Luis P. Candeias

Fenton chemistry: an introduction.

In 1876, Fenton described a colored product obtained on mixing tartaric acid with hydrogen peroxide and a low concentration of a ferrous salt. Full papers in 1894 and 1896 showed the product was dihydroxymaleic acid. Haber, Weiss and Willstätter proposed in 1932-1934 the involvement of free hydroxyl radicals in the iron(II)/hydrogen peroxide system, and Baxendale and colleagues around 1950 suggested that superoxide reduces the iron(III) formed on reaction, explaining the catalytic nature of the metal. Since Fridovich and colleagues discovered the importance of superoxide dismutase in 1968, numerous studies have sought to explain the deleterious effects of cellular oxidative stress in terms of superoxide-driven Fenton chemistry. There remain questions concerning the involvement of free hydroxyl radicals or reactions of metal/oxo intermediates. However, these outstanding questions may obscure a wider appreciation of the importance of Fenton chemistry involving hypohalous acids rather than hydrogen peroxide as the oxidant.

Enhancement of peroxidase-induced lipid peroxidation by indole-3-acetic acid: effect of antioxidants

Indole-3-acetic acid (IAA) enhanced the peroxidase-induced lipid peroxidation in phosphatidylcholine liposomes, as measured by loss of fluorescence of cis-parinaric acid. α-Tocopherol or β-carotene in the lipid phase or ascorbate or Trolox in the aqueous phase inhibited the loss of fluorescence induced by the peroxidase + IAA system, but glutathione had only a small inhibitory effect. The peroxyl radical formed by one-electron oxidation of IAA, followed by decarboxylation and reaction with oxygen, is suggested to act as the initiator of lipid peroxidation. The protection by ascorbate or Trolox is explained by the reactivity of these compounds with the IAA indolyl radical, as shown by pulse radiolysis experiments, whereas the weak effect of glutathione agrees with its low reactivity towards the IAA-derived peroxyl radical and its precursors.

Preparative, physico-chemical and cytotoxicity studies of prodrugs activated in hypoxia to give metal-binding analogues of bleomycin

The synthesis of 2,6-disubstituted pyridines 10, 23, 27a–28b is reported. These compounds are expected to complex iron(II) and yield hydroxyl radicals by interaction of the aqueous complex with oxygen. In addition a second series of 2,6-disubstituted pyridines 24a, 24b and 29 having additional features (nitro or N-oxide groups), which are expected to prevent complexation of iron, is described. These deactivated compounds are expected to be reduced in hypoxic tumour cells to yield products 25a, 25b and 10, respectively, which are able to complex metals and yield hydroxyl radicals. EPR and fluorescence spectroscopy provide evidence for the production of hydroxyl radicals from all the compounds except the prodrugs 10, 25a and 25b and the compounds not having an imidazole nucleus 27a–28b. The prodrugs were not cytotoxic in air alone to Chinese hamster V79 cells in vitro. However, when the prodrug was added to the cells and then exposed to hypoxia followed by air, the nitro compounds 24a and 24b showed slightly increased cytotoxicity. However, the N-oxide 29 showed marked cytotoxicity similar to that of the corresponding N-deoxygenated compound 10.

Rates of decarboxylation of the radical cations of indol-3-ylacetic acids and comparison with indolizin-1-ylacetic acids

The radical cations of indol-3-ylacetic acid and derivatives were nfound to eliminate CO2 to yield skatolyl radicals with rates nin the range ca. 102 to >105 ns-1, strongly dependent on substitution. For the nradical cations substituted at nitrogen, the rate of decarboxylation did nnot vary with pH 4–7.5, but for those unsubstituted at nitrogen, ndeprotonation caused the rate of decarboxylation to decrease with nincreasing pH. The rate of decarboxylation of the radical cations nexhibited a strong dependence on the respective reduction potentials, nwith a 100 mV increase in reduction potential corresponding to a nca. tenfold increase in the rate of decarboxylation. nMethylation at the side-chain α-position increased the nrate of decarboxylation >sixfold, but insertion of a methylene group, nas in 3-indol-3-ylpropionic acid or tryptophan, completely inhibited ndecarboxylation. In contrast, indolizin-1-ylacetic acids, which are nisomers of indolylacetic acids in which the heterocyclic nitrogen is the nbridgehead, did not decarboxylate on one-electron oxidation.

Preparation of some Quinoxaline Quinones, their Electrochemical Reduction, and EPR and Theoretical Studies on their Semiquinone Anions

Novel 2,3-disubstituted quinoxaline quinones and a tricyclic quinone containing the quinoxaline nucleus are reported together with their one-electron reduction chemistry and the EPR spectra of the radical anions.