SPECTROSCOPIC STUDIES OF CUTANEOUS PHOTOSENSITIZING AGENTS .18. INDOMETHACIN

The photochemistry, photophysics, and photosensitization (Type I and I I) of indomethacin (IN) p-chlorobenzoyl]-5-methoxy-2-methylindole-3-ac etic acid) has been studied in a variety of solvents using NMR, high p erformance liquid chromatography-mass spectroscopy, transient spectros copy, electron paramagnetic resonance in conjunction with the spin tra pping 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; obenzoyl]-5-methoxy-2-methyl-3-methylene-indoline) and a minor (3 ; N-[p-chlorobenzoyl]-5-methoxy-2,3-dimethyl-indole) decarboxylated pr oduct and a minor indoline (5; 1-en-5-methoxy-2-methyl-3-methylene-ind oline), which is formed by loss of the p-chlorobenzoyl moiety. In air- saturated solvents two minor oxidized products 4 chlorobenzoyl]-5-meth oxy-2-methylindol-3-aldehyde) and 6 (5-methoxy-2-methyl-indole-3-aldeh yde) are also formed. When photolysis was carried out in O-18(2)-satur ated benzene, the oxidized products 4 and 6 contained O-18, indicating that oxidation was mediated by dissolved oxygen in the solvent. In mo re 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 pola rity of solvent is increased. Flash excitation of IN in degassed ethan ol or acetonitrile produces no transients. A weak transient is observe d at 375 nm in degassed benzene, which is not quenched by oxygen. Irra diation 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 DMP O/.COC6H4-P-Cl, while the other was probably derived from a radical fo rmed during IN decarboxylation. In air-saturated benzene, (hydro) pero xyl and alkoxyl radical adducts of DMPO are observed. A very weak lumi nescence signal from O-1(2) at 1268 nm is observed initially upon irra diation (lambda(ex) = 325 nm) of IN in air-saturated benzene or chloro form. 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 ph otoproduct(s). Accordingly, when 2 and 3 were tested directly, 2 was f ound to be a much better sensitizer of O-1(2) than IN. In air-saturate d ethanol or acetonitrile no IN O-1(2) luminescence is detected even o n continuous irradiation. The inability of IN to cause phototoxicity m ay be related to its photostability in polar solvents, coupled with th e low yield of active oxygen species (O-1(2), O2-) upon UV irradiation .