SPECTROSCOPIC STUDIES OF CUTANEOUS PHOTOSENSITIZING AGENTS. XVIII. INDOMETHACIN

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Abstract
Abstract—The photochemistry, photophysics, and photosensitization (Type I and II) of indomethacin (IN) (N‐[p‐chlorobenzoyl]‐5‐methoxy‐2‐methylindole‐3‐acetic acid) has been studied in a variety of solvents using NMR, high performance liquid chromatography‐mass spectroscopy, transient spectroscopy, electron paramagnetic resonance in conjunction with the spin trapping technique, and the direct detection of singlet molecular oxygen (lO2) luminescence. Photodecomposition of IN (λex> 330 nm) in degassed or air‐saturated benzene proceeds rapidly to yield a major (2; N‐[p‐chlorobenzoyl]‐5‐methoxy‐2‐methyl‐3‐methylene‐indoline) and a minor (3; N‐[p‐chlorobenzoyl]‐5‐methoxy‐2, 3‐dimethyl‐indole) decarboxylated product and a minor indoline (5; 1‐en‐5‐methoxy‐2‐methyl‐3‐methylene‐in‐doline), which is formed by loss of the p‐chlorobenzoyl moiety. In air‐saturated solvents two minor oxidized products 4 (N‐[p‐chlorobenzoyl]‐5‐methoxy‐2‐methylindol‐3‐aldehyde) and 6 (5‐methoxy‐2‐methyl‐indole‐3‐aldehyde) are also formed. When photolysis was carried out in18O2‐saturated benzene, the oxidized products 4 and 6 contained18O, indicating that oxidation was mediated by dissolved oxygen in the solvent. In more polar solvents such as acetonitrile or ethanol, photodecomposition is extremely slow and inefficient. Phosphorescence of IN at 77 K shows strong solvent dependence and its emission is greatly reduced as polarity of solvent is increased. Flash excitation of IN in degassed ethanol or acetonitrile produces no transients. A weak transient is observed at 375 nm in degassed benzene, which is not quenched by oxygen. Irradiation of IN (λex> 325 nm) in N2‐gassed C6H6in the presence of 5, 5‐dimethyl‐1‐pyrroline‐N‐oxide (DMPO) results in the trapping of two carbon‐centered radicals by DMPO. One adduct was identified as DMPO/.COC6H4‐p‐CI, while the other was probably derived from a radical formed during IN decarboxylation. In air‐saturated benzene, (hydro) peroxyl and alkoxyl radical adducts of DMPO are observed. A very weak luminescence signal from1O2at 1268 nm is observed initially upon irradiation (λex= 325 nm) of IN in air‐saturated benzene or chloroform. The intensity of this1O2signal increases as irradiation is continued suggesting that the enhancement in1O2yield is due to photoproduct(s). Accordingly, when 2 and 3 were tested directly, 2 was found to be a much better sensitizer of1O2than IN. In air‐saturated ethanol or acetonitrile no IN1O2luminescence is detected even on continuous irradiation. The inability of IN to cause phototoxicity may be related to its photo stability in polar solvents, coupled with the low yield of active oxygen species (1O2, O2−‐) upon UV irradiation.