Triplet Photochemistry of Suprofen in Aqueous Environment and in the β-Cyclodextrin Inclusion Complex (original) (raw)
Related papers
Mechanism of Photoinduced Decomposition of Ketoprofen
Journal of Medicinal Chemistry, 2007
UV-induced decarboxylation of the NSAID ketoprofen, followed by activation of molecular oxygen or formation of a decarboxylated peroxide adduct, is explored using computational quantum chemistry. The excited energy surfaces reveal that the neutral species will not decarboxylate, whereas the deprotonated acid decarboxylates spontaneously in the triplet state, and with an associated 3-5 kcal/mol barrier from several low-lying excited singlet states. The observed long lifetimes of the decarboxylated anion is explained in terms of the high stability of the triplet benzoyl ethyl species with protonated carbonylic oxygen, from which there is no obvious decay channel. Mechanisms for the generation of singlet oxygen and superoxide are discussed in detail. Addition of molecular oxygen to give the corresponding peroxyl radical capable of initiating propagating lipid peroxidation reactions is also explored. The computed data explains all features of the observed experimental observations made to date on the photodegradation of ketoprofen. a Abbreviations: NSAID, nonsteroidal antiinflammatory drug; KP, ketoprofen; ROS, reactive oxygen species; ISC, intersystem crossing; DFT, density functional theory; CNDO/S, complete neglect of differential overlap-singles excitations; ZPE, zero-point vibrational energy; IEFPCM, integral equation formalism of the polarized continuum model; TD-DFT, time-dependent density functional theory; LDA, local density approximation.
Articles Mechanism of Photoinduced Decomposition of Ketoprofen
UV-induced decarboxylation of the NSAID ketoprofen, followed by activation of molecular oxygen or formation of a decarboxylated peroxide adduct, is explored using computational quantum chemistry. The excited energy surfaces reveal that the neutral species will not decarboxylate, whereas the deprotonated acid decarboxylates spontaneously in the triplet state, and with an associated 3-5 kcal/mol barrier from several low-lying excited singlet states. The observed long lifetimes of the decarboxylated anion is explained in terms of the high stability of the triplet benzoyl ethyl species with protonated carbonylic oxygen, from which there is no obvious decay channel. Mechanisms for the generation of singlet oxygen and superoxide are discussed in detail. Addition of molecular oxygen to give the corresponding peroxyl radical capable of initiating propagating lipid peroxidation reactions is also explored. The computed data explains all features of the observed experimental observations made to date on the photodegradation of ketoprofen. a Abbreviations: NSAID, nonsteroidal antiinflammatory drug; KP, ketoprofen; ROS, reactive oxygen species; ISC, intersystem crossing; DFT, density functional theory; CNDO/S, complete neglect of differential overlap-singles excitations; ZPE, zero-point vibrational energy; IEFPCM, integral equation formalism of the polarized continuum model; TD-DFT, time-dependent density functional theory; LDA, local density approximation.
Photochemistry and Photobiology, 2007
The photodecarboxylation reaction of 2-(3-benzoylphenyl)propionate (ketoprofen anion, KP Ϫ ) was studied in water and in 0.1 M phosphate buffer solutions in the pH range 5.7-11.0 by laser-induced optoacoustic spectroscopy (LIOAS, T range 9.5-31.6؇C). Upon exciting KP Ϫ with 355 nm laser pulses under anaerobic conditions, two components in the LIOAS signals with well-separated lifetimes were found ( 1 Ͻ 20 ns; 250 Ͻ 2 Ͻ 500 ns) in the whole pH range, whereas a long-lived third component (4 Ͻ 3 Ͻ 10 s) was only detected at pH Յ 6.1. The heat and structural volume changes accompanying the first step did not depend on pH or on the presence of buffer. The carbanion resulting from prompt decarboxylation within the nanosecond pulse (Ͻ10 ns) drastically reduces its molar volume ([Ϫ18.9 ؎ 2.0] cm 3 /mol) with respect to KP Ϫ and its enthalpy content is (256 ؎ 10) kJ/ mol. At acid pH (ca 6), a species is formed with a lifetime in the hundreds of ns. The enthalpy and structural volume change for this species with respect to KP Ϫ are (181 ؎ 15) kJ/mol and (؉0.6 ؎ 2.0) cm 3 /mol, respectively. This species is most likely a neutral biradical formed by protonation of the decarboxylated carbanion, and decays to the final product 3-ethylbenzophenone in several s. At basic pH (ca 11), direct formation of 3-ethylbenzophenone occurs in hundreds of ns involving a reaction with the solvent. The global decarboxylation reaction is endothermic ([45 ؎ 15] kJ/mol) and shows an expansion of (؉14.5 ؎ 0.5) cm 3 /mol with respect to KP Ϫ . At low pH, the presence of buffer strongly affects the magnitude of the structural volume changes associated with the intermolecular proton-transfer processes of the long-lived species due to reactions of the buffer anion with the decarboxylated ketoprofen anion. ¶Posted on the web on 24 May 2000.
Photochemistry and Photobiology, 1994
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.
