonalbino rabbits to UVA radiation.251 However, the semiquantitative measurement of 8-oxodGuo that was achieved251 using a non-specific immunofluorescence assay82,251 awaits further confirmation from HPLC-based measurements. Comparative studies of the formation of the main UVA photoproducts indicated that cyclobutane pyrimidine dimers (CPDs) are directly generated through oxygen-independent pathways in a higher yield than sensitized 8-oxodGuo in Chinese hamster ovary cells,239 human fibroblasts and keratinocytes,252 and skin explants.84 This clearly indicates that oxidatively generated damage to cellular DNA is a minor UVA-induced degradation pathway. It has been shown as an important feature that carcinogenic UVA radiation is able to penetrate deeper into the skin than the more energetic and less abundant UVB photons. Therefore, a higher vulnerability of the basal layer of human epidermis for the UVA-sensitized formation of 8oxodGuo is expected,253 as has been observed for the generation of CPDs.254 2.4.3.2. Mechanisms of 8-oxodG Formation and Other Oxidized DNA Photoproducts. UVA radiation that is weakly absorbed by canonical nucleobases has been reported to induce the formation of 8-oxodGuo through the generation of 1O2 in isolated DNA.28 The mechanism of 1O2 production and the importance of this reaction with respect to the expected overwhelming contribution of endogenous photosensitizers to the generation of 8-oxodGuo in UVA-irradiated cellular DNA remain to be established. The large number of putative chromophores that may be involved in the observed generation of 1O2 in UVA-irradiated skin255 include flavins, porphyrins, quinones, urocanic acid, and B6 vitamin pyridoxal among others.255−258 It is widely admitted that 1O2 is involved in the induced formation of 8-oxodGuo upon exposure of cells and human skin to UVA radiation.259 However, since 8-oxodGuo is a ubiquitous DNA oxidation product that has been shown to be also generated as well by •OH and one-electron oxidants,76,81 it has been necessary to design appropriate experiments in order to gain information on the relative importance of the possible UVA-mediated oxidative degradation pathways of DNA in cells.247 This has consisted of comparing the spectrum of UVA generated oxidatively DNA damage with the well-characterized ionizing radiation-induced degradation pattern that is dominated by the •OH contribution. Thus, three main classes of UVA-induced DNA lesions were detectedstrand breaks and/ or alkali-labile sites, oxidized pyrimidine bases, and modified purine nucleobasesand their presence was quantified in the DNA of human monocytes.247 This was achieved using the modified alkaline comet assay that allows the measurement of oxidized bases revealed as DNA repair glycosylase-sensitive sites. The two patterns thus obtained show large differences in the quantitative distribution of the DNA lesions. In agreement with previous findings it was found that UVA irradiation led to the preferential oxidation of purine bases, predominantly guanine, with an about 6-fold higher efficiency that the generation of oxidized pyrimidine modifications and direct strand breaks including alkali-labile sites.247

In contrast, the distribution of the three main radiationinduced classes of DNA damage that are mostly accounted for by the involvement of •OH is more balanced. Thus, strand breaks and/or alkali-labile sites are now predominant over modified purine bases and oxidized pyrimidine bases, being generated in a relative ratio of 2.5:1:1 (Table 2).247 Only •OH is Table 2. Oxidatively Generated Damage to DNA of Human THP1 Monocytes upon Exposure to UVA and Ionizing Radiationsa lesions 8-oxo-7,8dihydroguanineb FapyGuac Fpg-sensitive sitesd Endo III-sensitive sitesd strand breakse

control

190 195 265

UVA radiation (per 100 kJ·m−2)

γ rays (per Gy)

98

11

not determined 190 30 90

27 48 53 130

a Data from ref 247. The frequency of the lesions is expressed in number of modifications per 109 bases and either per kJ·m−2 (dose range 0−150 kJ·m−2) or per Gy of ionizing radiation (dose range 0− 40 Gy). bHPLC-ECD. cHPLC/GC-MS. dModified comet assay. e Direct strand breaks and alkali-labile sites.

able to both oxidize all the DNA components including the nucleobases and the 2-deoxyribose moieties, whereas 1O2 exclusively reacts with guanine. It may be added that oneelectron oxidation reactions mediated by type I photosensitizers are expected to mostly damage guanine.69,74 These observations, since the contribution of type I photosensitizers to the oxidation of guanine is unlikely, may be rationalized in terms of major implication of 1O2 in the UVA-mediated formation of 8oxodGuo in the DNA of human monocytes. Thus, it was estimated that the contributions of 1O2 and •OH to the UVA generation of 8-oxodGuo are approximately 80% and 20%, respectively. The formation of highly reactive •OH that is involved in the generation of SSBs and oxidized pyrimidine bases detected as endonuclease III (endo III)-sensitive sites is initiated by the production of superoxide anion radical (O2•−) either photochemically and/or as part of cellular response to UVA irradiation.82 This is followed by the spontaneous or enzymatic dismutation of low reactive O2•− into H2O2 that is reduced to generate •OH according to the Fenton reaction. It may be pointed out that UVA has been shown to trigger the release of Fe2+, a key actor of the Fenton reaction, from heme in human fibroblasts.260 8-OxodGuo is also generated in cellular DNA upon UVB irradiation, however as a minor oxidative pathway.239 This is illustrated by the low strand breaks yield, representing less than 0.1% of the total formation of UVB-induced DNA photoproducts. The contribution of 1O2 to the formation of 8oxodGuo that may be mostly rationalized in terms of •OHmediated reaction is expected to be at best rather low. However, ionization of the guanine that was shown to occur in UVirradiated isolated DNA with the formation of a reactive purine radical cation261 cannot be totally discarded. 2.4.3.3. Formation of 8-oxodG in Melanocytes. The first evidence showing that melanin is able to photo-oxidize nuclear DNA was provided by the measurement of 8-oxodGuo in melanoma cells from human and mouse skin.262 It was found that the UVA-sensitized formation of 8-oxodGuo increases with the melanin content of the cells.262 In a more recent study it was found on the basis of quantitative HPLC-ESI-MS/MS measureN


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Scheme 10. Linoleic Acid Hydroperoxides Produced by 1O2 and Radical-Mediated Oxidationa

a

The positional cis−trans isomers of hydroperoxyoctadecadienoate (HPODE) and their relative abundance (in %) are depicted.

molecular species and the characterization of their spatial and temporal changes in different biological matrices under physiological and/or pathological conditions.276,278,279 Importantly, lipids are potential targets of oxidation by enzymatic and non-enzymatic pathways, and much attention has been given to the characterization/detection of the oxidized products, their reaction mechanisms, and biological consequences.280 Lipid oxidation can be triggered as the result of three main pathways: the free-radical-mediated oxidation, the free-radicalindependent (non-radical) oxidation, and the enzymatic oxidation. The mechanisms and products of free-radicalmediated oxidation of lipids, also known as “autoxidation”, have been extensively studied, and excellent reviews on this topic can be found elsewhere.280−286 Here we will focus on freeradical independent reactions mediated by non-radical reactive species such as 1O2 (type II mechanism). As described above, 1 O2 is produced by light-dependent and -independent reactions (dark reactions).5,287,288 The primary oxidation products generated in the oxidation of lipids by both radicals and 1O2 are lipid hydroperoxides (LOOH). In the next section we will describe the hydroperoxide products and their transformation reactions. Lipids are also oxidized by several oxygenases, such as lipoxygenases, cyclooxygenases, and enzymes of the cytochrome P450 family.289 However, this topic will not be covered in detail here.

ments that 8-oxodGuo is generated with a 4-fold higher efficiency in melanocytes than in keratinocytes, both cultured cells that were growth from the same human donors.263 Relevant mechanistic information was gained from the comparison of the levels of Fpg-sensitive sites and strand breaks including alkalilabile sites with a 1.6-fold higher ratio in favor of oxidized guanine bases.263 This is strongly suggestive of the preferential oxidation of cellular DNA by 1O2 together with a significant participation of •OH that explains the formation of SSBs. The suggested ability of excited melanin to oxidize cellular DNA received confirmation from the detection of enhanced formation of Fpg- and endo III-sensitive sites in highly pigmented murine cells upon exposure to visible light.264 Early spectroscopic investigations showed that photoexcitation of melanin, known as a redox-sensitive pigment,265 led to an efficient generation of O2•− and H2O2,266 its dismutation product. More recently, evidence was provided for the generation of 1O2 in human hair267 and fungal pathogen Mycosphaerella f ijiensis268 as the result of excitation of melanin and 1,8-dihydroxynaphthalenemelanin, respectively, by visible light. Recent extensive spectroscopic measurements have shown that UVA irradiation of synthetic eumelanins and pheomelanins gave rise to 1O2 in addition of O2•−.268 Interestingly, the two latter ROS are both efficiently quenched by the melanin pigments.268,269 However, it was proposed that the generation of 1O2 would lead to further oxidation of DHICA to final pyrrole-2,3,5-tricarboxylic acid (PTCA) through the transient formation of an endoperoxide that, however, has not yet been characterized.268,270 Exposure of human melanocytes to UVA radiation was recently reported to induce the delayed dark formation of CPDs in nuclear DNA according to a chemiexcitation reaction that was proposed to involve a transient melanin dioxetane as the result of peroxynitrite oxidation.271,272

3.1. Lipid Hydroperoxide Formation

3.1.1. Unsaturated Fatty Acids. 1O2 reacts with free and esterified forms of unsaturated fatty acid species, mostly by enetype reaction, producing isomeric allylic hydroperoxides.290−296 1 O2 adds to both edges of each carbon−carbon double bond to produce hydroperoxide regioisomers. Upon 1O2 addition, the double bond is shifted to an allylic position and is isomerized to the trans configuration.292,297 1 O2 oxidation of mono-unsaturated fatty acids such as methyl oleate (18:1, n-9, Δ9) results in two products that are formed in equal amounts, the 9-hydroperoxy-10E-(9-OOH-trans) and 10hydroperoxy-8E-octadecenoid acid (10-OOH-trans). Conversely, radical oxidation of oleate gives rise to hydroperoxides at positions 8, 9, 10, and 11.298 H-atom abstraction from C-8 leads to 8-hydroperoxy-9Z- (8-OOH-cis), 8-hydroperoxy-9E(8-OOH-trans), and 10-hydroperoxy-8E-octadecenoate (10-

