Miguel A. Miranda

Organic photocatalysts for the oxidation of pollutants and model compounds

Organic Photocatalysts for the Oxidation of Pollutants and Model Compounds M. Luisa Marin, Lucas Santos-Juanes, Antonio Arques, Ana M. Amat, and Miguel A. Miranda* Instituto Universitario Mixto de Tecnología Química-Departamento de Química (UPV-CSIC), Avda. de los Naranjos s/n, E-46022, Valencia, Spain Departamento de Ingeniería Textil y Papelera, Universidad Polit ecnica de Valencia, Campus de Alcoy, Plaza Ferr andiz y Carbonell s/n, E-03801 Alcoy, Spain

New Trends in Photobiology (Invited Review) Photosensitizing drugs containing the benzophenone chromophore

The nonsteroidal anti-inflammatory agents ketoprofen, tiaprofenic acid, suprofen and tolmetin, together with the anti-hyperlipoproteinemic drug fenofibrate and the anti-arrhythmic amiodarone can be included in the group of benzophenone-derived photosensitizing drugs. They contain a diaryl ketone chromophore and mediate the development of phototoxic reactions. In some cases, photoallergic responses have been reported. These properties have been substantiated in clinical reports, as well as by means of in vivo and in vitro assays. Tolmetin is phototoxic in vitro, however there are no reports on photosensitization by this drug in humans. In general, photochemical and photobiological studies strongly suggest that photosensitization involves formal hydrogen abstraction (either in a single step or via electron transfer followed by proton transfer) by the benzophenone-like chromophore from the excited triplet state. In the case of amiodarone, the radicals generated by photodehalogenation from the triplet are responsible for the photosensitivity side-effects.

PHOTOCHEMICAL AND PHOTOBIOLOGICAL PROPERTIES OF KETOPROFEN ASSOCIATED WITH THE BENZOPHENONE CHROMOPHORE

Abstract Irradiation of ketoprofen in neutral aqueous medium gave rise to 3‐ethylbenzophenone as the major photoproduct. Its formation is justified via protonation of a benzylic carbanion or hydrogen abstraction by a benzylic radical. Minor amounts of eight additional compounds were isolated. Four of them are derived from the benzylic radical: 3‐(1‐hydroperoxyethyl)benzophenone, 3‐(1‐hydroxyethyl)benzophenone, 3‐acetylbenzophenone and 2,3‐bis‐(3‐benzoylphenyl)butane. The other four products involve initial hydrogen abstraction by the excited benzophenone chromophore of ketoprofen: 1,2‐bis‐(3‐ethylphenyl)‐1,2‐diphenyl‐1,2‐ethanediol, 2‐(3‐benzoylphenyl)‐1‐(3‐ethylphenyl)‐1 ‐phenylpropan‐1 ‐01,α ‐(3‐ethylphenyl)phenylmethanol, 1,2‐bis‐[3‐(2‐hydroxycarbonylethyl)phenyl]‐1,2‐di‐phenyl‐1,2‐ethanediol. The latter process was found to mediate the photoperoxidation of linoleic acid through a type I mechanism, as evidenced by the inhibition produced by the radical scavengers butylated hydroxyanisole and reduced glutathione. The major photoproduct, which contains the benzophenone moiety but lacks the propionic acid side chain, also photosensitized linoleic acid peroxidation. Because lipid peroxidation is indicative of cell membrane lysis, the above findings are highly relevant to explain the photobiological properties of ketoprofen.

Photoreactivity of the Nonsteroidal Anti-inflammatory 2-Arylpropionic Acids with Photosensitizing Side Effects¶

The photoreactivity of the nonsteroidal anti‐inflammatory 2‐arylpropionic acids benoxaprofen, carprofen, naproxen, ketoprofen, tiaprofenic acid, and suprofen is reviewed with special emphasis on fundamental photophysical and photochemical properties. The absorption and emission properties of the excited states of these drugs as well as their main photodegradation routes are summarized. The photochemical mechanisms are discussed on the basis of product studies and detection of short‐lived intermediates by means of laser flash photolysis. After dealing with the unimolecular processes, attention is focused on the photosensitized reactions of key biomolecules, such as lipids, proteins or nucleic acids. Finally, a short section on the photobiological effects on simple biological models is also included. Although some earlier citations are included, the literature coverage is in general limited to the last decade.

Ozonisation coupled with biological degradation for treatment of phenolic pollutants: a mechanistically based study.

Phenolic acids constitute an important group of pollutants which are reluctant to biological treatment. Solutions containing a mixture of cinnamic acid, p-coumaric acid, caffeic acid and ferulic acid were submitted to ozonisation. Then, the changes in biodegradability along the process were studied by means of respirometry. There is an optimum ozone dosage in the interval 3-5 min of treatment which allows to achieve the maximum increase in biodegradability (more than 10 times) and a high efficiency of the ozonisation process (COD decreases to a half of its initial value). Further ozonisation does not help to increase biodegradability and is clearly disadvantageous. Similar results are obtained with actual samples of olive oil wastewaters. This behaviour is explained based on the formation of highly biodegradable benzaldehydes as key ozonisation intermediates, in the early reaction stages.

