Photophysical studies on antimalarial drugs.

Most drugs used in the treatment of malaria produce phototoxic side effects in both the skin and the eye. Cutaneous and ocular effects that may be caused by light include changes in skin pigmentation, corneal opacity, cataract formation and other visual disturbances including irreversible retinal damage (retinopathy) leading to blindness. The mechanism for these reactions in humans is unknown. We irradiated a number of antimalarial drugs (amodiaquine, chloroquine, hydroxychloroquine, mefloquine, primaquine and quinacrine) with light (lambda > 300 nm) and conducted electron paramagnetic resonance (EPR) and laser flash photolysis studies to determine the possible active intermediates produced. Each antimalarial drug produced at least one EPR adduct with the spin-trap 5,5-dimethyl-1-pyrroline N-oxide in benzene: superoxide/hydroperoxyl adducts (chloroquine, mefloquine, quinacrine, amodiaquine and quinine), carbon-centered radical adducts (all but primaquine), or a nitrogen-centered radical adduct only (primaquine). In ethanol all drugs except primaquine produced some superoxide/hydroperoxyl adduct, with quinine, quinacrine, and hydroxychloroquine also producing the ethoxyl adduct. As detected with flash photolysis and steady-state techniques, mefloquine, quinine, amodiquine and a photoproduct of quinacrine produced singlet oxygen ([symbol: see text]delta = 0.38; [symbol: see text]delta = 0.36; [symbol: see text]delta = 0.011; [symbol: see text]delta = 0.013 in D2O, pD7), but only primaquine quenched singlet oxygen efficiently (2.6 x 10(8) M-1 s-1 in D2O, pD7). Because malaria is a disease most prevalent in regions of high light intensity, protective measures (clothing, sunblock, sunglasses or eye wraps) should be recommended when administering antimalarial drugs.

An EPR study of free radicals formed by antipsoriatic and tumor-promoting 9-anthrones in nonpolar solvents.

Certain 9-anthrone derivatives are useful in treating psoriasis and are also known to be tumor promoters in mouse skin. Their therapeutic use is accompanied by side effects of severe skin inflammation, irritation, and staining. The precise biochemical mechanisms of therapeutic action, tumor promotion, and side effects are presently uncertain, although the corresponding 9-anthron-10-yl radicals have been proposed as important intermediates. In order to gain insight into the possible role of anthrone-derived radicals in mediating the biological effects of these compounds, in the present study free radicals from a number of anthrone derivatives were generated by thermolysis in nonpolar solvents. Hyperfine splitting constants (hfsc) of the radicals were determined by electron paramagnetic resonance (EPR) spectroscopy. The experimentally determined hfsc's were also compared with spin densities obtained by molecular calculations (MOPAC 6.0). The experimental and theoretical data were found to be consistent in all cases. The formation of 9-anthron-10-yl radicals appears to be a general phenomenon among 9-anthrones regardless of therapeutic or tumor-promoting effectiveness, although there is a trend toward easier radical formation for the more active compounds.

Spectral and photochemical properties of curcumin.

Curcumin, bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, is a natural yellow-orange dye derived from the rhizome of Curcuma longa, an East Indian plant. In order to understand the photobiology of curcumin better we have studied the spectral and photochemical properties of both curcumin and 4-(4-hydroxy-3-methoxy-phenyl)-3-buten-2-one (hC, half curcumin) in different solvents. In toluene, the absorption spectrum of curcumin contains some structure, which disappears in more polar solvents, e.g. ethanol, acetonitrile. Curcumin fluorescence is a broad band in acetonitrile (lambda max = 524 nm), ethanol (lambda max = 549 nm) or micellar solution (lambda max = 557 nm) but has some structure in toluene (lambda max = 460, 488 nm). The fluorescence quantum yield of curcumin is low in sodium dodecyl sulfate (SDS) solution (phi = 0.011) but higher in acetonitrile (phi = 0.104). Curcumin produced singlet oxygen upon irradiation (lambda > 400 nm) in toluene or acetonitrile (phi = 0.11 for 50 microM curcumin); in acetonitrile curcumin also quenched 1O2 (kq = 7 x 10(6) M-1 s-1). Singlet oxygen production was about 10 times lower in alcohols and was hardly detectable when curcumin was solubilized in a D2O micellar solution of Triton X-100. In SDS micelles containing curcumin no singlet oxygen phosphorescence could be observed. Curcumin photogenerates superoxide in toluene and ethanol, which was detected using the electron paramagnetic resonance/spin-trapping technique with 5,5-dimethyl-pyrroline-N-oxide as a trapping agent. Unidentified carbon-centered radicals were also detected.(ABSTRACT TRUNCATED AT 250 WORDS)

The photooxidation of diethylhydroxylamine by rose bengal in micellar and nonmicellar aqueous solutions.

The photooxidation of N,N-diethylhydroxylamine (DEHA) by Rose Bengal (RB) has been investigated in micellar and nonmicellar aqueous solutions. We measured the quantum yield of oxygen consumption forming H2O2 and monitored two intermediates, the superoxide and diethylnitroxide radicals. When the pH was varied, the quantum yield of oxidation remained constant for 6 < pH < 10.5, decreased in acidic pH, and increased considerably in NaOH solution; these changes could be attributed to the protonation and dissociation processes of the > N-OH moiety of DEHA. The formation of diethylnitroxide radical was enhanced by superoxide dismutase or strong alkaline solution. Around neutral pH, the oxidation proceeded mainly via electron transfer from DEHA to the RB triplet (kq = 10(7) M-1 s-1) with little 1O2 participation (kq < 10(5) M-1 s-1). However, when RB was incorporated into micelles in alkaline solution, the contribution of the singlet oxygen pathway increased at the expense of electron transfer, which was inhibited by the less polar micellar environment. Dark autoxidation of DEHA was accelerated by heavy metal impurities and increased very strongly in NaOH solution.

