One-electron reduction potentials of substituted nitroimidazoles measured by pulse radiolysis

Abstract

The differences between the one-electron reduction potentials at pH 7 (E:) of a quinone couple (Q/Q-), and seventeen nitroimidazole couples ( S / S -) were estimated for S = substituted 2-, 4-, and 5-nitroimidazoles, by measuring the equilibrium constant Kc of the reaction S-+ Q + S + Q-. The radical-ions Sand Qwere generated by pulse radiolysis, and their concentrations measured spectrophotometrically after the equilibrium was attained (typically 1-50 ps after the pulse). Estimated values of E:(S/S-) range from -243 mV for S = 5-formyl-1-methyl-2-nitroimidazole ; -398 mV for 1 -(2-hydroxyethyl)-2-nitroimidazole ; -486 mV for l-(2-hydroxyethyl)-2-methyl-5-nitroimidazole to < -527 mV for 4-nitroimidazole (all F 10 mV). In the absence of other factors, 2-nitroimidazoles have more positive E$ values than the 5-nitro-analogues, and 4-nitroimidazoles are still weaker oxidants. Substitution with electron-withdrawing groups in the side chain can increase E+ by amounts greater than the difference between 2-and 5-nitroimidazoles. These values are based on E+(Q/Q-) = -244 k 7 mV for duroquinone, and -375 k 8 mV for 9,10-anthraquinone-2-sulphonate.These reference potentials were determined by measuring K, for one-electron transfer equilibria between the quinones and 1,1'-dibenzyl-4,4'-bipyridylium ion (BV2+), assuming E+(BVZ+/BV+) = -354k 6 mV. The usefulness of viologens as redox indicators in this type of study is discussed, There is evidence that modification of the redox properties of nitro-aromatic compounds (by substitution of electron-withdrawing groups in the ring) can have a considerable effect on the potential usefulness of these compounds as hypoxic cell radiosensitizers in radiotherapy. Electron spin resonance (e.s.r.) studies have provided much information concerning the effects of substitution upon nitro-aromatic radical-anionsy2# and Meisel and Neta have shown that these e.s.r. parameters can be related to the one-electron reduction potentials of the parent compounds. Much less is known about the effects of substitution upon the free-radical chemistry of nitro-heterocyclic compounds. Nitroimidazoles are also being investigated as potential radio sensitizer^,^ and we report here measurements of the one-electron reduction potentials of several of these compounds.The position of the one-electron transfer equilibrium : 4* 6-9 S-+Q + S + Q -(1) is a measure of the difference in reduction potential between the reference Q (e.g. duroquinone 4* ' 9 or 9,1O-anthraquinone-2-sulphonate) and the nitro-compound S.If in water at pH 7 the radical-ions S-or Q-are stable only for milliseconds, then production, and measurement of the concentrations of these species are conveniently achieved by pulse radiolysis and fast, kinetic spectrophotometry ; the potentials of the reference compounds have been previously e~timated.~. ** l o g l 1 EXPERIMENTAL Duroquinone (Sigma) was recrystallized from ethanol+ water, and 9, lo-anthraquinone-2-sulphonate (B.D.H., purified) was recrystallized 3 times from water (as the monohydrate). 1 ,l'-...

Redox properties of free radicals

“…These radicals can participate in one-electron transfer equilibria P~NO%-+ Q i2 P~N O Z + Q-(34) which allow the measurements of one-electron redox potentials. Such measurements were carried out with a large number of aromatic and heterocyclic nitro compounds (19,20,23), using as references various quinones and hipyridinium ions. A nitro compound cannot serve as a reference for another nitro compound since the electron transfer reactions PhN& + Ph'N02 PhN02 + Ph'N6%- nism of radiosensitization was sumested to involve one-eleca t high pH or X = OH at lower pH values (pK, = 11.4).…”

Split dose cytotoxic experiments with misonidazole

“…The time scale of this "repair" is similar to the initial repair of radiation sub-lethal damage (SLD) at 37°C, but, whereas repair of SLD is inhibited by heating at 41WC between doses (Ben-Hur and Elkind, 1 974a; Stratford, unpublished), repair of toxicity damage is not. It has been suggested that *Electron affinity has been related to one electron reduction potential, E71, measured by pulse radiolysis (Wardman and Clarke, 1976b (Wong et al, 1978) and a decrease in Do . The present data would suggest that misonidazole-induced damage is not related to radiation-induced sublethal damage and that drug/radiation interaction must occur via other processes.…”

Mode of Action Studies on Nitrodiphenyl Ether Herbicides

“…Deoxygenated solutions in propan-2-ol/5 mm aqueous phosphate buffer (pH 7) (1:3 v/v) containing 10 to 40 gM DPE and 30 to 90 gM 1,1'-butano-2,2'-bipyridinium dibromide (E' -635 mV in aqueous phosphate buffer [1]) were irradiated with electron pulses as described by Wardman and Clarke (29). Rather low concentrations of redox compounds were used in these measurements owing to the low solubilities of the DPEs.…”

“…The one-electron reduction potentials of DPEs were measured from the equilibrium concentrations of the reduced and oxidized forms after pulse radiolysis (29) in the presence of 1,1'-butano-2,2'-bipyridinium dibromide. Deoxygenated solutions in propan-2-ol/5 mm aqueous phosphate buffer (pH 7) (1:3 v/v) containing 10 to 40 gM DPE and 30 to 90 gM 1,1'-butano-2,2'-bipyridinium dibromide (E' -635 mV in aqueous phosphate buffer [1]) were irradiated with electron pulses as described by Wardman and Clarke (29).…”