Nitroimidazoles as anaerobic electron acceptors for xanthine oxidase

Clarke, Eric D.; Goulding, K. H.; Wardman, Peter

doi:10.1016/0006-2952(82)90556-1

Cited by 68 publications

(28 citation statements)

References 9 publications

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“…Studies of the rates of reduction of nitroarenes by free, reduced flavin mononucleotide (FMNH 2 ) [79,112] or by xanthine/xanthine oxidase [80,112] in the absence of oxygen have revealed a similar redox dependence. These studies, and earlier work [113] showed that reduction proceeds to the hydroxyamine (four electrons) via the formation of the nitro radical-anion (one electron reduction) [114], which is probably the rate-limiting step.…”

Section: Redox Properties and The Rates Of Reductive Activationmentioning

confidence: 94%

“…The low reduction potential of the enzyme facilitates reduction of compounds such as metronidazole (one-electron reduction potential = −0.50 V) which are poor electron acceptors for other, mammalian flavoproteins and react very slowly with free, reduced flavin [79,80]. Thus the selectivity of enzyme-catalysed reduction of metronidazole in microorganisms is a factor in its target:host selectivity, in addition Redox Properties of Nitroarene Bioreductive Drugs effects of substituents with other nitroarenes using ρ of 0.15 ± 0.03 V (if σ p − values are used when appropriate).…”

Section: Redox Properties Of Some Typical Reductases and Of Oxygen Qmentioning

confidence: 99%

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Electron Transfer and Oxidative Stress as Key Factors in the Design of Drugs Selectively Active in Hypoxia.

Wardman

2001

CMC

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140

110

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Hypoxia is a feature of some regions of many tumours, ischaemic events, and arthritis. Drugs activated in hypoxia have wide potential application, particularly in overcoming the resistance of hypoxic tumour cells to radiotherapy. Key features of such drugs include redox properties appropriate for activation by reductase enzymes (typically flavoproteins), and oxygen-sensitive reduction chemistry such that normal levels of oxygen inhibit or reverse reduction. In many cases this selectivity is achieved by a fast, free-radical reaction in which the drug radical (often an obligate intermediate in drug reduction) reduces oxygen to form superoxide radicals and thus 'futile cycles' the drug in normoxic tissues. However, this enhances cellular oxidative stress, which may be linked to normal tissue toxicity. Appropriate redox properties are found with nitroarene, quinone, or aromatic N-oxide moieties. A particularly promising and versatile exploitation of bioreductive activation is for reduction of such 'triggers' to activate release of an 'effector', an agent that can obviously be active against diverse conditions associated with hypoxia. The same approach can also be used in diagnosis of hypoxia. Much information concerning the reactions of intermediates in drug action and the quantitative prediction of redox properties of analogues has been accrued. Drug design can be mechanism-led, with the wealth of literature quantifying redox properties of drug candidates a rich source of potential new leads. There is a clear appreciation of the kinetic factors that limit drug efficacy or selectivity. Thus the potential for rapid expansion of these concepts to diverse diseases is considerable.

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Section: Redox Properties and The Rates Of Reductive Activationmentioning

confidence: 94%

Section: Redox Properties Of Some Typical Reductases and Of Oxygen Qmentioning

confidence: 99%

Electron Transfer and Oxidative Stress as Key Factors in the Design of Drugs Selectively Active in Hypoxia.

Wardman

2001

CMC

Self Cite

140

110

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“…Although this is included in the redox hypothesis as a disruption of redox signalling and control, excessively reducing conditions are distinct from more common conditions of excessive oxidants, which have been frequently linked to disease. Reductive stress was considered by Chance [57] as a possible mechanism of anoxic injury, and subsequently as a component of hypoxic potentiation of halothane-induced liver toxicity [58], reoxygenation injury [59] and enhanced killing of hypoxic tumour cells [60].…”