3. LIPIDS Lipids comprise a class of small molecules with an enormous number of chemically distinct molecular species.273−276 They exert multiple fundamental functions as essential components of cellular membranes, energy storage sources, and also effectors and intermediates in several signaling processes.277,278 Recent advances in mass spectrometry technologies and bioinformatics tools are enabling the identification of thousands of lipid O


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Scheme 11. Free-Radical-Mediated Oxidation of Cholesterol

positions. Thus, specific measurement of conjugated 9- and 13HPODEs and unconjugated 10- and 12-HPODEs can provide an index of radical versus 1O2-mediated oxidation.285,304 In biological media, hydroperoxides are readily reduced to related alcohols by antioxidant compounds and enzymes. Moreover, hydroperoxides are less stable to sample processing. Thus, analytical methods have focused on the detection of alcohol isomers, either formed in situ or generated ex vivo by the use of hydroperoxide reducing agents (e.g., NaBH4). In this context, the linoleate isomers 10- and 12-OH have been used as fingerprints of 1O2-mediated oxidation. These isomers have been detected in the skin of live mice submitted to short-term UVA irradiation305 and the blood plasma of diabetic patients.306 Similarly, arachidonic acid oxidation yields hydroperoxides at carbon positions 5, 6, 8, 9, 11, 12, 14, and 16, of which the isomers at positions C-6 and C-14 are specifically formed upon 1 O2 oxidation.293 Docosahexaenoic acid reacts with 1O2 to yield 12 positional hydroperoxide isomers, of which the hydroperoxides at positions C-5 and C-19 are specifically formed by 1 O2.302 Thus, sensitive and specific analysis of fatty acid hydroperoxide/hydroxide isomeric species can provide ways to detect 1O2-mediated oxidation pathways in vivo. 3.1.2. Cholesterol. Cholesterol (5α-cholestan-3β-ol, Ch) is one of the major components of biological membranes that is especially concentrated in lipid rafts and lipoprotein particles in the blood. It has essential functions in the modulation of membrane physical properties, as well as in the regulation of multiple signaling pathways.307 Its oxidation has been related to several pathological conditions, including cardiovascular and neurodegenerative diseases.308−310

OOH-trans). Abstraction from C-11 generates three additional isomeric hydroperoxides: 9-hydroperoxy-10E- (9-OOH-trans), 11-hydroperoxy-10Z- (9-OOH-cis), and 11-hydroperoxy-10E(11-OOH-trans) octadecenoate. Likewise, 1 O 2 adds to the double bonds of other polyunsaturated fatty acids (PUFA) giving rise to a mixture of isomeric fatty acids that contain conjugated and unconjugated double bonds. Oxidation of linoleic acid (18:2, n-6, Δ9,12) has been extensively studied in the contexts of both radical and photosensitized mediated oxidation. 1O2-induced oxidation gives rise to four hydroperoxide regio-isomers (9-, 10-, 12-, and 13-Z,E-HpODE) (Scheme 10). The equal accessibility of the double bonds in the unsaturated fatty acids would predict a uniform distribution of the isomeric hydroperoxides formed upon 1O2 reaction. However, studies reported a non-uniform distribution.293,299,300 For linoleic acid, a predominance of the conjugated hydroperoxides (9-Z,E- and 13-Z,E-HPODE) has been demonstrated over the unconjugated forms (10-Z,E-12Z,E-HpODE).292,295 In a similar way, the more highly unsaturated fatty acids, such as linolenic (18:3), arachidonic (20:4), eicosapentaenoic (20:5), docosapentaenoic (22:5), and docosahexaenoic (22:6) acid, are oxidized by 1O2, producing mixtures of hydroperoxide regio-isomers.291−293,296,301−303 Importantly, specific analysis of regio- and stereoisomeric hydroperoxides can provide information on their mechanism of generation. For instance, radical-induced oxidation of linoleic acid generates the cis,trans and trans,trans hydroperoxides at 9and 13-positions (9-Z,E-HPODE, 9-E,E-HPOD, 10-Z,EHPODE, and 10-E,E-HPODE), whereas 1O2-mediated oxidation introduces hydroperoxides at the 9-, 10-, 12-, and 13P


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Scheme 12. 1O2-Mediated Oxidation of Cholesterol

not the C5-radical.326 The radical at C7 reacts rapidly with O2 on either the α- or β-face of cholesterol ring B, yielding C7-peroxyl radical intermediate. This intermediate reacts with a hydrogen atom donor to generate the epimeric pair of 3β-hydroxycholest5-ene-7α-hydroperoxide (7α-OOH) and 3β-hydroxycholest-5ene-7β-hydroperoxide (7β-OOH) as major products. These hydroperoxides are the precursors of diol derivatives (7α-OH, 7β-OH), 7-ketone (7-one), and also epimeric 5,6-epoxides that are subsequently converted by hydrolysis into triols (5αcholestane-3β,5α,6β-triol). Based on the detection of 7-OOH and their products, it has been assumed that Ch radical oxidation proceeds mostly through C7 hydrogen atom abstraction. However, it was recently demonstrated that Ch autoxidation in vitro gives rise to products derived not only from C7- but also from C4-H-atom abstractions, analogously to what occurs with the unsaturated fatty acids.280,327 In support of this, Zienlinski et al. demonstrated that Ch autoxidation produces not only the 7OOH epimers but also the epimeric mixture of 4-OOH and 6OOH, which are formed by free-radical-mediated C4-H-atom abstraction.280,327 It should be noted that 4α-OH-Ch and 4βOH-Ch products have been identified in vivo and that only 4βOH-Ch can be produced from Ch by cytochrome P450 3A4 (CYP3A4).328 Cholesterol oxidation by 1O2 has been extensively explored in the context of photosensitized oxidations.290,320,329 It is known that 1O2 adds at the C5 and C6 positions by the ene-type reaction, yielding hydroperoxides (Scheme 12). This reaction generates 3β-5α-cholest-6-ene-5-hydroperoxide (5α-OOH) as

Cholesterol oxidation produces various oxidized products collectively called oxysterols, including hydroperoxides, alcohols, epoxides, ketones, and aldehydes. Several excellent reviews are available on non-enzymatic311−313 and enzymatic cholesterol oxidation.309,310,314 Enzymatically, cholesterol is oxidized by several enzymes of the P450 cytochrome family (CYP).315 Cholesterol 7αhydroxylase (CYP7A1) initiates the classical bile acid pathway by converting Ch to 7α-OH Ch in the liver.314 CYP3A4 and CYP3A5 are responsible for the synthesis of 4β-OHCh.316 CYP27A1 is involved in the conversion of Ch to 27-OH-Ch.314 CYP46A1 (cholesterol 24-hydroxylase) is highly expressed in neurons, where it is responsible for the conversion of Ch to 24(S)-OH Ch.317,318 This metabolite crosses the blood−brain barrier before being further metabolized in the liver.317 Cholesterol is also oxidized by cholesterol 25-hydroxylase enzymes to 25-OH-Ch.319 Cholesterol can be non-enzymatically oxidized by radical processes and non-radical species such as 1O2290,320,321 and O3.322,323 Free-radical-mediated oxidation (Scheme 11) involves strong oxidants like •OH or peroxyl/alkoxyl radicals. As mentioned for the unsaturated fatty acids, oxidation is initiated by the abstraction of a hydrogen atom from the allylic methylene group. For cholesterol, a hydrogen atom is preferentially abstracted from the C7 position, yielding resonance-stabilized radicals at C7 and C5324 (Scheme 11). Although both radicals could, in principle, react with O2, the major oxidation products observed in Ch autoxidation have been the C7-oxysterols.325 EPR experiments detected only the C7- and C25-radicals and Q


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Scheme 13. Proposed Mechanisms Involved in the Formation of Cholesterol Aldehydes in the Reaction of 1O2 with Cholesterol

and THF led to a quantitative formation of the aldehyde.334 The second mechanism that could account for the formation of doubly [18O]-labeled cholesterol aldehydes is a pathway involving a dioxetane intermediate.321 However, judging from the yield of doubly labeled cholesterol aldehydes (∼10%), the dioxetane route seems to be a minor pathway compared to the Hock cleavage route.321 3.1.3. Membrane Phospholipids. Membrane phospholipids are important targets for 1O2 produced by UVA- and visible-light-induced sensitized oxidation reactions.335 These oxidative reactions have been pathologically implicated in skin aging (e.g., photoaging336) and carcinogenesis, but they also have antimicrobial effects337 and can be used in cancer photodynamic therapy (PDT).338 Oxidation of cellular membranes by 1O2 can elicit cell toxicity but the molecular mechanisms behind this process remains still poorly established. In a typical membrane, phospholipid hydroperoxides (PLOOH) are formed by 1O2 addition to the unsaturated fatty acids (Scheme 14).335 Usually, the sn-2 position of phospholipids is esterified to unsaturated fatty acids, and most of the oxidized fatty acids are formed at this position. As described above, 1O2 adds to both edges of the double bond yielding several hydroperoxide positional isomers. Alternatively, for ether type phospholipids (e.g., plasmalogens), 1O2 was also reported to undergo cycloaddition to the vinyl ether linkage to generate dioxetane intermediate.339 Early works allowed structural assignment of several phospholipid and cholesterol hydroperoxides formed by photosensitized oxidation of lipids in solution,340 as well as in model membranes (reviewed by Girotti in 2001).335 Membrane lipid hydroperoxides can undergo a number of different decomposition pathways, including (1) reduction to alcohols by antioxidant enzymes, (2) conversion to highly reactive peroxyl or alkoxyl radicals followed by cyclization or

the major product. An epimeric pair of two other hydroperoxides, 3β-hydroxycholest-4-ene-6α-hydroperoxide (6αOOH) and 3β-hydroxycholest-4-ene-6β-hydroperoxide (6βOOH), is also generated, but in much lower yields.290 The 7OOH epimers are not produced directly by the reaction but more likely through the [2,3] allylic rearrangement of 5αOOH.330 In addition to hydroperoxides, cholesterol oxidation by 1O2 also yields two electrophilic secosterol aldehydes, the 3βhydroxy-5-oxo-5,6-secocholestan-6-al (Seco-A) and 3β-hydroxy-5β-hydroxy-B-norcholestane-6β-carboxaldehyde (SecoB), that are capable to promote protein modification and aggregation.331,332 These secosterols were first described for the reaction of cholesterol with O3313,323,333 and initially claimed to be ozone signature products.323 However, later studies showed that these aldehydes are also formed in reactions involving 1 O2321 or free radicals.327 Two mechanisms have been proposed to account for their generation: the acid-catalyzed Hock cleavage of 5α-OOH334 and the decomposition of an 1,2dioxetane intermediate at the Δ5 bond.321 More recently, the acid-catalyzed 6-OOH Hock fragmentation has been also shown to generate cholesterol aldehydes.327 [18O]-labeling studies were used to clarify the mechanism by which singlet oxygen leads to cholesterol aldehyde formation. Cholesterol photosensitized oxidation conducted under [18O]enriched O2-saturated atmosphere yielded the expected 5α-18O18OH and the [18O]-labeled cholesterol aldehydes321 (Scheme 13). Interestingly, most of the aldehydes (85%) contained only one 18O atom, and a small fraction (10%) contained the doubly [18O]-labeled aldehyde. This is strongly indicative that cholesterol aldehydes are most likely produced by the Hock cleavage mechanism in which the protonation of the hydroperoxide group is accompanied by the loss of an [18O]labeled H2O. In fact, acidification of purified 5α-OOH in CHCl3 R