Supramolecular Photochemistry in β-Cyclodextrin Hosts: A TREPR, NMR, and CIDNP Investigation
Langmuir, 2010
A systematic investigation of the photochemistry and ensuing radical chemistry of three guest ketones encapsulated in randomly methylated β-cyclodextrin (β-CD) hosts is reported. Dibenzyl ketone (DBK), deoxybenzoin (DOB), and benzophenone (BP) triplet states are rapidly formed after photolysis at 308 nm. Time-resolved electron paramagnetic resonance (TREPR) spectroscopy, steady-state NMR spectroscopy, and time-resolved chemically induced nuclear polarization (TR-CIDNP) experiments were performed on the ketone/CD complexes and on the ketones in free solution for comparison. The major reactivity pathways available from these excited states are either Norrish I R-cleavage or H-atom abstraction from the interior of the CD capsule or the solvent. The DOB triplet state undergoes both reactions, whereas the DBK triplet shows exclusively R-cleavage and the BP triplet shows exclusively H-atom abstraction. Radical pairs are observed in β-CDs by TREPR, consisting of either DOB or BP ketyl radicals with sugar radicals from the CD interior. The TREPR spectra acquired in CDs are substantially broadened due to strong spin exchange. The electron spin polarization mechanism is mostly due to S-T 0 radical pair mechanism (RPM) in solution but changes to S-T-RPM in the CDs due to the large exchange interaction. The TR-CIDNP results confirm the reactivity patterns of all three ketones, and DOB shows strong nuclear spin polarization from a novel rearrangement product resulting from the R-cleavage reaction.
Journal of the American Chemical Society, 1997
The transient intermediates in the nanosecond laser flash photolysis of ketoprofen, an aryl propionic acid, show the formation of a carbanion in aqueous solutions at pH 7.1. This carbanion incorporates spectroscopic properties from both a ketyl radical anion and a benzylic radical. The ketoprofen carboxylate undergoes biphotonic photoionization, a process that contributes less than 10% to its photodecomposition and leads to a benzylic-type radical after decarboxylation with a rate constant g1 × 10 7 s-1. On the other hand, the carbanion forms monophotonically and the unsuccessful attempts to sensitize the formation of the ketoprofen triplet excited state in aqueous solutions suggest that the carbanion precursor is either an excited singlet state or an extremely short-lived triplet. In organic solvents of lower polarity, the excited triplet state is readily detectable.
Photochemical & Photobiological Sciences, 2011
The chiral recognition ability of b-cyclodextrin (b-CyD) vs. Sand R-ketoprofen (KP) enantiomers has been studied by circular dichroism (CD), isothermal titration calorimetry (ITC) and NMR. The association constants of the 1 : 1 complexes obtained from CD and ITC titration experiments resulted to be the same for both enantiomers within the experimental uncertainty. Well differentiated CD spectra were determined for the diastereomeric complexes. Their structure was assessed by molecular mechanics and molecular dynamics calculations combined with quantum mechanical calculation of the induced rotational strengths in the low energy KP:b-CyD associates, upon comparison of the calculated quantities with the corresponding experimental CD. The inclusion geometry is similar for both enantiomers with the aromatic carbonyl inserted in the CyD cavity, the monosubstituted ring close to the primary CyD rim and the carboxylate group exposed to the solvent close to the secondary rim. NMR spectra fully confirmed the geometry of the diastereomeric complexes. Tiny structural differences were sensibly probed by CD and confirmed by 2D ROESY spectra. Photoproduct studies with UV absorption and MS detection as well as nanosecond laser flash photolysis evidenced lack of chiral discrimination in the photodecarboxylation of KP within the cavity and formation of a photoaddition product to b-CyD by secondary photochemistry of 3-ethylbenzophenone.
Mechanisms of drug photobinding to proteins: photobinding of suprofen to human serum albumin
Toxicology in Vitro, 2001
Photobinding of drugs to biomolecules constitutes an important early event in the onset of photoallergy. In the present work, UV irradiation of human serum albumin in the presence of either suprofen (SUP) or its major photoproduct, decarboxylated suprofen (DSUP), has been studied as a model system for drug-photosensitised protein binding. Both dark binding and binding in the presence of light were investigated since this will affect the mode, site and mechanism of drug interaction with the protein. In order to determine the binding features of SUP to albumin, competitive binding experiments were carried out using fluorescent probes specific for site I and II. Suprofen was found to selectively dark bind to site II on HSA. Photobinding of DSUP to HSA was more efficient than SUP. Parallel to this, the intrinsic tryptophan fluorescence of HSA decreased when the protein was previously irradiated in the presence of the photoactive compounds, again being DSUP more efficient compared with SUP. As fluorescence quenching involves electron transfer from the excited Trp to the ground state DSUP, it follows that the photoactive compound binding to HSA must be on (or in close proximity to) site I Trp 214 residue. It appears that photobinding of SUP is largely preceded by its photodecomposition to DSUP which, in turn, associates and photobinds to HSA. #
Molecular mechanism of drug photosensitization part 3. Photohemolysis sensitized by diflunisal
Journal of Photochemistry and Photobiology B: Biology, 1991
When carried out in the presence of additives, the observed photohemolysis suggests the involvement of free radicals and singlet oxygen in the membrane damage induced by both CPF and photoproduct I irradiation, whereas there is no evidence of any role for hydroxyl radicals. Superoxide anion is involved only in the photosensitization process induced by photoproduct I.