Spectroscopic studies of cutaneous photosensitizing agents. XVII. Benzanthrone.

The photochemistry of benzanthrone (7H-benz[de]-anthracene-7-one) has been studied using electron paramagnetic resonance (EPR) in conjunction with the spin trapping technique and the direct detection of singlet molecular oxygen luminescence. Irradiation (lambda ex = 394 nm) of benzanthrone (BA) in aerated ethanol, dimethylsulfoxide or benzene resulted in the generation of superoxide (O2-.) which was trapped by 5,5-dimethyl-1-pyrroline-N-oxide. The ethoxy radical was also detected in ethanol. Photolysis of BA in deaerated basic ethanol led to the formation of BA anion radical, BA-., which was detected directly by ESR. This radical anion decayed back to BA with a unimolecular rate constant of 1.5 x 10(-3) s-1. The 1O2 quantum yields (lambda ex greater than 345 nm) for BA in ethanol, 90% ethanol and basic ethanol (0.1N NaOH) were 0.89, 0.88 and 0.28 respectively relative to Rose Bengal. The lower yield of 1O2 in basic ethanol may be attributable to the reaction of oxygen with BA-. (which is generated in higher yield at alkaline pH) to give O2-.. These findings suggest that on exposure to light BA can generate active oxygen species which may be responsible for the photocontact dermatitis caused by BA in industrial workers exposed to this chemical.

Superoxide dismutase amplifies dye photosensitized production of desferal free radical: an electron spin resonance study.

Desferal free radical (DFFR) photogenerated from dye sensitization was studied by electron spin resonance. When irradiated at the visible maximum in the presence of O2, both rose bengal and riboflavin sensitized the oxidation of Desferal (DF) and generated the DFFR. The yield of DFFR was amplified by superoxide dismutase (SOD). The SOD enhancement was attributed to the inhibition of superoxide-induced DFFR destruction. Similar SOD enhancement was observed with dyes Rhodamine 123 and Gentian Violet. Our studies suggest that when Desferal is used as a chelating agent in the presence of SOD, systems involving O2- could face interference from DFFR even at concentrations as low as 10 microM DF. DFFR may interfere with the chain reaction of lipid peroxidation resulting in an apparent protective action which, in fact, has very little to do with chelating the catalytic iron.

The stepwise biphotonic photoionization of chlorpromazine as seen by laser flash photolysis.

It is generally accepted that both promazine (PZ) and chlorpromazine (CPZ) photionize monophotonically to their respective cation radicals and the corresponding hydrated electrons. It is also supposed that this photoinization has a role in the phototoxic effects of these drugs. However, using laser flash photolysis, we have observed that photoionization of CPZ during S1 excitation (lambda greater than 300 nm) is a stepwise biphotonic process. In the case of PZ our flash photolysis results are less clearcut, but are consistent with stepwise biphotonic photoionization for S1 excitation. We demonstrate, using computer simulation of the intramolecular kinetics, that the estimated triplet state lifetime of CPZ is sufficiently long (23 ns at room temperature) to account for the apparent monophotonic photoionization that has been observed by others at high light intensities and short pulse times. Our laser flash photolysis results also suggest that the photo-ionization mechanism of PZ and CPZ is wavelength-dependent. Both drugs exhibit apparent monophotonic photoionization when they are excited at 266 nm under conditions of laser pulse width and intensity similar to those at 355 nm. We suggest that photoionization is not an important mechanism in the observed phototoxic and photoallergic effects of PZ and CPZ in sunlight.

Generation of radical anions from metronidazole, misonidazole and azathioprine by photoreduction in the presence of EDTA.

Ultraviolet irradiation of the nitroimidazole derivatives metronidazole, misonidazole, azathioprine and 1-methyl-4-nitroimidazole in aqueous solution with various reductants produced the respective nitro radical anions, as detected by electron spin resonance spectroscopy. The most effective reductant, yielding high concentrations of the radical anions, was EDTA at pH 10. NADH, NADPH, formaldehyde glutathione and methanol were also tested but were less efficient as reductants.

Photoinduced free radicals from chlorpromazine and related phenothiazines: relationship to phenothiazine-induced photosensitization.

Chlorpromazine and several other related phenothiazines are known to cause both phototoxic and photoallergic reactions in the skin and eyes of patients receiving these drugs. While the detailed mechanisms of photosensitization are not known, it is obvious that the first step must be the absorption of light by the drug, its metabolites, or photoproducts, or possibly an induced endogenous chemical. In this review, the free-radical photochemistry of phenothiazines is described, and the evidence for the involvement of photoinduced free radicals in photosensitization is examined. Upon irradiation chlorpromazine yields a variety of free radicals including the corresponding cation radical (via photoionization), the neutral promazinyl radical and a chlorine atom (Cl.) (via homolytic cleavage), and a sulfur-centered peroxy radical. The chlorpromazine cation radical is probably responsible for some of the observed in vitro phototoxic effects of this drug. However, it seems unlikely that the cation radical is involved in phototoxicity in vivo, since photoionization only occurs when chlorpromazine is excited into the S2 level (lambda ex less than 280 nm). The promazinyl radical is a more likely candidate for the phototoxic species both in vivo and in vitro. In addition, this radical can react covalently with proteins and other macromolecules to yield antigens which could be responsible for the photoallergic response to chlorpromazine. Neither oxygen-derived radicals nor singlet oxygen (1O2*), appear to be important in chlorpromazine photosensitization. In contrast, it would seem that promazine-induced phototoxicity may result in part from the generation of superoxide (O2-.).(ABSTRACT TRUNCATED AT 250 WORDS)