PHOTOLYTIC DEGRADATION OF IBUPROFEN. TOXICITY OF THE ISOLATED PHOTOPRODUCTS ON FIBROBLASTS and ERYTHROCYTES

The photodegradation of Ibuprofen, a widely used non‐steroidal anti‐inflammatory drug (NSAID), was examined. Several photoproducts (I‐VI) were isolated and identified on the basis of their IR‐1H‐NMR‐ and 13C‐NMR‐ spectra. The chemical structures were confirmed by unambiguous alternative synthesis from available reagents. The most significant primary photochemical process was the cleavage of the C‐C bond a to the carboxy group. Subsequent secondary processes (hydrogen abstraction, dimerization, incorporation of methanol, or reaction with oxygen) might account for the formation of the different photoproducts. The cytotoxic effects were assayed using the red‐blood cell lysis test and the enzyme leakage (LDH and GOT) from cultured fibroblasts. Compound V [l‐(4 isobutylphenyl)‐ethanol] was found to be toxic for both system at concentrations greater than 1 mM while compound IV [l‐(4 isobutylphenyl acetophenone)] was toxic for fibroblasts but not for erythrocytes at the same concentration. Ibuprofen and the other photocompounds were apparently non‐toxic. The significance of these results is discussed in connection with the possible in vivo phototoxicity of Ibuprofen.

PHOTODYNAMIC LIPID PEROXIDATION BY THE PHOTOSENSITIZING NONSTEROIDAL ANTIINFLAMMATORY DRUGS SUPROFEN AND TIAPROFENIC ACID

Abstract The photochemistry of the photosensitizing nonsteroidal antiinflammatory drugs tiaprofenic acid and suprofen involves the intermediacy of short‐lived species (i.e. radicals). The data obtained in the present work strongly suggest that such intermediates may be responsible for the phototoxicity of 2‐arylpropionic acids by inducing photodynamic lipid peroxidation at drug concentrations likely to be reached in the skin. This has been investigated using linoleic acid as a model lipid and determining the amount of hydroperoxides by measuring the spectrophotometric absorption at 233 nm, associated with the formation of dienic hydroperoxides. The major photoproducts of tiaprofenic acid and suprofen are derivatives bearing an ethyl side chain. Photoproducts of this type, due to the lack of polar moieties, are highly lipophilic and likely to accumulate in the lipid bilayer of cell membranes. Taking into account their ability to induce photodynamic lipid peroxidation and their marked photostability, it is conceivable that such photoproducts can participate in many catalytic cycles, playing a significant role in the mechanism of photosensitizatinn by tiprofenic acid and suprofen.

A Blocked Diketo Form of Avobenzone: Photostability, Photosensitizing Properties and Triplet Quenching by a Triazine‐derived UVB‐filter

Novel sunscreens are required providing active protection in the UVA and UVB regions. On the other hand, there is an increasing concern about the photosafety of UV filters, as some of them are not sufficiently photostable. Avobenzone is one of the most frequently employed sunscreen ingredients, but it has been reported to partially decompose after irradiation. In the present work, photophysical and photochemical studies on a methylated avobenzone‐derivative have shown that the diketo form is responsible for photodegradation. A transient absorption was observed at 380 nm after laser flash photolysis excitation at 308 nm. It was assigned to the triplet excited state of the diketo form, as inferred from quenching by oxygen and β‐carotene. This transient also interacted with key building blocks of biomolecules by triplet–triplet energy transfer (in the case of thymidine) or electron transfer processes (for 2′‐deoxyguanosine, tryptophan and tyrosine). Irradiation of the avobenzone derivative in the presence of a triazine UV‐B filter (E‐35852) diminished the undesirable effects of the compound by an efficient quenching of the triplet excited state. Thus, sunscreen formulations including triplet quenchers could provide effective protection from the potential phototoxic and photoallergic effects derived from poor photostability of avobenzone.

Lysosomes are sites of fluoroquinolone photosensitization in human skin fibroblasts: a microspectrofluorometric approach.

Abstract. The fluoroquinolone antibiotics are widely used despite their strong phototoxicity under solar UV irradiation. Although they are known as good photodynamic photosen‐sitizers, other factors than production of activated oxygen species may play a role in the effectiveness of the phototoxic effect. Subcellular localization is one of the important parameters that may determine this strength. Using microspectrofluorometry, it is shown that norfloxacin, ofloxacin, lomefloxacin, ciproflaxin and BAYy3118 are readily incorporated into lysosomes of HS68 human skin fibroblasts although weak staining of the whole cytoplasm also occurs especially with norfloxacin. Consistent with their photoinstability in solutions, the fluoroquinolones under study are readily photobleached by UVA in the HS68 fibroblasts. The BAYy3118 derivative that has the fastest bleaching rate also shows the strongest phototoxicity toward HS68 fibroblasts. Photosensitization with these fluoroquinolones induces lysosomal membrane damage as shown by the increased rate of leakage of the lysosomal probe lucifer yellow as compared to that observed with untreated cells.

Photosensitised pyrimidine dimerisation in DNA

Triplet-mediated pyrimidine (Pyr) dimerisation is a key process in photochemical damage to DNA. It may occur in the presence of a photosensitiser, provided that a number of requirements are fulfilled, such as favourable intersystem crossing quantum yield and high triplet energy. The attention has been mainly focused on cyclobutane pyrimidine dimers, as they are by far the most relevant Pyr photoproducts obtained by sensitisation. The present perspective deals with the involved chemistry, not only in DNA but also in its simple building blocks. It also includes the photophysical characterisation of the Pyr triplet excited states, as well as a brief discussion of the theoretical aspects.