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Scheme 14. Membrane Phospholipid Oxidation by 1O2a

a

The top part shows the reduction and repair of phospholipid hydroperoxides (PL-OOH), while the part below shows the conversion of PL-OOH to peroxyl and alkoxyl radicals. β-Scission of intermediate oxyl radicals generates reactive short-chain aldehydes and truncated phospholipids.61

lization. In a recent study, the photosensitized phospholipid oxidation products (hydroperoxides, alcohols, ketones, and aldehydes) were detected by LC-MS/MS measurements.61 Quantification of the reaction products showed the formation of POPC-OOH together with minor amounts of alcohols and ketones at the initial steps of oxidation pathways when membranes were still intact. Importantly, at the time membranes were permeabilized, a significant increase in truncated phospholipids bearing aldehyde moieties were detected.61 This study was the first to clearly uncover the nature of the products responsible for membrane permeabilization upon membrane photosensitized oxidation.

fragmentation reactions to generate truncated phospholipids and short-chain electrophiles, or (3) fatty acyl hydroperoxide/ alcohol release through phospholipase action. In the case of cholesterol hydroperoxides, a number of studies have shown that these hydroperoxides can translocate across membranes.341 Moreover, the introduction of a polar hydroperoxide moiety in the phospholipid acyl chain leads to alterations of several membrane biophysical properties (e.g., lipid packing, membrane thickness). It has been shown that hydroperoxide groups in esterified fatty acyl chains can migrate to bilayer surface, altering membrane surface area, lipid packing, and fluidity.342 Investigations using giant unilamelar vesicle (GUV) membrane models composed of palmitoyl-2-oleoyl-sn-glycero-phosphocholine (POPC) and different photosensitizers (e.g., MB, porphyrin-based photosensitizers) have shown expansion of membrane area accompanied by the loss of optical contrast across the membrane, which has been interpreted as the result of pore formation.343 Of note, biophysical and computational studies demonstrated that lipid hydroperoxides form stable membranes and are not responsible for membrane permeabi-

3.2. Lipid Hydroperoxide Reactions

As already mentioned, lipid hydroperoxides can participate in reactions that either reduce and/or increase their toxicity, reactivity, or signaling responses.344 Lipid hydroperoxides are effectively reduced to the corresponding alcohols by enzymes of the glutathione peroxidase (GPx) and peroxyredoxins (Prx) families.345 Emphasis has been placed on both mammalian and S


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Scheme 15. Proposed Mechanisms for Peroxyl Radical Recombination Reactions Yielding 1O2a

a

Route a shows the termination reaction for primary and secondary radicals, leading to a linear tetroxide intermediate that decomposes to give a mixture of ketone, alcohol, and molecular oxygen. Reaction exothermicity predicts the formation of either ketone or dioxygen in the excited states. Route b shows the termination reaction for tertiary peroxyl radicals. Homolysis of the tetroxide yields alkoxyl radical and molecular oxygen.

organic hydroperoxides, metal ions, heme, and other oxidants supported the hypothesis that free-radical-mediated reactions are important sources of excited species.373 Importantly, spectral analysis has shown evidence toward the generation of 1O2 and triplet-excited carbonyls.374−376 Accumulating evidence supports the hypothesis that 1O2 observed in biological system can be produced by an energytransfer mechanism involving excited carbonyls272,377 as well as from peroxyl radical termination reactions (Russell mechanism)18,50 (Scheme 15). Rate constants for the termination reaction of different types of peroxyl radicals decrease along the series from primary (108 M−1 s−1) > secondary (106 M−1 s−1) > tertiary peroxyl radicals (104 M−1 s−1).378 A mechanism for peroxyl radical self-reaction was originally proposed by Russell in 1957.18 According to the mechanism, a linear tetroxide intermediate (ROOOOR) is formed upon “head-to-head” reaction of two peroxyl radicals. The unstable tetroxide intermediate decomposes by at least two pathways (Scheme 15). In the case of primary and secondary alkylperoxyl radicals, tetroxide decomposition gives non-radical products, a ketone (RO), an alcohol (ROH), and molecular oxygen through a concerted mechanism involving α-H-atom transfer.18 On the other hand, tetroxides lacking α-H formed from tert-alkylperoxyl radicals undergo a different path involving O−O bond homolysis, yielding alkoxyl radicals and molecular oxygen.378 More recently, computational calculations have suggested that non-tertiary tetroxides would also follow the asymmetric O−O cleavage pathway.379 However, caged non-tertiary alkoxyl radicals intermediates undergo α-carbon−hydrogen transfer to yield the classic Russell products, ketone, alcohol, and oxygen. According to the Wigner’s spin conservation rule, (singlet) tetroxide decomposition would release dioxygen in the excited (singlet) state (1O2) and the ketone in its ground (singlet) state (RO). Alternatively, this process could also produce groundstate triplet oxygen (3O2) and ketone in the excited triplet state (RO*).18,380 In 1968, Howard and Ingold detected 1O2 in about 1% yield for the reaction of sec-butyl hydroperoxide with cerium ions.380 Subsequently, Niu and Mendenhall381 carefully estimated the relative yield of excited ketone and 1O2 and concluded that primary and secondary peroxyl radicals generate O21Δg as a major product (with a yield of 3−14%), while triplet excited carbonyl species are generated in much lower yields (less than 0.01%).381,382 3.2.2. [18O]-Labeled Lipid Hydroperoxides and Singlet Oxygen Generation. The generation of 1O2 from lipid

bacterial cysteine- and selenium-based peroxidases as important sensors or regulators of hydroperoxide dependent pathways.346−348 For instance, GPx4 deficiency has been a key factor related to the induction of ferroptosis, an iron-dependent form of regulated cell death that involves lipid hydroperoxide induced cell damage.349 More recently, organic hydroperoxide resistance (Ohr) enzymes, which are present in many bacteria, have been shown to display unique biochemical properties, reducing fatty acid hydroperoxides and peroxynitrite into alcohols and nitrite, respectively, with extraordinary efficiency.350 These enzyme activities were also suggested to play important roles in host−pathogen interactions.350 While free fatty acid hydroperoxides can be directly reduced by antioxidant enzymes, fatty acid hydroperoxides esterified to membrane phospholipids may require the consecutive action of several enzymes. Phospholipid hydroperoxides in membranes can be reduced directly by type 4 glutathione peroxidase (GPx4)351 or by Prx 6.352 Another route involves the combined action of phospholipase A2 (PLA2) and type 1 glutathione peroxidase (GPx1).353,354 First, PLA2 releases the esterified fatty acid hydroperoxides, which are then reduced to the corresponding alcohols by the antioxidant enzymes (Scheme 14). Lipid hydroperoxides that are not efficiently reduced by GPx and Prx enzymes can react with free metal ions, heme proteins, peroxidases, or other oxidants, generating highly reactive radical intermediates, including peroxyl (LOO•) and alkoxyl radicals (LO•).355−358 These radicals can attack other lipids, promoting the propagation step of lipid peroxidation. They can also cause damage to other important biomolecules (e.g., proteins or DNA), thus altering normal cellular function. Alternatively, lipid radicals (LOO• and LO•) can undergo addition reactions, cyclization, and fragmentation reactions to generate secondary products such as cyclic peroxides, endoperoxides, aldehydes, ketones, and epoxides, as well as excited species, such as 1O2 and excited ketones.36 3.2.1. Lipid Peroxyl RadicalsLight Emission (Russell Mechanism). Several chemical and biochemical reactions are able to produce electronically excited species.359 These reactions are responsible for the phenomenon of low-level chemiluminescence observed in isolated tissues/organs, microorganisms, plants, and humans.360−369 Early studies360−363,370,371 demonstrated a strong correlation between tissue homogenate or intact organ low-level chemiluminescence and lipid peroxide content levels.364,372 The enhancement of chemiluminescence by the addition of external T


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hydroperoxides has been studied in detail by the use of [18O]labeled linoleic acid (LA) hydroperoxides (LA18O18OH)50,383 (Scheme 16), cholesterol (Ch18O18OH),384 and cardiolipin

converted into unlabeled hydroperoxides (L16O16OH) under [O2] atmosphere. Exchange is proposed to occur through a pathway involving the oxygen exchange between the peroxyl oxygen atoms with the oxygen dissolved in the reaction media (Scheme 18). Early studies by Brill showed that the mechanism proceeds by free radical intermediates.387 Later, Chan et al.,388 using 18O-enriched methyl linoleate hydroperoxides, demonstrated that pentadienyl radicals undergo a rearrangement whereby the oxygen atoms in the hydroperoxide group exchange with atmospheric oxygen within a caged intermediate. The second mechanism is based on the possibility of an energy transfer from [18O]-labeled 1O2 (36[1O2]) to groundstate molecular oxygen, yielding the unlabeled 1O2 (32[1O2]). This energy-transfer mechanism was first documented in the gas phase by Jones and Bayes389 and later demonstrated to occur in the aqueous phase by using DHPN18O2 as a clean source of labeled 1O2 and EAS as a chemical trap for 1O2.53 16

