RESUMO
New asymmetric organotellurides exhibiting good antioxidant properties in vitro and in cell culture can be attached to human serum albumin.
Assuntos
Antioxidantes/síntese química , Sobrevivência Celular/efeitos dos fármacos , Compostos Organometálicos/síntese química , Albumina Sérica/metabolismo , Telúrio/farmacologia , Antioxidantes/farmacologia , Glutationa Peroxidase/metabolismo , Humanos , Cinética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Metalotioneína/metabolismo , Compostos Organometálicos/farmacologia , Peróxidos/química , Fenóis/química , Compostos de Sulfidrila/química , Telúrio/química , Zinco/metabolismoRESUMO
Oxidative stress is implicated, either directly or indirectly, in the pathology of a range of human diseases. As a consequence, the development of efficient antioxidants for medical use has become increasingly important. We have synthesised a range of structurally related organo-sulfur, -selenium and -tellurium agents and demonstrated that a combination of electrochemical methodology, in vitro assays and cell culture tests can be used to rationalise the antioxidant activity of these catalytic agents. Based on its exceptionally low anodic oxidation potential (Epa) and high activity against the representative oxidative stressors tert-butyl hydroperoxide and peroxynitrite, 4,4'-dihydroxydiphenyltelluride is predicted to be a potent antioxidant. This compound exhibits a correspondingly high activity with a remarkably low IC50 value of 20 nM, when tested in PC12 cell culture using a bioassay indicative of the early stages of Alzheimer's disease.
Assuntos
Antioxidantes/metabolismo , Selênio/metabolismo , Enxofre/metabolismo , Telúrio/metabolismo , Doença de Alzheimer/metabolismo , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Catálise , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/metabolismo , Concentração de Íons de Hidrogênio , Metalotioneína/química , Metalotioneína/metabolismo , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , Ácido Peroxinitroso/química , Ácido Peroxinitroso/metabolismo , Ratos , Selênio/química , Selênio/farmacologia , Relação Estrutura-Atividade , Enxofre/química , Enxofre/farmacologia , Telúrio/química , Telúrio/farmacologia , Zinco/química , Zinco/metabolismoRESUMO
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.
