Type I and Type II photosensitization of DNA etheno adducts.

Photophysical and photochemical studies were carried out to examine the photoreactivity of etheno adducts, 1,N-ethenoadenine (εdA) and 1,N-ethenoguanine (εdG), in the presence of two well-known photosensitizers acting by Type I and/or Type II mechanisms such as 4-carboxybenzophenone (CBP) and rose Bengal (RB), respectively. Steady-state photolysis experiments combined with HPLC and mass spectroscopy measurements lead to photoproducts that correspond to the repaired nucleosides. To determine the mechanism of this photooxidation processes, phosphorescence spectroscopy, direct detection of singlet oxygen luminescence and laser flash photolysis were carried out.

Photosensitizing Properties of the Topical Retinoid Drug Adapalene.

Photoreactivity is an important issue for topical drugs especially when these are applied on the sun-exposed skin area. In this context, third-generation retinoids are of special interest due to their conjugated chemical structure and their use in the treatment of acne. Herein, the phototoxic potential of one of these drugs, adapalene, is established using an in vitro 3T3 Neutral Red Uptake (NRU) test.

Environmentally sensitive fluorescence of the topical retinoid adapalene.

Intrinsic fluorescence of drugs brings valuable information on their localization in the organism and their interaction with key biomolecules. In this work, we investigate the absorption and emission properties of the topical retinoid adapalene in different solvents and biological media. While the UVA/UVB absorption band does not exhibit any significant solvent-dependent behavior, a strong positive solvatochromism is observed for the emission.

The Excited State Dynamics of a Mutagenic Guanosine Etheno Adduct Investigated by Femtosecond Fluorescence Spectroscopy and Quantum Mechanical Calculations.

Femtosecond fluorescence upconversion experiments were combined with CASPT2 and time dependent DFT calculations to characterize the excited state dynamics of the mutagenic etheno adduct 1,N-etheno-2'-deoxyguanosine (ϵdG). This endogenously formed lesion is attracting great interest because of its ubiquity in human tissues and its highly mutagenic properties. The ϵdG fluorescence is strongly modified with respect to that of the canonical nucleoside dG, notably by an about 6-fold increase in fluorescence lifetime and quantum yield at neutral pH.

Reductive Photocycloreversion of Cyclobutane Dimers Triggered by Guanines.

The quest for simple systems achieving the photoreductive splitting of four-membered ring compounds is a matter of interest not only in organic chemistry but also in biochemistry to mimic the activity of DNA photorepair enzymes. In this context, 8-oxoguanine, the main oxidatively generated lesion of guanine, has been shown to act as an intrinsic photoreductant by transferring an electron to bipyrimidine lesions and provoking their cycloreversion. But, in spite of appropriate photoredox properties, the capacity of guanine to repair cyclobutane pyrimidine dimer is not clearly established.

Pterin-lysine photoadduct: a potential candidate for photoallergy.

Photoallergy is a photosensitivity disorder associated with a modified ability of the skin to react to the combined effect of drugs and sunlight. It has been attributed to the covalent conjugation of proteins with a photosensitizer, yielding modified macromolecules that can act as antigen provoking the immune system response. The potential role of some endogenous compounds as photoallergens has not been fully established.

Model Studies on the Photoreduction of the 5-Hydroxy-5,6-dihydrothymine and 5-Methyl-2-pyrimidone Moieties of (6-4) Photoproducts by Photolyase.

Photorepair mechanism of (6-4) photoproducts (6-4PP) by photolyase has been the subject of active debate over the years. The initial rationalization based on electron transfer to an oxetane or azetidine intermediate formed upon binding to the enzyme has been questioned, and there is now a more general consensus that the lesion is directly reduced from the excited flavin cofactor. However, the accepting moiety, i.

The Excited State Dynamics of a Mutagenic Cytidine Etheno Adduct Investigated by Combining Time-Resolved Spectroscopy and Quantum Mechanical Calculations.

Joint femtosecond fluorescence upconversion experiments and theoretical calculations provide a hitherto unattained degree of characterization and understanding of the mutagenic etheno adduct 3,N4-etheno-2'-deoxycytidine (εdC) excited state relaxation. This endogenously formed lesion is attracting great interest because of its ubiquity in human tissues and its highly mutagenic properties. The εdC fluorescence is modified with respect to that of the canonical base dC, with a 3-fold increased lifetime and quantum yield at neutral pH.