Scheme 16. [18O]-Labeled Linoleic Acid Hydroperoxides Generated by 18[1O2]

Apart from the detection of unlabeled singlet oxygen, labeling experiments also provided evidence for the detection of 1O2 with mixed isotope composition (16O18O). This finding has been also used as a support for the Russell proposal of a “head-to-head” interaction. Accordingly, partially labeled 1O2 arises from the reaction between labeled and unlabeled peroxyl radicals. Besides the detection of labeled 1O2, the occurrence of the Russell mechanism has been supported by the detection of peroxyl radical intermediates by EPR51 and also by the detection of ketone and alcohol products by mass spectrometry.50 3.2.3. Cholesterol and Phospholipid Hydroperoxides. Cholesterol and phospholipid hydroperoxides formed in the course of membrane oxidation can potentially generate 1O2. These hydroperoxides, if not efficiently reduced by antioxidant enzymes, may react with metal ions or HOCl to generate 1O2.51 Model membranes prepared with synthetic cholesterol and phospholipid hydroperoxides generate 1O2, as evidenced by light emission measurements in the NIR region (1270 nm) and by chemical trapping experiments.384 Tracer studies conducted with labeled cholesterol hydroperoxides (Ch18O18OH), and DPA as a chemical trap, showed the formation of 18[1O2],384 indicating the occurrence of a Russell-type mechanism. The efficiency of different positional isomers of ChOOH to generate O2(1Δg) was compared. All hydroperoxides, including the tertiary hydroperoxide, 5α-OOH, generated 1O2, which has been explained by the sigmatropic rearrangement of 5α-OO• into 7α-OO•. In agreement with this hypothesis, the reaction of cholesterol 5α-OOH resulted in the detection of the 7-OH and 7-keto products.384 Further evidence for 1O2 generation from oxidized membrane lipids has been obtained in experiments using a mitochondrial membrane mimetic model containing cardiolipin hydroperoxides and cytochrome c.52 The study showed that direct 1O2 formation from cardiolipin hydroperoxides is a minor process. However, it revealed that a substantial amount of 1O2 can be generated by the membrane peroxidation induced by

(CL18O18OH) hydroperoxides.52 These hydroperoxides can be obtained at purity higher than 99% by photooxidation using MB as the photosensitizer in a sealed chamber fully saturated with 18 O2 atmosphere.50 Important mechanistic information on 1O2 generation was obtained by reacting labeled hydroperoxides in the presence of either lipophilic (DPA) or hydrophilic anthracene (EAS) derivatives as 1O2 chemical traps followed by the detection of the corresponding stable endoperoxides by LC-coupled to mass spectrometry.50 One of the critical findings was the consistent detection of fully labeled singlet oxygen (18[1O2]) upon reaction of LA18O18OH with Ce4+50, peroxynitrite,49 or HOCl.51 These results served as an unequivocal evidence for the generation of 1 O2 through the Russell mechanism (Scheme 17), where two labeled peroxyl radical reacts to give an unstable labeled tetroxide that decomposes to form the corresponding labeled ketone, alcohol, and 1O2. Noteworthy, labeling studies also revealed critical details involved in the oxygen- and energy-transfer mechanisms. For example, one interesting finding was that the yield of the fully labeled 18[1O2] was drastically affected by the atmospheric oxygen present in the reaction system.50,51 Variations in oxygen isotope distribution in 1O2 have been explained by at least two processes. The first mechanism is based on the well-known rearrangement of allylic peroxyl radicals.283,385,386 According to this mechanism, labeled hydroperoxides (L18O18OH) are

Scheme 17. Generation of 18[1O2] from [18O]-Labeled Hydroperoxides by the Russell Mechanism

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Scheme 18. [18O]-Exchange Mechanism Involved in the Conversion of [18O]-Labeled Linoleic Acid Hydroperoxides into Unlabeled Hydroperoxides

cytochrome c bound to cardiolipin.52,288 These data, together with previous findings on membrane and tissue chemiluminescence,364,373,375,390 highlight the potential of peroxyl radicals derived from membrane peroxidation and/or from hydroperoxide decomposition as critical sources of 1O2 in biological systems. It should be mentioned that chemiluminescent species (1O2 and triplet carbonyl species) may arise not only from membrane lipid oxidation but also from the oxidation of other biomolecules (e.g., proteins,391 nucleic acids392), or from a combination of both. 3.2.4. Lipid Hydroperoxides and Reactive Nitrogen Species (Nitro-lipids). Nitrogen dioxide (NO2•) and, most notably, peroxynitrite (ONOOH), are oxidants that display unique properties as mediators of lipid oxidation/nitration.393 Peroxynitrite is generated by the fast reaction (4.4 × 109−19 × 109 M−1 s−1)394 of NO• and O2•−.395 At physiological pH, peroxynitrite (pKa = 6.5−6.8) exists as both the anion (ONOO−) and protonated forms (ONOOH). The anion is stable at alkaline pH, whereas under these conditions the acid form is unstable, undergoing either fast decomposition or isomerization.396 Although still debated,397 it is widely accepted that ONOOH undergoes homolysis to give HO• and NO2•398 (Scheme 19). However, from a biochemical point of view the reaction of peroxynitrite with CO2399 (5.7 × 104 M−1 s−1)399 is more important. This generates an unstable nitrosoperoxycarbonate (ONOOCO2−) that readily decomposes into NO2• and CO3•−,400 a strong one-electron oxidizing agent, in approx-

imately 35% yield. For more detailed discussion on peroxynitrite biochemistry and its generation and reactions in biological media, see the recent review by the group of Radi.401 Peroxynitrite reacts rapidly with a number of biological targets, including lipids, thiols (103 M−1 s−1), metal centers (105−107 M−1 s−1), amino acid residues (e.g., tyrosine nitration), and DNA (e.g., 8-oxoG and 8-nitroguanine formation by oxidation and nitration of guanine, respectively, generating also strand breaks).402−404 Interestingly, peroxyredoxins contain a fast-reacting (0.1 × 107−7 × 107 M−1 s−1)350,404 peroxidatic thiol in their active site that readily reduces peroxynitrite to nitrite. Many molecules are oxidized and/or nitrated by peroxynitrite. Peroxynitrite reactions can be divided into two types: direct reactions, in which peroxynitrite itself or its protonated form reacts directly with the substrate, and indirect reactions, where secondary free radicals derived from peroxynitrite homolysis (HO• and NO2•) or from its reaction with CO2 (CO3•− and NO2•), play major roles.394,403 The reaction of peroxynitrite with lipids induces lipid peroxidation and the formation of a number of nitrogencontaining (nitrito, nitro, nitrosoperoxo, nitrated) oxidized lipids.394,405 Similar products are also formed upon reaction of unsaturated fatty acids with nitric oxide (NO•), nitrogen dioxide (NO2•), and nitrous acid (HNO2). The most important examples of nitrogen-containing lipids are the nitrated fatty acids (e.g., nitro-oleic, linoleic, and arachidonic acids) and cholesteryl esters (e.g., nitro-cholesteryl linoleate).406−408 Their formation and role in biology have been extensively investigated. In particular, studies have focused on the electrophilic nature of nitrated fatty acids and their potential to modify critical proteins and modulate signaling pathways.393,409 Peroxynitrite reactions with hydroperoxides have been shown to generate 1O2.8,49,410 The mixture of peroxynitrite and H2O2 or tert-butylhydroperoxide produces a fast increase in light emission corresponding to dimol8 and monomol410 emission of 1 O2. However, the proposal that peroxynitrite alone could yield stoichiometric amounts of 1O2411 has been demonstrated to be invalid.9,398 Thermodynamic calculations and experimental data indicate that peroxynitrite cannot yield 1O2 in such high yields.9,398 Thus, the most plausible explanation for the detection of high yields of 1O2 from peroxynitrite solutions411 attributes them to the presence of H2O2 at relatively high concentrations in peroxynitrite preparations.

Scheme 19. Peroxynitrite Decomposition Reactions

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form a chlorohydroperoxy intermediate, [HOO-Cl-OH]−, as the active intermediate that subsequently generates 1O2. Similar to H2O2, lipid hydroperoxides either as free linoleic acid hydroperoxide (LAOOH) in solution or in its esterified form as phosphatidylcholine hydroperoxides also react with HOCl generating 1O2.51 The formation of 1O2 was clearly demonstrated by the detection of the 1O2 monomol emission at 1270 nm as well by 18O labeling studies51 (Scheme 21). As

Using a synthetic salt of peroxynitrite, completely free of H2O2, it has been estimated that direct generation of 1O2 from peroxynitrite is very low ( 6.7 decomposes to yield NO2− and O2 or NO2• and O2•− in about 50% yields.413 Thermodynamically, the N−O bond breakage would be sufficiently exothermic to allow the release of oxygen in the singlet excited state.415 Indeed, peroxynitrate preparations were found to generate 1O2,10 confirming that this intermediate might be an important source of 1O2 in hydrogen peroxide free peroxynitrite preparations or in reactions involving simultaneous generation of NO2• and O2•−. Peroxynitrite itself and its decomposition products (e.g., HO•, CO3•−, NO2•) are oxidants capable of abstracting hydrogen atoms from hydroperoxides to generate peroxyl radicals. In fact, similarly to the reactions triggered by metal ions with lipid hydroperoxides, reactions of [18O]-labeled linoleic acid hydroperoxides with ONOO− at physiological pH yielded fully labeled 1 O2. This result points to the generation of 1O2 from [18O]labeled peroxyl radicals recombination through the Russell mechanism. In addition to hydrogen atom abstraction reactions, peroxynitrite undergoes nucleophilic addition to the carbonyl carbon atom of free aldehydes (e.g., acetaldehyde, glyoxal), forming a 1-hydroxyalkylperoxynitrite anion adduct.416,417 This hypothetical adduct decomposes, giving rise, among other products, to carbon-centered radicals that can further efficiently react with oxygen to generate peroxyl radicals.417 Consistent with these findings is the observation of 1O2 in the reaction of the peroxynitrite−glyoxal system.418 3.2.5. Lipid Hydroperoxides and Hypohalous Species. It is well known that H2O2 reacts with hypochlorous acid to generate stoichiometric amounts of 1O2 in vitro.419 This reaction is responsible for the chemiluminescence observed from activated phagocytes.420−424 The first important evidence for 1 O2 generation in this reaction came from the pioneering works by Seliger, in 1960,425 who recorded a sharp emission band centered at 634 nm for the in vitro reaction of H2O2 and NaOCl. Additional evidence was obtained several years later by Khan and Kasha upon the acquisition of the full visible spectrum corresponding to 1O2 dimol emission bands at 634 and 703 nm.426 Important insights into the mechanisms of 1O2 generation were obtained by Cahill and Taube, who demonstrated, using [18O]-labeled hydrogen peroxide (H18O18OH), that dioxygen formed in the presence of HOCl is derived exclusively from the hydroperoxide without noticeable interference from water or oxygen.32 The result is consistent with a mechanism involving a chlorohydroperoxide intermediate (HOOCl). The reaction most likely proceeds through a mechanism involving the nucleophilic attack of HO2− on the chlorine atom of HOCl to

a

This reaction involves a chlorine atom transfer reaction to generate a chlorohydroperoxide intermediate that decomposes to generate peroxyl and chlorine radicals. Recombination of labeled peroxyl radicals yields labeled 1O2.

