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The reaction of the para-quinone 6,7-dichloroquinoline-5,8-dione with various transition metal dimers led to the unexpected formation of quinoline-ortho-quinone metal complexes. Systematic variation of the reaction conditions helped identify the solvent as the source of the carbonyl oxygen.

The radical species underlying the activity of the bioreductive anticancer prodrug, SN30000, have been identified by electron paramagnetic resonance and pulse radiolysis techniques. Spin-trapping experiments indicate both an aryl-type radical and an oxidising radical, trapped as a carbon-centred radical, are formed from the protonated radical anion of SN30000. The carbon-centred radical, produced upon the one-electron oxidation of the 2-electron reduced metabolite of SN30000, oxidises 2-deoxyribose, a model for the site of damage on DNA which leads to double strand breaks. Calculations using density functional theory support the assignments made.

The ˙OH radical is released from 3-trifluoromethyl-quinoxaline 1,4-dioxides upon one-electron reduction by cytochrome P450 oxidoreductase. This process effectively competes with back oxidation of the intermediate radical anion by oxygen and underlies the increased aerobic cytotoxicity of such compounds compared to that seen for the related clinical bioreductive benzotriazine drug, tirapazamine.

The one-electron reduction chemistry of the antituberculosis drug PA-824, together with a series of closely related compounds, has been investigated in irradiated anaerobic propan-2-ol solution. The protic solvent, of low dielectric constant, was chosen to mimic the environment of a water-restricting active site of a model protein, which is capable of reducing the compounds. Radiolytic reduction of the compounds containing electron donating substituents in the 2-position of the imidazole ring released nitrite, with compounds that are highly active against Mycobacterium tuberculosis exhibiting high yields of nitrite. The release of cytotoxic reactive nitrogen species through a one-electron pathway, by as yet unidentified proteins, may play a role in the activity of this class of compounds against TB. The described radiolytic quantification of nitrite release may have utility as a preliminary screening test for nitroaromatic candidate drugs against the disease.

The dependency of the rate of intramolecular electron transfer in DNA in aqueous solution on the free energy change (ΔG°) and distance (L) is determined by observing electron transfer from DNA base radical anions to a series of eight compounds which are randomly intercalated into the DNA. Electron transfer initiated in DNA is found to be activation energy-controlled with k=k° exp(constant/L), which is different from published studies on electron transfer between photodonor–acceptor complexes attached to DNA that invoke an electron tunnelling description.

The radical anions of the pyranonaphthoquinone antibiotic kalafungin 1 and analogues have been studied in aqueous solution by pulse radiolysis using transient absorption spectrophotometry. Radical absorption spectra were similar regardless of the nature of the substituent at C-5 or C-7 and the decay followed second-order kinetics showing any potential first-order ring opening was too slow to compete with bimolecular disproportionation at the concentration of radicals produced by pulse radiolysis. Spectral studies using steady-state radiolysis confirmed the absence of ring opening. The pKa of each of the semiquinones of compounds 1–5 were determined and whereas replacing a hydrogen at C-7 by a methoxy, 2 and 4, raises the pKa by 2.5–2.9 units demonstrating a significant substituent effect, no such increase occurs for OH, 1. This and the fact that kalafungin, 1, has the most positive one-electron reduction potential E(1), –63 ± 10 mV in neutral solution, is attributed to H-bonding between the 7-OH and the oxygen of the semiquinone, with the H-bonding effectively nullifying the substituent effect. The presence of an OH on C-5 has a much less significant effect on the E(1) and pKa values. Comparison of kinetics and products in systems with and without tert-butanol brings into question a report that 2-(methoxymethyl)benzo-1,4-quinone and 2-(phenoxymethyl)benzo-1,4-quinone undergo dissociation on one-electron reduction.

