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1.
Data Brief ; 8: 207-10, 2016 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-27331089

RESUMEN

We have recently reported SAR data describing the pharmacological activity of a series of phenyl alkyl selenides and tellurides which catalyse the oxidation of thiols by hydrogen peroxide (H2O2), "The design of redox active thiol peroxidase mimics: dihydrolipoic acid recognition correlates with cytotoxicity and prooxidant action" B. Zadehvakili, S.M. McNeill, J.P. Fawcett, G.I. Giles (2016) [1]. This thiol peroxidase (TPx) activity is potentially useful for a number of therapeutic applications, as it can alter the outcome of oxidative stress related pathologies and modify redox signalling. This article presents data describing the molecular changes that occur to a TPx mimic upon exposure to H2O2, and then the thiol mercaptoethanol, as characterised by UV-vis spectroscopy and HPLC retention time.

2.
Biochem Pharmacol ; 104: 19-28, 2016 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-26801688

RESUMEN

Redox active molecules containing organoselenium or organotellurium groups catalyse the oxidation of cellular thiols by hydrogen peroxide and are currently being developed as therapeutic agents. Potentially these synthetic thiol peroxidase (TPx) mimics can protect cells from oxidative stress by catalysing the reduction of reactive oxygen species by the cellular thiol glutathione, an activity which mimics the function of the antioxidant enzyme glutathione peroxidase. Alternatively they can act as prooxidants by catalysing the oxidation of essential thiol species within the cell. However the structure-activity relationships which determine the choice of thiol substrate, and hence the overall antioxidant or prooxidant outcome of drug administration, remain unknown. We report the first study that relates the pharmacological properties of TPx mimics with their solubility and catalytic activity using different thiol substrates. We used a series of structurally related compounds PhMCnH2n+1 (M=Se, Te; n=4-7) and investigated their ability to catalyse the oxidation of the cellular thiols glutathione and dihydrolipoic acid by hydrogen peroxide. The resulting rate constants (kobs) were then related to compound cytotoxicity and antioxidant versus prooxidant action in A549 cancer cells. The results show that the dihydrolipoic acid kobs values correlate with both cytotoxicity and prooxidant function. This enabled us to define a relationship, IC50=10+280e(-5(DHLA) (kobs)), which allows the prediction of TPx mimic cytotoxicity. In contrast, hydrophobicity and glutathione kobs were unrelated to the compounds' redox pharmacology.


Asunto(s)
Materiales Biomiméticos/farmacología , Diseño de Fármacos , Glutatión Peroxidasa/metabolismo , Peróxido de Hidrógeno/metabolismo , Oxidantes/metabolismo , Compuestos de Sulfhidrilo/metabolismo , Materiales Biomiméticos/química , Catálisis , Técnicas de Cultivo de Célula , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Técnicas Electroquímicas , Electrodos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Estructura Molecular , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Compuestos de Organoselenio/química , Compuestos de Organoselenio/farmacología , Oxidación-Reducción , Solubilidad , Relación Estructura-Actividad , Telurio/química
3.
Biochem Soc Trans ; 32(Pt 6): 1015-7, 2004 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-15506951

RESUMEN

Intense interest has been generated by the discovery that reactive oxygen species can function as intracellular second messengers. Reactive oxygen species have been implicated in diverse cellular processes, including growth factor signal transduction, gene expression and apoptosis. Additionally, there is evidence for proteins that are regulated by redox environment through the reversible oxidation of their cysteine residues. However, the direct reaction of reactive oxygen species with cysteine at physiological concentrations is generally a slow process, suggesting that intermediates are required to convey efficiently the oxidative stimulus. Here, we discuss the evidence that DSOs (disulphide-S-oxides) are formed from glutathione under oxidizing conditions and specifically modulate the redox status of thiols, indicating the existence of specialized cellular oxidative pathways. DSO inactivated glyceraldehyde 3-phosphate and alcohol dehydrogenases and released zinc from metallothionein and a zinc finger domain. In contrast, equivalent concentrations of H(2)O(2) showed minimal effect. The antioxidants ascorbate, NADH, trolox and melatonin were unable to quench DSO-induced oxidation. These findings support the paradigm of oxidative signal transduction and provide a general pathway whereby reactive oxygen species can convert thiols into disulphides.