Section: Reductive Stress Through Extracellular E H Cyssmentioning

confidence: 99%

Redox compartmentalization and cellular stress

Jones¹,

Go²

2010

Diabetes Obesity Metabolism

214

176

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Mammalian cells are highly organized to optimize function. For instance, oxidative energy-producing processes in mitochondria are sequestered away from plasma membrane redox signalling complexes and also from nuclear DNA, which is subject to oxidant-induced mutation. Proteins are unique among macromolecules in having reversible oxidizable elements, 'sulphur switches', which support dynamic regulation of structure and function. Accumulating evidence shows that redox signalling and control systems are maintained under kinetically limited steady states, which are highly displaced from redox equilibrium and distinct among organelles. Mitochondria are most reducing and susceptible to oxidation under stressed conditions, while nuclei are also reducing but relatively resistant to oxidation. Within compartments, the glutathione and thioredoxin systems serve parallel and non-redundant functions to maintain the dynamic redox balance of subsets of protein cysteines, which function in redox signalling and control. This organization allows cells to be poised to respond to cell stress but also creates sites of vulnerability. Importantly, disruption of redox organization is a common basis for disease. Research tools are becoming available to elucidate details of subcellular redox organization, and this development highlights an opportunity for a new generation of targeted antioxidants to enhance and restore redox signalling and control in disease prevention. Keywords: cysteine; glutathione; oxidative stress; redox signalling; thioredoxin Date submitted 25 March 2010; date of final acceptance 31 May 2010 IntroductionTranslation of basic science knowledge into human research and improved health care is a contemporary focus of many funding agencies and research sponsors. In oxidative stress research, however, there is a considerable need for reverse translation, that is from clinical observations back to basic science. Such an effort is warranted because large-scale doubleblind interventional trials with moderately high doses of free radical scavengers provided little health benefit, although the basic science research, preclinical studies and observational studies in humans clearly implicate oxidative stress as an underlying mechanism of many disease processes.The present review addresses one aspect of this reverse translation, investigation of possible cause-effect relationships between oxidative stress, measured in terms of thiol oxidation in human plasma, and its underlying biochemistry at the subcellular level. Most of the information reviewed has not been gained from studies of diabetes or the stressed β-cell, but the mechanistic information is relevant to understanding of β-cell function and dysfunction. Several studies show that plasma thiol/disulphide systems are oxidized in association with diabetes in humans and animal models, and the meaning of changes in oxidation of the thiol systems and subcellular stress signalling is now beginning to emerge.A seminal observation which led to the current development of redox compa...

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“…1, 2002 Since the efficiency of redox cycling agents depends upon the rate of catalytic turnover (Scheme 1), optimum activity would result when the one-electron redox potential of the agent is in-between that of cellular reductants, ca. 44 …”

Section: Main Classes Of Compounds Biologically and Electrochemicallymentioning

confidence: 99%

Some Applications of Electrochemistry in Biomedical Chemistry. Emphasis on the Correlation of Electrochemical and Bioactive Properties

Abreu¹,

Ferraz²,

Goulart³

2002

J. Braz. Chem. Soc.

153

126

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Essa revisão resume alguns dos aspectos mais relevantes na correlação entre processos e parâmetros eletroquímicos e atividades biológicas, relacionadas, principalmente, a doenças tropicais e câncer. Apesar da gama de possibilidades e da complexidade da química celular/tecidual/extracelular, é possível racionalizar o papel da eletroquímica em poucas bases teóricas, principalmente: transferência eletrônica -estresse oxidativo, geração eletroquímica in situ de agentes tóxicos diferentes das espécies oxigenadas reativas, interação com endobióticos, com ênfase particular em alquilação biorredutiva e substituição de endobióticos com função em reações de oxi-redução biológicas. O uso de métodos eletroquímicos para a obtenção de mecanismos de ação de drogas e na análise de eventos celulares é também apresentado. Nessas correlações, métodos e/ou parâmetros eletroquímicos exercem papel relevante, porém, não absoluto.This review summarises some of the more relevant achievements in the correlation between electrochemical processes and parameters and bioactive properties, mainly related to cancer and tropical diseases. Despite the broad range of possibilities and the complexity of cell/tissue/extracell chemistry, it is possible to rationalise the role of electrochemistry in few basic theoretical frameworks, mainly, the one based on electron transfer-oxidative stress and in situ generation of toxic species, other than the reactive oxygen species; interaction with endobiotics, with emphasis on bioreductive alkylation and replacement of endobiotics with function in biological redox reactions. The use of electrochemical methods to obtain relevant informations about drugs' mechanism of action and analysis of cellular events is also presented. Electrochemical methods and/or parameters play essential but not absolute roles.

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Nitroimidazoles as anaerobic electron acceptors for xanthine oxidase

Cited by 68 publications

References 9 publications

Electron Transfer and Oxidative Stress as Key Factors in the Design of Drugs Selectively Active in Hypoxia.

Electron Transfer and Oxidative Stress as Key Factors in the Design of Drugs Selectively Active in Hypoxia.

Redox compartmentalization and cellular stress

Some Applications of Electrochemistry in Biomedical Chemistry. Emphasis on the Correlation of Electrochemical and Bioactive Properties

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