ABSTRACT
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.
Subject(s)
Chalcogens/chemistry , Cytochrome Reductases/chemistry , Oxidative Stress , Quinones/chemistry , Animals , Catalysis , Cell Line, Tumor , Chalcogens/pharmacology , Electrochemistry , Humans , Jurkat Cells , Models, Molecular , Molecular Structure , Oxidation-Reduction/drug effects , Oxidative Stress/drug effects , PC12 Cells , Quinones/pharmacology , Rats , Reactive Oxygen Species/chemistry , Reactive Oxygen Species/metabolismABSTRACT
Numerous human diseases are linked to a biochemical condition known as oxidative stress (OS). Antioxidants are therefore becoming increasingly important as potential disease prevention and therapeutic agents. Since OS is a multi-stressor event, agents combining a range of different antioxidant properties, such as redox catalysis and metal binding, might be more effective and selective than mono-functional agents. Selenium derivatives of aniline and pyridine combine redox activity with metal binding properties. These multifunctional agents have a distinct electrochemical profile, and exhibit good catalytic activity in the glutathione peroxidase mimic and metallothionein assays. They also show antioxidant activity in a skin cell model of UVA-induced stress. These compounds might therefore provide the basis for novel agents combining two or more distinct antioxidant properties.
Subject(s)
Antioxidants/chemical synthesis , Antioxidants/chemistry , Catalysis , Cell Line , Copper/chemistry , Electrochemistry , Fibroblasts , Humans , Ligands , Molecular Structure , Peroxidase/metabolism , Reactive Oxygen Species/chemistryABSTRACT
New asymmetric organotellurides exhibiting good antioxidant properties in vitro and in cell culture can be attached to human serum albumin.
Subject(s)
Antioxidants/chemical synthesis , Cell Survival/drug effects , Organometallic Compounds/chemical synthesis , Serum Albumin/metabolism , Tellurium/pharmacology , Antioxidants/pharmacology , Glutathione Peroxidase/metabolism , Humans , Kinetics , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Metallothionein/metabolism , Organometallic Compounds/pharmacology , Peroxides/chemistry , Phenols/chemistry , Sulfhydryl Compounds/chemistry , Tellurium/chemistry , Zinc/metabolismABSTRACT
Integrated catalysts as redox sensitisers towards cancer.
Subject(s)
PC12 Cells/drug effects , Quinones/metabolism , Quinones/pharmacology , Animals , Catalysis , Cell Survival/drug effects , Electrochemistry , Hydrogen Peroxide/chemistry , Hydrogen Peroxide/metabolism , Molecular Structure , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Oxidation-Reduction , Oxidative Stress/drug effects , PC12 Cells/metabolism , Quinones/chemistry , RatsABSTRACT
Kynurenines are formed as part of the tryptophan metabolism and are known to exhibit pro- and anti-oxidant activities in vitro. The mapping of these biological redox-systems and identification of potential in vivo targets are therefore of great interest in cellular physiology. Here the redox-behavior of different kynurenines and anthranilic acids is evaluated electrochemically and compared to that of simple model compounds. Electrochemical results are correlated with the activity of these compounds in redox-bioassays where 3-hydroxyanthranilic acid and 3-hydroxykynurenine have significant redox-activity. The specific electrochemical redox-behavior of these two compounds, indicating a particular redox-mechanism involving the hydroxyl group, can be used to rationalize these findings. The results indicate that tryptophan metabolites can undergo a range of complex redox-reactions in vivo whose precise nature critically depends on structural details. As a consequence, some of the kynurenines have the potential to contribute to neuronal damage in brain disorders and stroke.
Subject(s)
Kynurenine/chemistry , Electrochemistry , Kynurenine/analogs & derivatives , Models, Chemical , Oxidation-Reduction , Structure-Activity Relationship , ortho-Aminobenzoates/chemistryABSTRACT
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.