observed for the reaction of LA18O18OH with metal ions, 18Otracer studies revealed alterations in the relative amounts of the labeled compounds by atmospheric oxygen dissolved in the solution, indicating the occurrence of the same exchange mechanisms. The detection of fully [18O]-labeled 1O2 as well as peroxyl radicals by EPR51 provided strong evidence for the involvement of Russell mechanism. The relative yields of 1O2 formation in the reaction of hydroperoxides with HOCl were compared. The highest yield of 1 O2 was observed when H2O2 was used as the peroxide source, which is consistent with the stoichiometric generation of 1O2 in this reaction.419 In contrast, the reaction with lipid hydroperoxides gave 1O2 in approximately 10% yield, a value that is similar to the metal-catalyzed decomposition of organic hydroperoxides.50,376 Moreover, in accordance with the Russell mechanism, 1O2 was not formed in the reaction of HOCl with tertiary hydroperoxides (tert-butyl hydroperoxide and cumene hydroperoxide).51

4. PROTEINS Initial studies on the photosensitized oxidation of proteins by 1 O2 date back to the 1900s.427 Early studies focused on the determination of the susceptibility of amino acids and reaction rate constants. Those studies found that 1O2 reacts selectively with a few amino acids residues in proteins, including cysteine, histidine, methionine, tryptophan, and tyrosine.428 The reaction of 1O2 with these amino acids is essentially described in terms of chemical quenching, with the exception of tryptophan, for which collisional deactivation as the result of physical quenching is not negligible.429 With the efforts of different research groups, the 1 O2 oxidation products of reactive amino acids has been at least partly elucidated. The study of 1O2-generated damage to proteins in cells and organisms is still a challenging issue, but significant advances are being made employing theoretical studies430−432 and new techniques such as LC-MS/MS,433−436 genetically encoded protein encapsulated sensitizers,213 and direct 1O2 optical excitation.369 Here, we will start by reviewing W


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the reactions of 1O2 with each amino acid, either as an isolated component or when incorporated in peptides or proteins. This is followed by a brief description of advances in the field that will enable us to pinpoint 1O2 oxidation reactions of amino acids in biological systems.

reaction of 1O2 with protonated ((HSCH2CH(NH3+)CO2H) or deprotonated cysteine (HSCH2CH(NH2)CO2−) in the gas phase gives rise to a sulfur hydroperoxide/persulfoxide as the first intermediate.430,432 In the case of protonated cysteine, this intermediate decomposes into H2NCHCO2H+, CH3SH, and 3 O2.430 Deprotonated cysteine reacts with 1O2 in the gas phase, yielding mainly NH2CH2CO2−, neutral CH2S, and 3O2.432 Aiming to resemble reaction in aqueous solution, another gasphase study investigated the effects of hydration on 1O2 oxidation of protonated and deprotonated cysteine molecules.444 Thus, contrasting with gas-phase reactions with dehydrated protonated/deprotonated Cys, where the intermediate hydroperoxide/persulfoxide could not be detected, reactions with hydrated protonated and deprotonated cysteine in the gas phase generate a more stable persulfoxide/ hydroperoxide intermediate, detected by guided-ion-beam mass spectrometry.444

4.1. Cysteine

The rate constant of 1O2 chemical reaction with cysteine (8.9 × 106 M−1 s−1) was obtained by time-resolved measurements of the decay of 1O2 phosphorescence at 1270 nm.437 Chemical reactivity accounts fully for the quenching of singlet oxygen by thiols.438 Evidence points toward the reaction of 1O2 with the ionized thiol group of cysteine.438,439 Thus, the experimental pK values, inferred from the pD-dependent variation of 1O2 quenching for cysteine, N-acetylcysteine, and the tripeptide glutathione (GSH), were 8.6, 10.0, and 9.2, respectively, in very good agreement with the corresponding −SH acid dissociation constants of 8.3, 9.65, and 8.75 (considering that pK in D2O = pK in H2O + 0.4).439 Cysteine disulfide (cystine) and glutathione disulfide do not react with 1O2.438,440,441 Early studies showed that proflavin-mediated photosensitization of cysteine leads quantitatively to cystine.442 Exposure of cysteine to 1O2, chemically generated by the HOCI−H2O2 system at pH 6.8, gives rise to the same product, contrasting with 1 O2-independent photosensitization by crystal violet, which produces only cysteic acid.442 The mechanism of reaction of 1O2 with cysteine has not been explored in detail. The reaction is proposed to proceed via addition of 1O2 to the unprotonated thiol (Cys-S−), leading to a persulfoxide intermediate and, eventually, to disulfide formation (Scheme 22).437,439 It is believed that 1O2 oxidation of cysteine

4.2. Methionine

The chemical rate constant for the reaction of 1O2 with methionine in D2O is 1.7 × 107 M−1 s−1.429 No physical quenching occurs. Early studies showed photooxidation of methionine in the presence of MB gives rise to the corresponding sulfoxide, along with a small amount of dehydromethionine.445 Much of the understanding of the photooxidation of methionine is derived from the reaction of 1O2 with organic sulfides. Thus, a persulfoxide is the first formed intermediate, independently of the sulfide structure. The next steps depend on the reaction conditions and substituents.446,447 For instance, dialkyl sulfide photooxidation in aprotic solvents is an inefficient process, with decomposition of the persulfoxide to sulfide and triplet oxygen.447,448 More relevant to methionine oxidation, in protic media, the initially formed persulfoxide (or secondary intermediate) subsequently reacts with starting material to give two equivalents of sulfoxide.446,447,449,450 Thus, the photooxidation of alkyl sulfides showed a stoichiometric requirement of one oxygen molecule to two sulfides (1:2).448 The stoichiometry of methionine photooxidation is more complex than the one seen for alkyl sulfides, being pH dependent but independent of oxygen concentration and solvent composition. An elegant work published more than 40 years ago proposed competing reactions for methionine oxidation by 1O2.451 A persulfoxide is a common intermediate at all pH values. At low pHs, the reaction of methionine with 1O2 follows the reaction for alkyl sulfides. Thus, the intermediate persulfoxide is trapped by a second methionine, yielding two molecules of methionine sulfoxide (Scheme 23, pathway a) whereas no H2O2 is formed. As pH rises, the contribution of this pathway is reduced, and other reactions start to compete. At high pHs (mainly above pH 9), the nucleophilic substitution on the sulfur atom of the methionine persulfoxide intermediate by hydroxide yields equimolecular amounts of sulfoxide and H2O2 (Scheme 23, pathway b). Moreover, a third reaction occurs when the free amino group of methionine nucleophilically attacks the intermediate persulfoxide, generating dehydromethionine and H2O2 (Scheme 23, pathway c). The maximum yield of dehydromethionine is observed around pH 9, coinciding with the pKa of the amino group (9.2). Further increasing the pH also raises the hydroxide concentration, therefore favoring sulfoxide instead of the dehydromethionine pathway.443,451 Competition among these processes in the photooxidation of methionine

Scheme 22. 1O2 Oxidation of Cysteine

leads to cystine, while type I reactions give rise to cysteic acid and H2O2.443 Depending on the photosensitizer used to generate 1O2, both type I and type II reactions might be present. For cysteine, there are no data available using a clean source of 1O2. However, thermodissociation of the endoperoxide of 3,3′-(1,4-naphthylidene) dipropionate was used to investigate the reaction products of 1O2 with cysteine residue incorporated in the tripeptide GSH, the most abundant naturally occurring thiol. Thus, upon reaction with 1O2, GSH is converted to disulfide (GSSG, accounting for 63% of the products formed), sulfoxide (accounting for 14%), sulfonate (accounting for 8%), glutathione sulfinate (accounting for 2%), and other oxidation products (13%).438 Recent studies carried out in the gas phase found that cysteine oxidation by 1O2 in the absence of water yielded different products when compared with reaction in solution.430,432 Thus, X


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Scheme 23. 1O2-Mediated Oxidation of Methionine