Pterin-photosensitization of thymine under anaerobic conditions in the presence of guanine.

Pterin (Ptr) is a model photosensitizer that acts mainly through type I mechanism and is able to photoinduce the one-electron oxidation of purine and pyrimidine nucleobases. However, under anaerobic conditions Ptr reacts with thymine (T) to form photoadducts (Ptr-T) but does not lead to the photodegradation of guanine (G), which is the nucleobase with the lowest ionization potential. Accordingly, G is thermodynamically able to reduce the radicals of the other nucleobases and has been described in this sense as the "hole sink" of the DNA double helix.

Theoretical Study on the Photo-Oxidation and Photoreduction of an Azetidine Derivative as a Model of DNA Repair.

Photocycloreversion plays a central role in the study of the repair of DNA lesions, reverting them into the original pyrimidine nucleobases. Particularly, among the proposed mechanisms for the repair of DNA (6-4) photoproducts by photolyases, it has been suggested that it takes place through an intermediate characterized by a four-membered heterocyclic oxetane or azetidine ring, whose opening requires the reduction of the fused nucleobases. The specific role of this electron transfer step and its impact on the ring opening energetics remain to be understood.

Triplet stabilization for enhanced drug photorelease from sunscreen-based photocages.

Recently, sunscreen-based drug photocages have been introduced to provide UV protection to photoactive drugs, thus increasing their photosafety. Here, combined experimental and theoretical studies performed on a photocage based on the commercial UVA filter avobenzone (AB) and on the photosensitizing non-steroidal anti-inflammatory drug ketoprofen (KP) are presented unveiling the photophysical processes responsible for the light-triggered release. Particular attention is paid to solvent stabilization of the drug and UV filter excited states, respectively, which leads to a switching between the triplet excited state energies of the AB and KP units.

Experimental and theoretical studies on thymine photodimerization mediated by oxidatively generated DNA lesions and epigenetic intermediates.

Interaction of nucleic acids with light is a scientific question of paramount relevance not only in the understanding of life functioning and evolution, but also in the insurgence of diseases such as malignant skin cancer and in the development of biomarkers and novel light-assisted therapeutic tools. This work shows that the UVA portion of sunlight, not absorbed by canonical DNA nucleobases, can be absorbed by 5-formyluracil (ForU) and 5-formylcytosine (ForC), two ubiquitous oxidatively generated lesions and epigenetic intermediates present in living beings in natural conditions. We measure the strong propensity of these molecules to populate triplet excited states able to transfer the excitation energy to thymine-thymine dyads, inducing the formation of cyclobutane pyrimidine dimers (CPDs).

Spectroscopic characterization of dipicolinic acid and its photoproducts as thymine photosensitizers.

Dipicolinic acid (DPA), present in large amount in bacterial spores, has been proposed to act as an endogenous photosensitizer in spore photoproduct formation. The proposed mechanism involves a triplet-triplet energy transfer from DPA to thymine. However, up to now, no spectroscopic studies have been performed to determine the interaction between the endogenous compound and the nucleobase, probably due to its photolability in aqueous solutions.

Photoinduced intersystem crossing in DNA oxidative lesions and epigenetic intermediates.

The propensity of 5-formyluracil and 5-formylcytosine, i.e. oxidative lesions and epigenetic intermediates, in acting as intrinsic DNA photosensitizers is unraveled by using a combination of molecular modeling, simulation and spectroscopy.

A Sunscreen-Based Photocage for Carbonyl Groups.

Photolabile protecting groups (PPGs) have been exploited in a wide range of chemical and biological applications, due to their ability to provide spatial and temporal control over light-triggered activation. In this work, we explore the concept of a new photocage compound based on the commercial UVA/UVB filter oxybenzone (OB; 2-hydroxy-4-methoxybenzophenone) for photoprotection and controlled release of carbonyl groups. The point here is that oxybenzone not only acts as a mere PPG, but also provides, once released, UV photoprotection to the carbonyl derivative.

Chemical Modifications of Globular Proteins Phototriggered by an Endogenous Photosensitizer.

The main goal of the present work was to investigate the damages photoinduced by pterin (Ptr), an endogenous photosensitizer present in human skin under pathological conditions, on a globular protein such as ubiquitin (Ub). Particular attention has been paid on the formation of covalent adducts between Ptr and the protein that can behave as photoantigen and provoke an immune system response. Here, a multifaceted approach including UV-visible spectrophotometry, fluorescence spectroscopy, electrophoresis, size exclusion chromatography, and mass spectrometry is used to establish the Ub changes triggered by UV-A irradiation in the presence of Ptr.