The reactions of nitroquinolines with radical sites on DNA, formed by OH˙ radical attack in aqueous solution, have been studied. It is found that the small concentrations of compound, unbound to DNA, oxidise the essentially immobile DNA radicals with diffusion-controlled rate constants of ca. 5 × 109 dm3 mol–1 s–1to form absorbing radical anions. Oxidation of the radical sites by the proportion of the compounds bound to DNA does not occur, except to a small extent in the case of the 6-nitro regioisomer. Calculations based on the measured intrinsic association constant and migration rate along DNA of the 6-nitro regioisomer yield a jump time between neighbouring sites on the DNA of 2.76 ns. Competition studies between such compounds which bind to DNA and xenobiotica for OH˙ radical-damaged sites on DNA is illustrated by studies with three thiol compounds which yield second-order rate constants for repair of the DNA radicals, through H-atom donation; glutathione, 1.2 × 106 dm3 mol–1 s–1, cysteine, 6 × 106 dm3 mol–1 s–1 and cysteamine, 1.6 × 108 dm3 mol–1 s–1.

A series of 3-nitro-4-alkylbenzamides has been prepared, and the effects of nitro group torsion angle on reduction potential studied. Nitro and carboxamide group torsion angles have been determined by 17O NMR spectroscopy and X-ray crystallography, and one-electron reduction potentials by pulse radiolysis. 17O Chemical shifts indicated similar amide torsion angles (from 35° to 45°) as the alkyl group varied from hydrogen to tert-butyl, but widely differing nitro group torsion angles; from 36°(hydrogen) to 92°(tert-butyl). Crystal structures of the isopropyl and tert-butyl derivatives indicate amide group torsion angles (50° and 64°) somewhat larger than those predicted by 17O NMR, and nitro group torsion angles (59° and 65° respectively) considerably smaller than those predicted by 17O NMR (75° and 92° respectively). These results support earlier data that 17O chemical shifts predict for erroneously large nitro group torsion angles in non-rigid but sterically crowded molecules, because of additional contributions to the shift from van der Waals repulsions. The drop in reduction potential of 90 mV between the unsubstituted and tert-butyl derivatives is too large to be accounted for by the electronic effects of the alkyl groups, and indicates that increasing the nitro group torsion angle significantly lowers reduction potential.

The reactions of the aquated electron (e–aq) with intercalators of high reduction potential (nitracrine and related basic nitroacridines) has been investigated by pulse radiolysis in the presence of DNA in aqueous solution. Under conditions where the majority of the e–aq species react initially with DNA bases (high DNA: drug ratios) a slower subsequent electron transfer to the intercalator was observed. The rate of this intra-complex transfer, expressed as DNA base pairs traversed per second, was in the range (1.2–3.1)× 105 base pairs s–1 and increased in order of the one-electron reduction potentials of the DNA-bound intercalators. No transfer was seen to the much less electron affinic des-nitro analogue of the nitroacridines. Only a small proportion of the initial DNA base radicals (⩽50%) underwent this intra-complex electron transfer. Even for the most efficient electron trap, nitracrine, the apparent mean electron migration distance was only three base pairs. A slow secondary reduction of nitroacridines [(0.08–5.0)× 104 base pairs s–1] was also observed with a proportion of the essentially immobile ˙OH-induced DNA radicals. This secondary reaction may well serve as a measure of the mobility of the DNA-bound intercalators. This study therefore implies a lack of extensive migration of DNA-associated electrons in aqueous solution, although it does not exclude the possibility that more mobile electrons produced by direct ionization of DNA might migrate over large distances.

One-electron redox equilibria can be established between electron-affinic compounds (EA) intercalated into DNA and cationic viologens such as benzylviologen. The conditions under which the one-electron reduction potential of EA intercalated into DNA can be determined are described and validated.