Scheme 24. 1O2 Oxidation of 4,5-Diphenylimidazole

previous work was due to type I reactions.454 However, as reported by Sysak et al., the peak formation of dehydromethionine coincides with the pKa of the ammonium group (9.2), decreasing with further increases in pH. The authors calculated that, at pH 9.2, 0.4 equiv of dehydromethionine is formed for each mole of methionine, while at pH 10.2, only 0.1 mol of dehydromethionine is formed when starting with the same amount of methionine.451 More work is needed to address the uncertainty regarding the formation of dehydromethionine either as specifically generated by 1O2 or as the result of side type I reactions. This is particularly important since dehydromethionine has been proposed as a specific biomarker for hypohalous acids and haloamines in neutrophils.455,456

accounted for the variation in O2 uptake. Thus, the methionineto-O2 ratio is 2:1 below pH 5, and 1:1 above pH 7.452 The reactions of 1O2 with N-formylmethionine and Nformylmethionineamide do not yield dehydromethionine analogues, suggesting that this reaction is unlikely to occur with methionine inserted in proteins, where the amino group is involved in a peptide bond.443,451 Recent studies revisited the reaction of 1O2 with methionine in the gas phase and in solution. Thus, the reaction of 1O2 with protonated methionine in the gas phase yields H2O2 and a dehydro compound, H2NCH(COOH)C2H4S+CH2. As in solution, the first step involves addition of O2 to the methionine sulfur, yielding persulfoxide. The persulfoxide intermediate then evolves to an S-hydroperoxide, HN2CH(COOH)CH2CH2S(OOH+)CH3, that eliminates H2O2 in a subsequent step.431 Contrary to the protonated case, no products are formed in the reaction of 1O2 with dehydrated methionine in the gas phase.453 Recently, studies performed in solution have confirmed that oxidation of methionine by 1O2 is mediated by a persulfoxide in both acidic (pH 3.2) and basic (pH 10.4) conditions.454 Methionine sulfoxide was detected as the end product, after the reaction of persulfoxide with another methionine. The authors did not find dehydromethionine as a product at both pHs, and they concluded that the detection of dehydromethionine in

4.3. Histidine

The reported rates of reaction of 1O2 with histidine vary depending on the solvent and the pH of the solution. The chemical reaction rate was reported to be 9 × 107 M−1 s−1 in aqueous solution at pH 7.0.457 Chemical rates in D2O with pD close to neutrality are around 4 × 107 M−1 s−1, as measured by different authors.458−461 However, the rate of reaction increases with the pH of the solution; this is consistent with a faster reaction of 1O2 with the unprotonated imidazole ring (pKa = 5.8).461 Y


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Scheme 25. 1O2 Oxidation of Histidine and Its N-Benzoyl and N-Acetyl Derivatives

diphenylimidazole via a [4+2] cycloaddition to form a 2,5endoperoxide, which, upon warming, rearranges to a hydroperoxide (Scheme 24), that then decomposes according to two distinct pathways. One decomposition reaction (Scheme 24, pathway a) involves the loss of a water molecule to form an imidazolone, that is subsequently converted into 4,5-diphenyl-5hydroxyimidazol-2-one through hydration. In the second pathway, the hydroperoxide is reduced to a diol (Scheme 24, pathway b) that then gives rise to a carbamate through opening of the five-membered ring and subsequent reclosure. Further decomposition leads to CO2 and benzil diimine.157 In aqueous solution, the reaction of 1O2 with histidine, either as the free amino acid or when incorporated into peptides, gives rise to peroxides as monitored by the ferric iron−xylenol orange assay.434 Based upon the results obtained with substituted histidine derivatives, it is postulated that a 1,4-cycloaddition of 1 O2 across the 2,4 and 2,5 carbons of the imidazole ring generates two isomeric endoperoxides (Scheme 25). The endoperoxides undergo rearrangement, yielding three possible peroxides at carbons 3, 4, or 5 of the imidazole ring. In the case of

Early studies described photosensitized oxidation of histidine by 1O2, yielding aspartic acid and urea via several intermediates.462,463 In fact, a complex mixture of degradation products was generated; however, efforts to characterize intermediates of the reaction were unsuccessful due to the instability of these compounds. Therefore, first attempts to study the mechanism of histidine oxidation by 1O2 were carried out using its N-benzoyl derivative with MB as the photosensitizer in aqueous solution at pH 11.0.463 Two endoperoxides were proposed as the first intermediate products, arising from a 1,4 cycloaddition of 1O2 to the conjugated double bonds of N-benzoylhistidine.462,463 Generation of an endoperoxide through cycloaddition of 1O2 to the imidazole ring was confirmed by Kang and Foote using 4,5-diphenylimidazole as a model compound. Those authors successfully identified the 2,5-endoperoxide formed upon oxidation of 4,5-diphenylimidazole by 1O2 at −100 °C.464 This was achieved through careful 13C and 1H NMR measurements of the main photoproducts present in the irradiated solution. Subsequent studies proposed a detailed mechanism for the reaction. Thus, 1O2 reacts with 4,5Z


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Scheme 26. 1O2 Oxidation of Tyrosine

4.4. Tyrosine

Labile isomeric peroxides were the first products detected after careful photooxidation of tyrosine in the presence of RB. The complete characterization by NMR analyses of these initially formed 1O2 oxidation products was not achieved due to their high instability, but the presence of peroxidic groups was established from HPLC/MS and ferric iron−xylenol orange analyses.433 Further relevant reactivity and structural information was gained from time course examination of the reaction products after cessation of irradiation. Thus, the labile peroxides were found to be converted into an enantiomeric mixture of cyclic peroxides that were assigned by 1H and 13C NMR analyses as (2S,3aR,7aR)- and (2S,3aS,7aS)-3a-hydroperoxy-6-oxo2,3,3a,6,7,7a-hexahydro-1H-indole-2-carboxylic acids. In a subsequent step, the cyclic peroxides decayed to their corresponding alcohols that were identified by consideration of their NMR features as an enantiomeric mixture of the previously characterized HOHICA compounds.433 Thus, reaction of 1O2 and tyrosine can be rationalized in terms of a Diels−Alder [4+2] cycloaddition of 1O2 to the tyrosine ring, yielding diastereomeric 1,4-endoperoxides that are likely to be unstable, since no reports of their detection are available (Scheme 26).34 Subsequent opening of endoperoxides would give rise to labile hydroperoxides.433 A Michael-type addition of the free amino group to the phenolic ring is likely to explain the formation of the NMR-characterized bicyclic diastereomeric hydroperoxides, which then decompose into their corresponding alcohols (HOHICA) (Scheme 26, pathway a).34 Reaction of 1 O2 with tyrosine incorporated in peptides gives rise only to ringopened hydroperoxides (Scheme 26, pathway b).433 The absence of a cyclization reaction with the peroxide derived from tyrosine-containing peptides is probably due to the delocalization of the nitrogen lone pair on the peptide bond. This would decrease the nucleophile feature of the N-atom, thus preventing the cyclic Michael reaction from occurring. Interestingly, hydroperoxides formed in tyrosine-containing peptides were shown to be more stable than those formed upon photooxidation of the free amino acid.433

1

4.5. Tryptophan

the free amino acid, subsequent decomposition of these peroxides is followed by nucleophilic attack of the α-amino group onto the oxidized, but still preserved, imidazole ring, generating bicyclic products (Scheme 25, pathway a). These isomeric bicyclic products induced by RB-sensitized oxidation of histidine by UVA radiation in aerated solutions were identified by NMR analyses.434 When photooxidation of imidazole was carried out in methanol, the solvent served as a nucleophile to intercept unstable intermediates. Thus, 4,5-dimethoxyimidazolidin-2one, showing incorporation of one molecule of oxygen and two molecules of methanol, was isolated as the final product after 1O2 oxidation of imidazole.465 Indeed, cross-linked materials have repeatedly been reported as a result of histidine oxidation by 1O2 in model peptides or proteins.434,463,466−469 To avoid intramolecular reaction with the α-amino group, Nbenzoylhistidine and N-acetylhistidine were used as more relevant model compounds for elucidating the nature of His− His cross-links as produced by 1O2 oxidation in proteins.434,470 A major cross-linked product was identified on the basis of extensive NMR measurements in the reaction of 1O2 with both N-benzoyl and N-acetyl-histidine. The formation of the adducts was rationalized in terms of addition of a molecule of the parent compound to an oxygenated imidazole ring, with a subsequent elimination of H2O from the dimeric species (Scheme 25, pathway b).434,470 In theory, multiple dimers can be formed after decomposition of initially formed α-amino-protected histidine endoperoxides. Indeed, six different cross-linked products were identified upon photooxidation of N-benzoylhistidine at pH 11.463 However, the dimeric species shown in Scheme 25, pathway b, was the main structure identified by different researchers using distinct histidine derivatives. The depicted dimer shows the least steric hindrance during the nucleophilic addition process and has the most stable conjugated resonance structure.470 O2 reacts with tyrosine in deuterated aqueous solution (pD 7.4) at a chemical rate constant of 0.7 × 107 M−1 s−1, without evidence for a contribution of physical quenching.429 The first photoproduct reported in this reaction was a lactam (3ahydroxyhexahydro-1H-indole-2,6-dione).471 Further work using RB as the photosensitizer allowed the identification of 3a-hydroxy-6-oxo-2,3,3a,6,7,7a-hexahydro-1H-indol-2-carboxylic acid (HOHICA, 90% yield) and dityrosine (10% yield) as products of the reaction.472 However, only HOHICA was believed to result from type II photosensitization reaction.

Tryptophan is the only amino acid able to react with 1O2 by physical quenching and chemical oxidation. Thus, the total rate constant considering both chemical reaction and physical quenching in D2O and pD 8.4 was reported to be 5.1 × 107 M−1 s−1, while the reported chemical reaction rate was 3 × 107 M−1 s−1.429 In a mixture of D2O:ethanol (1:1, v/v), the total rate constant measured was 3.2 × 107 M−1 s−1. This has to be compared with the chemical reaction rate constant that was found to be 1.3 × 107 M−1 s−1.460 The chemical rate constant AA