Triplet photosensitization mechanism of thymine by an oxidized nucleobase: from a dimeric model to DNA environment.

Nucleic acids are constantly exposed to external agents that can induce chemical and photochemical damage. In spite of the great advances achieved in the last years, some molecular mechanisms of DNA damage are not completely understood yet. A recent experimental report (I.

Experimental and Theoretical Study on the Cycloreversion of a Nucleobase-Derived Azetidine by Photoinduced Electron Transfer.

Azetidines are interesting compounds in medicine and chemistry as bioactive scaffolds and synthetic intermediates. However, photochemical processes involved in the generation and fate of azetidine-derived radical ions have scarcely been reported. In this context, the photoreduction of this four-membered heterocycle might be relevant in connection with the DNA (6-4) photoproduct obtained from photolyase.

Sunscreen-Based Photocages for Topical Drugs: A Photophysical and Photochemical Study of A Diclofenac-Avobenzone Dyad.

Photosensitization by drugs is a problem of increasing importance in modern life. This phenomenon occurs when a chemical substance in the skin is exposed to sunlight. Photosensitizing drugs are reported to cause severe skin dermatitis, and indeed, it is generally advised to avoid sunbathing and to apply sunscreen.

Enhanced Drug Photosafety by Interchromophoric Interaction Owing to Intramolecular Charge Separation.

Imatinib is a synthetic tyrosinase inhibitor that is employed for the treatment of some kinds of human cancer. This drug has a low phototoxicity towards DNA, but its pyridylpyrimidine (1) fragment by itself exhibits significant phototoxicitiy. The intrinsic mechanism that leads to the enhanced photosafety of Imatinib is not yet known.

Oxidatively Generated Lesions as Internal Photosensitizers for Pyrimidine Dimerization in DNA.

In this work, the attention is focused on UVA-photosensitized reactions triggered by a DNA chromophore-containing lesion, namely 5-formyluracil. This is a major oxidatively generated lesion that exhibits an enhanced light absorption in the UVB-UVA region. The mechanistic study combining photochemical and photobiological techniques shows that irradiation of 5-formyluracil leads to a triplet excited state capable of sensitizing formation of cyclobutane pyrimidine dimers in DNA via a triplet-triplet energy transfer.

Drug-DNA complexation as the key factor in photosensitized thymine dimerization.

The crucial role of photosensitizer@DNA complexation in the formation of cyclobutane pyrimidine dimers (CPDs) has been demonstrated using femtosecond and nanosecond transient absorption and emission measurements in combination with in vitro DNA damage assays. This finding opens the door to re-evaluate the mechanisms involved in CPDs photosensitized by other chemicals.

Stereoselective Fluorescence Quenching in the Electron Transfer Photooxidation of Nucleobase-Related Azetidines by Cyanoaromatics.

Electron transfer involving nucleic acids and their derivatives is an important field in bioorganic chemistry, specifically in connection with its role in the photo-driven DNA damage and repair. Four-membered ring heterocyclic oxetanes and azetidines have been claimed to be the intermediates involved in the repair of DNA (6-4) photoproduct by photolyase. In this context, we examine here the redox properties of the two azetidine isomers obtained from photocycloaddition between 6-aza-1,3-dimethyluracil and cyclohexene.

Photocages for protection and controlled release of bioactive compounds.

Using a sunscreen-based photocage, we have demonstrated that it is possible to prevent photodegradation of a bioactive compound and to achieve its controlled photorelease. The concept has been proven linking avobenzone, one of the most important UVA blockers, to ketoprofen, which is a representative example of a photosensitive drug.

Photosensitivity to Triflusal: Formation of a Photoadduct with Ubiquitin Demonstrated by Photophysical and Proteomic Techniques.

Triflusal is a platelet aggregation inhibitor chemically related to acetylsalicylic acid, which is used for the prevention and/or treatment of vascular thromboembolisms, which acts as a prodrug. Actually, after oral administration it is absorbed primarily in the small intestine, binds to plasma proteins (99%) and is rapidly biotransformed in the liver into its deacetylated active metabolite 2-hydroxy-4-trifluoromethylbenzoic acid (HTB). In healthy humans, the half-life of triflusal is ca.