Photochemical and photophysical properties of indoprofen[para]

ABSTRACT

The photophysical properties and photochemistry of indoprofen (INP) have been investigated. Absorption and emission spectroscopies in phosphate buffer, ethanol and ether show that INP photophysics is dominated by a singlet-singlet transition of [pi][pi]* character. INP fluoresces at room temperature, with a quantum yield ~0.04. Flash photolysis experiments together with the lack of phosphorescence at room temperature point to a very weak intersystem crossing. The photoreactivity of INP is centered on the propionic acid chain and gives rise to photoproducts similar to those obtained with other arylpropionic acids (ethyl, hydroxyethyl and acetyl derivatives). Thus, irradiation of INP in aqueous buffer results in photodecarboxylation and leads mainly to oxidative compounds whose proportions increase with increasing oxygen concentration. These data suggest a photoreactivity occurring from the excited singlet state.

Abbreviations: HPLC, high-performance liquid chromatography; INP, indoprofen; MS, mass spectrometry; NSAID, nonsteroidal anti-inflammatory drug; PMT, photomultiplier tube; TEMP, 2,2,6,6-tetramethyl-4-piperidone; TEMPO, 2,2,6,6-tetramethyl-4-piperidone-N-oxyl.

INTRODUCTION

Indoprofen (INP) is a nonsteroidal anti-inflammatory drug (NSAID) which was used in the treatment of both osteoarthritis and rheumatoid arthritis (1). The adverse reaction profile of INP is similar to that of most NSAID, with mainly gastrointestinal troubles. INP belongs to the 2-arylpropionic acids family (Scheme 1). A side effect associated with this group of drugs is their potential for inducing photosensitivity reactions (2,3). This is particularly the case for ketoprofen, tiaprofenic acid or suprofen, which are benzophenone-like compounds. Their photobiological properties and their photochemistry have been intensively investigated (4). They were reported to cause photohemolysis (2,4-6), lipid peroxidation (4,7) as well as damage to proteins and nucleic acid chains (4,8-11). In aqueous medium at neutral pH, it has been established that the main photoreactivity of these arylpropionic acid derivatives, present almost exclusively as the carboxylate form, is photodecarboxylation (12). This process involves photoionization or intramolecular electron transfer from the carboxy to the carbonyl group leading to the corresponding ethyl derivative (both in aerated or deaerated solutions) and oxidative products (under aerobic conditions) (4,13,14). The same pattern has also been found in the photolysis of fenofibric acid, the major metabolite of the hypolipidemiant agent fenolibrate (15,16).

Despite the structural analogy, few in vitro investigations about photophysical and photochemical properties of INP have been published. It has been reported that contrary to most NSAID this compound does not induce inflammatory reaction under irradiation (17). However, peroxide formation during irradiation under oxygen and lipid photoperoxidation has been shown to occur (18). Nevertheless, no data exists in the literature concerning its photochemistry in aqueous or organic solutions. Thus, the purpose of the present study is on the one hand to establish the excited-state properties of INP and, on the other hand, to investigate its photoreactivity in different media, both under aerobic and anaerobic conditions. Special attention has been paid to the isolation and identification of the photoproducts to evidence whether the photoreaction takes place in the light absorbing isoindolinone chromophore or in the arylpropionic moiety.

MATERIALS AND METHODS

Chemicals

INP (2-[4-(1-oxo-2-isoindolinyl)phenyl]propionic acid) was purchased from Sigma Chemical Co., (St. Quentin Fallavier, France) and 2,2,6,6-tetrameihyl-4-piperidone hydrochloride (TEMP) (98%) from Acros Organics (Noisy-Le-Grand, France). Ethanol 95-96%, high-performance liquid chromatography (HPLC) grade, was purchased from Prolabo (VWR international, Fontenay-sous-Bois, France) and diethyl ether was provided by Carlo Erba (Val de Reuil, France).

Absorption and emission spectra and lifetime measurements

Absorption spectra of INP were measured in 5 mM phosphate buffer containing 10 mM NaCl at pH = 7.4, diethyl ether and ethanol by means of a HP 8452 A diode array spectrophotometer.

Emission and excitation spectra were recorded with a Quanta Master (PTI) spectrofluorometer (London, ON, Canada) equipped with a xenon source and a Hammamatsu R928 photomultiplier tube (PMT). Excitation and emission monochromator band passes of 4 nm were used. The emission intensity was detected at right angles by exciting INP solutions having an absorbance of about 0.05 in a 10 mm quartz cell, at the selected excitation wavelength. All spectra were recorded in the photon-counting mode and corrected with curves given by the constructor. The cell was thermostated at 25[degrees]C by water circulation. For the estimation of the fluorescence quantum yields of INP in different solvents, quinine bisulfate in 1 N sulphuric acid and anthracene in ethanol were used as standards ([Phi]^sub flu^ = 0.55 and 0.27, respectively).