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Scheme 27. 1O2 Oxidation of Tryptophan

obtained for reaction of 1O2 with tryptophan inserted into melittin, a small protein that contains only one tryptophan residue, was close to that obtained for the reaction with Nacetyltryptophan amide (both rate constants in the order of 107 M−1 s−1).473 Of note, tryptophan is an exposed residue in melittin. Another study reported that the rate constant for the reaction of 1O2 with tryptophan inserted in proteins depends not only on the position of this amino acid in the protein but also on the accessibility of the tryptophan residue to oxygen and the protein local environment.474 The generation of 1O2 was achieved in aerated aqueous solutions using RB or MB as the photosensitizer and visible light for the excitation. Thus, physical and chemical rate constants of 1O2 with proteins that contain a single tryptophan residue were found to decrease concomitantly with the accessibility of the amino acid to the solvent. The local environment is also important: the rate constant of 1O2 reaction with buried tryptophan in ribonuclease T1 was determined to be 6.4 × 106 M−1 s−1, which is much higher than the rate constant obtained for the 1O2 reaction with buried tryptophan in asparaginase (300 nm) irradiation of α-crystallin isolated from calf lenses in the presence of hypericin as the type II photosensitizer gave rise to aggregates that were detected by sodium dodecyl sulfate−polyacrylamide gel electrophoresis. Further analyses by mass spectrometry showed that oxidation takes place at methionine, tryptophan, and histidine residues of α-crystallin.494 Other studies have focused on the identification of 1O2 main targets and the reaction products in model protein systems. For instance, after photooxidation of calf α-crystallin with porphyrins as 1 O 2 generators, losses of histidine and methionine-containing peptides were reported. Besides, a tryptophan residue from the N-terminal region was converted to N-formylkynurenine, although a buried tryptophan residue remained intact.495 Cytochrome c was also used in a model study to investigate 1 O 2 reaction with amino acid residues. Interestingly, methionine, histidine, and tryptophan were found to be preferential amino acid targets for oxidation. In addition, phenylalanine was also oxidized, whereas tyrosine residues remained intact.496 In another study where lysozyme was exposed to 1O2, the same amino acids, including methionine, histidine, and tryptophan, were found to be the main oxidation targets.497 Thus, methionine residues were oxidized to sulfoxides (mass shift, +16), histidine to a hydroxyimidazolone (mass shift, +32) and its dehydration product (mass shift, +14), and tryptophan to a mixture of Nformylkynurenine (mass shift, +32), kynurenine (mass shift, +4), and an alcohol at C3 (mass shift, +16).496,497 It is interesting to point out that an unidentified cross-link involving histidine and lysine was also suggested to be generated upon 1O2 oxidation of cytochrome c.496 Cross-links involving tryptophan and tyrosine residues of glucose 6-phosphate dehydrogenase were also identified after reaction of this enzyme with 1O2.498 Cross-links caused by exposure to 1O2 have been proposed for a long time. In a seminal work published in 1980, cross-links were detected upon photosensitization of lens crystallins.499 However, a deep understanding of 1O2 oxidation reactions of proteins and the resulting biomolecular effects in cellular systems is still lacking. Recent advances in analytical tools, especially in mass spectrometry-based proteomics, are expected to allow a more profound characterization of 1O2 oxidation products of proteins in complex systems. In that respect, encouraging data are emerging. For instance, cross-links between DNA repair proteins and DNA were identified after UVA light exposure in the presence of 6-TG, an anti-cancer drug with photosensitization properties that is able to be metabolically incorporated into DNA.500

luminescent, and the spectrum obtained during the decomposition matches that of N-formylkynurenine emission.435 The mechanism of chemiluminescent decomposition of dioxetanes formed in substituted indoles is well accepted.483−485 Diastereomeric dioxindolylalanines (α-amino-2,3-dihydro-3hydroxy-2-oxo-1H-indole-3-propanoic acid) were also identified as minor products of the photooxidation of tryptophan.486,487 Thus, tryptophan dioxetane, formed by either cycloaddition of 1 O2 or hydroperoxide decomposition, would generate Nformylkynurenine as the expected ring cleavage product. However, a small fraction of this dioxetane would decompose through an initial O−O cleavage, followed by a hydrogen transfer and molecule rearrangement, giving rise to dioxindolylalanines.487 This type of dioxetane decomposition was previously reported in the photooxygenation of enamines and appears to involve a two-step cleavage mechanism.488 After photooxidation of tryptophan-containing peptides and proteins followed by complete enzymatic digestion, Nformylkynurenine and a bicyclic alcohol derivative at C3 of the indole ring were detected.486 Surprisingly, tricyclic alcohols derived from thermal decomposition of hydroperoxides were also detected after these reactions. These products were unexpected, given that in proteins the amino terminal group is incorporated in a peptide bond, therefore reducing the availability of the nitrogen lone pair for the ring closure reaction.486 On the other hand, RB-sensitized oxidation of the tryptophan-containing peptide LLWLR gave rise to hydroxyformylkynurenine.489 4.6. Reaction with Amino Acids in Proteins

There are several studies showing formation of peroxides upon photosensitization of proteins either isolated, in plasma, or in cell culture.490,491 However, very few reports address the identity of protein oxidation products formed upon photosensitization and the potential mechanisms of such reactions. Two major issues remain regarding 1O2 oxidation of proteins: First, it is necessary to distinguish the damage caused by 1O2 from that caused by other reactive species; a good strategy to address this issue is to clearly define specific markers of 1O2 damage to proteins. Second, after having established 1O2 as the oxidant, it is highly relevant to determine in a specific environment (i.e., a protein, a cell, or an organelle) the preferred targets for 1O2 and the key factors affecting the specificity. Aiming to identify molecular markers to distinguish 1O2mediated oxidation of tryptophan residues from •OH reaction, Plowman et al.489 used small model peptides containing either tryptophan or tyrosine. Tyrosine oxidation products could not be used as markers of 1O2-damage, since •OH reactions generate similar oxidation products (dihydroxyphenylalanine (DOPA) and trihydroxyphenylalanine (TOPA)). In contrast, oxidation of tryptophan by 1O2 yielded formylkynurenine and hydroxyformylkynurenine, while •OH-mediated oxidation gave rise to hydroxytryptophan. The authors then identified hydroxytryptophan after a keratin-enriched extract was exposed to UVB light, and they suggested that oxidative degradation occurred primarily via •OH attack.489 Given their exposure to light, skin and eyes are anticipated targets for 1O2 oxidation. Thus, in the presence of porphyrins, UVA-irradiated human lens epithelial cells accumulate Nformylkynurenine, as detected by a fluorescent antibody and confocal microscopy. The damage was shown to be mediated by 1 O2.492 Photooxidative damage was also detected in human lens epithelial cells exposed to UVA in the presence of hypericin.

5. CONCLUSIONS AND PERSPECTIVES Kinetic studies have defined the major targets of 1O2 in biological systems. Extensive product analysis and mechanistic studies have allowed a comprehensive characterization of the reactions of 1O2 with biomolecules. Thus, the main degradation pathways of the guanine in isolated nucleosides, oligonucleotides, and cellular DNA have been characterized.29,74,75 In addition, major efforts have been devoted to the elucidation of the main oxidation mechanisms of both isolated DNA and cellular DNA by one-electron oxidants and •OH, two other relevant oxidizing agents.29 It is well established that lipid hydroperoxides are the primary products of reaction of 1O2 with lipids, either isolated or in membranes, although dioxetane AC


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intermediates (e.g., cholesterol321 and plasmalogen339 oxidation) and endoperoxides (e.g., ergosterol and 7-dehydrocholesterol oxidation)280 have also been identified. For some time, it has been known that only five amino acidscysteine, histidine, methionine, tryptophan, and tyrosinereact with 1O2 at appreciable rates. Reaction products of 1O2 oxidation have been elucidated for all reactive amino acids, either isolated or when incorporated in peptides and proteins. Singlet oxygen was unambiguously identified as culprit in many relevant conditions in vivo, such as in photosensitization reactions caused by exogenous or endogenous photosensitizers or during PDT. Its presence was confirmed in cell systems and tissue through direct detection of its characteristic luminescence in the NIR region (1270 nm).211,255,501−503 However, assessment of 1O2 preferential targets in a specific condition is a challenging objective. The exact identity of the biomolecule targeted by 1O2 in a cellular system will depend on the site of its generation, and the measurement of key selected biomarkers can provide clues about 1O2 spatial occurrence and preferential targets. As reviewed here, many fatty acid and cholesterol hydro(per)oxide isomers can be used as signature/reporter molecules to trace 1O2 formation in vivo. Singlet oxygen constitutes a potential generator of lipid hydroperoxides in biological system together with other known sources, such as lipoxygenases and iron-induced lipid peroxidation. Attention has been focused on lipid hydroperoxide formation as a key event associated with biologically relevant processes. Interestingly, genetic and pharmacological interventions that disrupt hydroperoxide detoxification have been shown to induce a specific type of cell lethality, named ferroptosis.348 Importantly, major progress has been made toward analytical strategies to detect and quantify isomeric and isobaric lipid hydroperoxides and hydroxides with high specificity and sensitivity.504 In this context, the development of modern high-resolution mass spectrometry (HRMS)-based omics tools may provide a powerful way to detect 1O2 signature products. The cell type also influences the photosensitized formation of 1 O2 in human cells. It has been shown that the photosensitized formation of 8-oxoG is twice more elevated in melanocytes with respect to fibroblasts and keratinocytes.263 Melanin, a skin pigment, is known to photosensitize the formation of both 1O2 and O2•− while being a putative scavenger of both ROS. It remains to establish the relative contribution of 1O2 versus other oxidants in the formation of 8-oxodGuo in the DNA of melanocytes and other skin cells. Monomeric melanin component(s) are also implicated in the dark formation of 1 O2 subsequent to solar UV irradiation.268 This is likely to involve the transient generation of dioxetanes that subsequently decompose into triplet excited carbonyls giving rise to cyclobutane pyrimidine dimers according to chemiexcitation mechanism.272,505 The role of 1O2 in the formation of this reactive intermediate and the likely dark generation of 8oxodGuo in melanocytes and inflamed tissues remain to be further delineated. Strategies to address damage to a specific cellular compartment include the use of organelle-specific (or at least preferential) sensitizers, genetically encoded protein213,506,507 encapsulated sensitizers, and direct 1O2 optical excitation.369 The first approach was employed to show that MB concentrates in lysosomes of breast cancer cells and that PDT induces selective death of these cells.508 The use of 6-TG constitutes an excellent tool to understand cellular effects of 1O2 generation in the nucleus of cells. 6-TG is an immunosuppressive agent that is