The one-electron reduction potentials (E1) of certain pyrazinediium, diazepinediium and diazocinediium viologen compounds substituted with methyl groups, V2+, have been determined from the position of the one-electron transfer equilibria with reference compounds using pulse radiolysis. E1 ranges from –491 ± 6 mV (vs NHE) for 6,7-dihydro-2,11-dimethyldipyrido-[1,2-a : 2′,1′-c]pyrazinediium dibromide (V212+) to –832 ± 11 mV for 6,7,8,9-tetrahydro-2,3,12,13-tetramethyldipyrido[1,2-a : 2′,1′-c][1,4]diazocinediium dibromide (V422+).The rates of reduction by e–aq were found to be independent of E1 whereas the rates of electron transfer from CO˙–2 and (CH3)2ĊOH species do show a dependence on E1 for V2+ compounds of lowest E1. Marcus-type treatment of the rate-constant data yields a rate constant of electron exchange between propan-2-oxyl radicals and acetone in the range (2–6)× 106 dm3 mol–1 s–1 and between the radical cation of 6,7-dihydro-2,3,10,11-tetramethyldipyrido[1,2-a : 2′,1′-c]-pyrazinediium dibromide (V22˙+) and its unreduced form (V222+) of 5 × 107 dm3 mol–1 s–1.

The absorption spectrum of one-electron reduced m-AMSA+ has been measured by pulse radiolysis. The radical species formed, m-AMSA˙, is readily oxidized by oxygen, flavin mononucleotide, and triquat; m-AMSA+ itself acts as an oxidant of the one electron reduced species of nicotinamide adenine dinucleotide. The one-electron reduction potential of the m-AMSA+/m-AMSA˙ couple at pH 7, E17, has been determined to be –803 ± 10 mV (vs. NHE) by studying the equilibrium established between m-AMSA+/m-AMSA˙ and a low-potential bipyridinium compound used as a redox indicator.

The redox chemistry of the clinical antileukemia drug mAMSA (amsacrine) and of its dimethylamino analogue (diAMSA) has been investigated by radiolytic methods. Steady-state and pulse radiolysis experiments show that upon one-electron oxidation both compounds give quinone di-imine radicals (mAQDI˙ and diAQDI˙) which disproportionate to the parent compounds and the corresponding quinone di-imines (mAQDI and diAQDI). One-electron reduction of the quinone di-imines give the same intermediate radicals which are not oxidized by oxygen. Nanosecond pulse radiolysis experiments show that the initial one-electron reduction of the quinone di-imines also occurs at the acridine ring, but is followed by rapid intramolecular electron transfer to the quinone di-imine side-chain. One-electron reduction of mAMSA occurs at the acridine ring and leads to acridan formation. The redox potential at pH 7.4 of the mAMSA–mAQDI˙ couple is calculated as 915 mV (versus n.h.e.), while the redox potential of the mAMSA–mAQDI couple is 415 mV. The analogue diAMSA shows a similar reversible redox chemistry but is much more readily oxidizable, with a calculated redox potential diAMSA–diAQDI˙ of 635 mV, and a redox potential diAMSA–diAQDI of 330 mV.

The distribution of electrophilic OH˙ radical addition to 4-hydroxybenzoic acid (HBA) has been determined by oxidizing the radical intermediates (substituted hydroxycyclohexadienyl radicals) with quinones and viologens, to yield products. It is deduced from product analysis using high-performance liquid chromatography that the fractions of OH˙ attack at the 1 : 2 : 3 : 4 positions of HBA are 0.16 : 0.04 : 0.65 : 0.15 respectively. Pulse radiolysis studies show that the rate of electron transfer from the radical intermediate formed by OH˙ addition to position 3 of HBA is dependent on the one-electron reduction potential of the oxidant. This electron-transfer process is in competition with the elimination of water by general acid–base catalysis to yield the phenoxyl radical. Catalysis by OH– proceeds through the formation of the deprotonated species, pKa= 8.4 ± 0.2, followed by the elimination of water, Ke= 3.0 ± 0.3 × 105 s–1. The addition of an OH˙ radical to position 3 of HBA gives rise to an absorption band centred at 365 nm.