Reactive sulphur species: an in vitro investigation of the oxidation properties of disulphide S-oxides.

We have recently proposed that disulphide S-monoxides (thiosulphinates) and disulphide S-dioxides (thiosulphonates) are formed from their parent disulphides and 'reactive oxygen species' during oxidative stress. These 'reactive sulphur species' are themselves strong oxidizing agents that preferably attack the thiol functionality. We now show that under conditions where disulphides show little effect, disulphide S-oxides rapidly modify metallothionein, alcohol and glyceraldehyde 3-phosphate dehydrogenases and a zinc finger-protein fragment in vitro. The known antioxidants ascorbate, NADH, trolox and melatonin are unable to inhibit this oxidation pathway and only an excess of the cellular redox-buffer glutathione quenches the disulphide S-oxide activity. These results suggest that, under conditions of oxidative stress, despite the presence of high concentrations of antioxidants, reactive sulphur species formation may occur and inhibit the function of thiol-dependent proteins. Such a characterization of the disulphide S-oxide-oxidation pathway might also account for some previously observed anomalies in protein oxidation

Multifunctional redox catalysts as selective enhancers of oxidative stress

Certain cancer cells proliferate under conditions of oxidative stress (OS) and might therefore be selectively targeted by redox catalysts. Among these catalysts, compounds containing a chalcogen and a quinone redox centre are particularly well suited to respond to the presence of OS. These catalysts combine the specific electrochemical features of quinones and chalcogens. They exhibit high selectivity and efficiency against oxidatively stressed rat PC12, human Jurkat and human Daudi cells in cell culture, where their mode of action most likely involves the catalytic activation of existent and the generation of new reactive oxygen species. The high efficiency and selectivity shown by these catalysts makes them interesting for the development of anti-cancer drugs

Intracellular Targeting and Pharmacological Activity of the Superoxide Dismutase Mimics MnTE-2-PyP⁵⁺ and MnTnHex-2-PyP⁵⁺ Regulated by Their Porphyrin Ring Substituents

Manganese porphyrin-based drugs are potent mimics of the enzyme superoxide dismutase. They exert remarkable efficacy in disease models and are entering clinical trials. Two lead compounds, MnTE-2-PyP⁵⁺ and MnTnHex-2-PyP⁵⁺, have similar catalytic rates, but differ in their alkyl chain substituents (ethyl vs <i>n</i>-hexyl). Herein we demonstrate that these changes in ring substitution impact upon drug intracellular distribution and pharmacological mechanism, with MnTnHex-2-PyP⁵⁺ superior in augmenting menadione toxicity. These findings establish that both catalytic activity and intracellular distribution determine drug action