incorporated in DNA, thus increasing skin sensitivity to UVA light through 1O2 generation. Photochemical activation of DNAincorporated 6-TG has been shown to trigger DNA and protein oxidation.500,509 However, there is a need to gain further information on the efficiency for UVA-excited 6-TG to generate 8-oxodGuo in cellular DNA and possibly secondary oxidation products such as dSp. The use of genetically encoded protein-based chromophores is a relatively new field of research and, as such, still needs to overcome certain limitations. It is nevertheless a great approach to increase the specificity of intracellular 1O2 generation.213 Thus, improvement of genetically encoded tags such as the mini 1 O2 generator (miniSOG)510 and 1O2 photosensitizing protein (SOPP)507 will enable the study of 1O2-specific effects at the sub-organelle level in a cell. Phototoxic or signaling effects of the genetically encoded photosensitizers will depend on intracellular target, light intensity, and exposure times. Optogenetic approaches have many therapeutic applications, such as selective killing of tumor cells.511 An important point to address in protein-encapsulated photosensitizers is the ability of the generated 1O2 to diffuse the protein matrix.507 For example, molecular dynamics simulations for the fluorescent protein Killer Red showed that 1 O2 can diffuse out of the protein via a water-filled channel. However, subsequent studies showed that Killer Red acts preferentially by electron-transfer-mediated mechanisms.512 Therefore, for a given protein-encapsulated photosensitizer, a careful examination of the reactive species generated is needed, together with studies that address the ability of 1O2 to diffuse through the protein matrix and/or to react with amino acid residues of the encasing protein. This topic is reviewed by Westberg et al.213 Finally, direct optical excitation of 3O2 yielding 1O2 is a new area369,513 that, together with the deep knowledge obtained about 1O2 reaction chemistry with its biological targets, may help to understand the roles of 1O2 in living systems. Singlet molecular oxygen has established biological roles in plants in the context of photosynthesis,514 photosynthetic bacteria, and some fungi,515,516 and it can also be formed by certain mammalian enzymes.287 The reactivity of 1O2 with biomolecules, as amino acids or lipids, may generate specific stereoselective oxidation products. The elucidation of these structures and their specific targets can give important information and new horizons on the (patho)physiological function for 1O2 in mammals via formation of signaling molecules.

AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Paolo Di Mascio: 0000-0003-4125-8350 Sayuri Miyamoto: 0000-0002-5714-8984 Marisa H. G. Medeiros: 0000-0002-5438-1174 Notes

The authors declare no competing financial interest. Biographies Paolo Di Mascio obtained his Ph.D. at the Heinrich Heine Universität, Düsseldorf, Germany, and the Université Catholique de Louvain, Brussels, Belgium. He is full Professor of Biochemistry at the AD


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́ ́ Departamento de Bioquimica and director of the Instituto de Quimica, Universidade de São Paulo, São Paulo, Brazil. His main research activities deal with chemical and biochemical aspects of oxidatively generated and photoinduced damage to biomolecules. His studies focus on providing the mechanisms by which singlet molecular oxygen and other reactive oxygen species play their physiological and pathological roles. He has devoted efforts to developing singlet oxygen generators based on the thermolysis of endoperoxides, including endoperoxide isotopically labeled as a source of singlet molecular [18O]-oxygen. He was awarded a fellowship by the John Simon Guggenheim Memorial Foundation.

His main research interests focus on the elucidation of molecular effects and biochemical consequences of solar radiation and biologically relevant oxidants on nucleic acids ranging from model compounds to cells. He is co-author of 615 peer-reviewed articles and book chapters and his h-index is 84. Among several editorial activities, he has been Editor-in-Chief of Photochemistry & Photobiology since 2009.

ACKNOWLEDGMENTS We thank FAPESP (Fundaçaõ de Amparo à Pesquisa do Estado de São Paulo; P.D.M., No. 2012/12663-1; G.E.R., Programa Jovens Pesquisadores em Centros Emergentes 2016/00696-3), CEPID Redoxoma (P.D.M, M.H.G.M., S.M., and G.E.R., No. 2013/07937-8), CNPq (Conselho Nacional para o Desenvolví mento Cientifico e Tecnológico; P.D.M., No. 302120/2018-1; G.R.M., No. 309880/2017-3, M.H.G.M., No. 301404/2016-0; S.M., No. 424094/2016-9; and G.E.R., No. Universal 402683/ 2016-1), CAPES (Coordenaçaõ de Aperfeiçoamento de Pessoal ́ Superior), PRPUSP (Pro-Reitoria de Pesquisa da de Nivel Universidade de Sã o Paulo, NAP Redoxoma No. 2011.1.9352.1.8), and John Simon Guggenheim Memorial Foundation (P.D.M. fellowship) for financial support.

Glaucia Regina Martinez graduated in Chemistry from the University of São Paulo (USP) in 1998, received the Lavoisier Prize from Regional Council of Chemistry-IV region (diploma of honor to merit as best student−Industrial Option in the period 1995−1998), Ph.D. (2003) in Sciences−Biochemistry from USP, with an intermediate stay at CEA Grenoble, France (2002), and postdoctoral degree from USP (2004). Currently she is Associate Professor at the Department of Biochemistry and Molecular Biology of the Federal University of Paraná (UFPR). Her research work has emphasis on reactive oxygen species, biomolecule damage, metabolism, and bioenergetics. In 2007, she received a scholarship grant for Women in Science from L’Oreal, the Brazilian Academy of Sciences and UNESCO.

REFERENCES

Sayuri Miyamoto received her B.S. degree (1994) in Pharmacy and Biochemistry from the University of São Paulo. She then spent 5 years in Japan under the guidance of Prof. Junji Terao, studying lipid hydroperoxides and antioxidants. After receiving a M.S. degree in Nutrition (2000) from the University of Tokushima, Japan, she returned to Brazil, where she obtained her Ph.D. degree in Biochemistry (2005) from the University of São Paulo. Her doctoral work, performed under the supervision of Prof. Paolo Di Mascio, focused on reaction mechanisms involving lipid hydroperoxides and the generation of singlet molecular oxygen. She is now Associate Professor at the Department of Biochemistry, Institute of Chemistry, University of São Paulo. Her research interest is focused on understanding the chemical and biological mechanisms involving oxidized lipids (e.g., lipid hydroperoxides) in biological systems.

(1) Kautsky, H. Quenching of Luminescence by Oxygen. Trans. Faraday Soc. 1939, 35, 216−219. (2) Foote, C. S.; Wexler, S. Singlet Oxygen. A Probable Intermediate in Photosensitized Autoxidations. J. Am. Chem. Soc. 1964, 86, 3880− 3881. (3) Foote, C. S. Photosensitized Oxygenations and the Role of Singlet Oxygen. Acc. Chem. Res. 1968, 1, 104−110. (4) Foote, C. S. Mechanisms of Photosensitized Oxidation. There are Several Different Types of Photosensitized Oxidation which may be Important in Biological Systems. Science 1968, 162, 963−970. (5) Adam, W.; Kazakov, D. V.; Kazakov, V. P. Singlet-Oxygen Chemiluminescence in Peroxide Reactions. Chem. Rev. 2005, 105, 3371−3387. (6) Klebanoff, S. J. Myeloperoxidase: friend and foe. J. Leukocyte Biol. 2005, 77, 598−625. (7) Kanofsky, J. R.; Axelrod, B. Singlet Oxygen Production by Soybean Lipoxygenase Isozymes. J. Biol. Chem. 1986, 261, 1099−1104. (8) Di Mascio, P.; Bechara, E. J. H.; Medeiros, M. H. G.; Briviba, K.; Sies, H. Singlet Molecular-Oxygen Production in the Reaction of Peroxynitrite with Hydrogen-Peroxide. FEBS Lett. 1994, 355, 287− 289. (9) Martinez, G. R.; Di Mascio, P.; Bonini, M. G.; Augusto, O.; Briviba, K.; Sies, H.; Maurer, P.; Rothlisberger, U.; Herold, S.; Koppenol, W. H. Peroxynitrite does not Decompose to Singlet Oxygen ((1)Delta (g)O(2)) and Nitroxyl (NO(−)). Proc. Natl. Acad. Sci. U. S. A. 2000, 97, 10307−10312. (10) Miyamoto, S.; Ronsein, G. E.; Correa, T. C.; Martinez, G. R.; Medeiros, M. H. G.; Di Mascio, P. Direct Evidence of Singlet Molecular Oxygen Generation from Peroxynitrate, a Decomposition Product of Peroxynitrite. Dalton Trans 2009, 5720−5729. (11) Cilento, G. In Chemical and biological generation of excited states; Adam, W., Ed.; Academic Press: London, 1982; pp 277−307. (12) Cilento, G.; Adam, W. Photochemistry and Photobiology without Light. Photochem. Photobiol. 1988, 48, 361−368. (13) Briviba, K.; Saha-Moeller, C. R.; Adam, W.; Sies, H. Formation of Singlet Oxygen in the Thermal Decomposition of 3-Hydroxymethyl3,4,4-Trimethyl-1,2-Dioxetane, a Chemical Source of Triplet-Excited Ketones. Biochem. Mol. Biol. Int. 1996, 38, 647−651. (14) Bastos, E. L.; Farahani, P.; Bechara, E. J. H.; Baader, W. J. FourMembered Cyclic Peroxides: Carriers of Chemical Energy. J. Phys. Org. Chem. 2017, 30, e3725.

Graziella E. Ronsein obtained her Ph.D. in Biochemistry from the University of Sao Paulo. She subsequently took a postdoctoral position in the Department of Medicine, Division of Metabolism, Endocrinology and Nutrition at the University of Washington. After that, she started her own lab in the Department of Biochemistry at University of São Paulo. Her group is interested in understanding how chemical modifications and alterations in protein levels caused by oxidative and inflammatory processes influence the metabolism of cells. Marisa Helena Gennari de Medeiros earned her bachelor degree in Chemistry and her Ph.D. in Biochemistry at São Paulo University, Brazil. She performed postdoctoral studies at University of Düsseldorf, working with Prof. Helmut Sies. In 1988, she returned to Brazil, where she is now a Professor at the Biochemistry Department , São Paulo University. Her current focus is to understand how each redox-active intermediate reacts with specific biomolecules and the resulting effects, essential for designing biomarkers. Studies about singlet oxygen reactivity and detection in cells as well as aldehydes and their reactivity with DNA have proven promising to characterize biomarkers. She is coauthor of 180 peer-reviewed articles and her h-index is 36. Jean Cadet graduated and obtained his Ph.D. from the University of Grenoble before becoming the head of the laboratory “Lésions des Acides Nucléiques” that he created at the French Atomic Energy Institute in Grenoble, France. He has been affiliated since 2001 as Adjunct Professor to University of Sherbrooke, Sherbrooke, Canada. AE


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