SPECTROSCOPIC STUDIES OF CUTANEOUS PHOTOSENSITIZING AGENTS .18. INDOMETHACIN

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 (O-1(2)) luminescence. Photodecomposition of IN (lambda(ex) > 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-indoline), 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 in O-18(2)-saturated benzene, the oxidized products 4 and 6 contained O-18, 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 (lambda(ex) > 325 nm) in N2-gassed C6H6 in 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-Cl, 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 from O-1(2) at 1268 nm is observed initially upon irradiation (lambda(ex) = 325 nm) of IN in air-saturated benzene or chloroform. The intensity of this O-1(2) signal increases as irradiation is continued suggesting that the enhancement in O-1(2) yield is due to photoproduct(s). Accordingly, when 2 and 3 were tested directly, 2 was found to be a much better sensitizer of O-1(2) than IN. In air-saturated ethanol or acetonitrile no IN O-1(2) luminescence is detected even on continuous irradiation. The inability of IN to cause phototoxicity may be related to its photostability in polar solvents, coupled with the low yield of active oxygen species (O-1(2), O2-) upon UV irradiation.