Asunto(s)
Disulfuros/metabolismo , Estrés Oxidativo/fisiología , Transducción de Señal/fisiología , Glutatión/metabolismo , Compuestos de Sulfhidrilo/metabolismo
4.
Gen Physiol Biophys ; 21(1): 65-72, 2002 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-12168727

RESUMEN

Oxidative stress involves the generation of a number of reactive species, among them 'reactive oxygen species' and 'reactive nitrogen species'. Recent reports have indicated that disulfide-S-monoxides (thiosulfinates) and disulfide-S-dioxides (thiosulfonates) are formed under conditions of oxidative stress. We have now been able to demonstrate that these species are highly reactive and rapidly oxidise thiols. Glutathione and cysteine were oxidised to mixed disulfides by the action of disulfide-S-oxides. Oxidative attack on the zinc/sulfur protein metallothionein with concomitant zinc release was readily accomplished by these 'reactive sulfur species' whereas hydrogen peroxide showed minimal zinc release.


Asunto(s)
Disulfuros/química , Disulfuro de Glutatión/análogos & derivados , Óxidos/química , Compuestos de Sulfhidrilo/química , Azufre/química , Cisteína/química , Glutatión/química , Disulfuro de Glutatión/síntesis química , Peróxido de Hidrógeno/química , Metalotioneína/química , Oxidantes/química , Oxidación-Reducción , Estrés Oxidativo , Especies Reactivas de Oxígeno , Sensibilidad y Especificidad
5.
Free Radic Biol Med ; 31(10): 1279-83, 2001 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-11705707

RESUMEN

Oxidative stress arises from an imbalance in the metabolism of redox-active species promoting the formation of oxidizing agents. At present, these species are thought to include reactive oxygen, reactive nitrogen, and reactive nitrogen oxygen species (ROS, RNS, and RNOS, respectively). Reactive species have their origin in enzymatic synthesis, environmental induction, or by the further chemical reaction of an active species with other endogenous molecules to generate a second-generation reactive species. These second-generation species possess a different spectrum of activity to the parent species, with different redox reactions and biological targets. We now propose that an additional group of redox active molecules termed "reactive sulfur species" (RSS) are formed in vivo under conditions of oxidative stress. RSS are likely to include disulfide-S-oxides, sulfenic acids, and thiyl radicals, and are predicted to modulate the redox status of biological thiols and disulfides.


Asunto(s)
Radicales Libres/metabolismo , Estrés Oxidativo/fisiología , Azufre/metabolismo , Disulfuros/metabolismo , Glutatión/metabolismo , Metalotioneína/metabolismo , Modelos Químicos , Oxidación-Reducción , Ácidos Sulfénicos/metabolismo , Zinc/metabolismo
6.
Chem Commun (Camb) ; (23): 2490-1, 2001 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-12240029

RESUMEN

Synthesis and characterisation of organochalcogens has demonstrated a high correlation between their electrochemical oxidation potential on the glassy carbon electrode, their activity in bioassays and an unprecedented antioxidant activity in neuronal cell culture (EC50 approximately 20 nM) making electrochemical methodology a valuable tool in drug design for Alzheimer's and related diseases.


Asunto(s)
Antioxidantes/química , Antioxidantes/farmacología , Calcógenos/química , Calcógenos/farmacología , Animales , Canales de Calcio/metabolismo , Supervivencia Celular/efectos de los fármacos , Electroquímica , Oxidación-Reducción , Células PC12 , Ratas , Relación Estructura-Actividad
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