Studies on the action of nitroimidazole drugs

Knox, Richard J.; Knight, R.C.; Edwards, David I.

doi:10.1016/0006-2952(83)90220-4

Cited by 59 publications

(12 citation statements)

References 24 publications

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“…Through reductive processes, nitroaromatic compounds are often converted to the corresponding amines (Heimbrook and Sartorelli 1986; Kennedy et al 1980; Knox et al 1983), whereas the reduction of benzofurazans can involve a ring-opening event (Stradyn et al 1974; Tsveniashvili et al 1966). In the case of NBF-SPh, redox-cycling may involve either of the two reductive pathways, and delineation of this mechanism would contribute to the design of future BFZs.…”

Section: Resultsmentioning

confidence: 99%

7-Nitro-4-(phenylthio)benzofurazan is a potent generator of superoxide and hydrogen peroxide

et al. 2012

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Here, we report on 7-nitro-4-(phenylthio) benzofurazan (NBF-SPh), the most potent derivative among a set of patented anticancer 7-nitrobenzofurazans (NBFs), which have been suggested to function by perturbing protein–protein interactions. We demonstrate that NBF-SPh participates in toxic redox-cycling, rapidly generating reactive oxygen species (ROS) in the presence of molecular oxygen, and this is the first report to detail ROS production for any of the anticancer NBFs. Oxygraph studies showed that NBF-SPh consumes molecular oxygen at a substantial rate, rivaling even plumbagin, menadione, and juglone. Biochemical and enzymatic assays identified superoxide and hydrogen peroxide as products of its redox-cycling activity, and the rapid rate of ROS production appears to be sufficient to account for some of the toxicity of NBF-SPh (LC50 = 12.1 µM), possibly explaining why tumor cells exhibit a sharp threshold for tolerating the compound. In cell cultures, lipid peroxidation was enhanced after treatment with NBF-SPh, as measured by 2-thiobarbituric acid-reactive substances, indicating a significant accumulation of ROS. Thioglycerol rescued cell death and increased survival by 15-fold to 20-fold, but pyruvate and uric acid were ineffective protectants. We also observed that the redox-cycling activity of NBF-SPh became exhausted after an average of approximately 19 cycles per NBF-SPh molecule. Electrochemical and computational analyses suggest that partial reduction of NBF-SPh enhances electrophilicity, which appears to encourage scavenging activity and contribute to electrophilic toxicity.

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Section: Resultsmentioning

confidence: 99%

7-Nitro-4-(phenylthio)benzofurazan is a potent generator of superoxide and hydrogen peroxide

et al. 2012

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“…After removal of LC-MS artefacts and known contaminants, measured exact masses were compared with theoretical exact masses of Bzn derived metabolites contained in Bznmet database (“targeted sheet”, Files S1 and S2). This database included reported and putative Bzn reduction products and covalent adducts of Bzn with small cellular metabolites, all retrieved from existing reports on in vivo and in vitro modification processes for Bzn and similar nitroimidazoles, covering enzymatic and non-enzymatic conversions [17], [25], [26], [27]. Accurate mass and relative isotope abundance was used to determine the chemical formulae for the remaining unidentified metabolites detected specifically in the 50 µM Bzn treated samples.…”

Section: Methodsmentioning

confidence: 99%

Benznidazole Biotransformation and Multiple Targets in Trypanosoma cruzi Revealed by Metabolomics

et al. 2014

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BackgroundThe first line treatment for Chagas disease, a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi, involves administration of benznidazole (Bzn). Bzn is a 2-nitroimidazole pro-drug which requires nitroreduction to become active, although its mode of action is not fully understood. In the present work we used a non-targeted MS-based metabolomics approach to study the metabolic response of T. cruzi to Bzn.Methodology/Principal findingsParasites treated with Bzn were minimally altered compared to untreated trypanosomes, although the redox active thiols trypanothione, homotrypanothione and cysteine were significantly diminished in abundance post-treatment. In addition, multiple Bzn-derived metabolites were detected after treatment. These metabolites included reduction products, fragments and covalent adducts of reduced Bzn linked to each of the major low molecular weight thiols: trypanothione, glutathione, γ-glutamylcysteine, glutathionylspermidine, cysteine and ovothiol A. Bzn products known to be generated in vitro by the unusual trypanosomal nitroreductase, TcNTRI, were found within the parasites, but low molecular weight adducts of glyoxal, a proposed toxic end-product of NTRI Bzn metabolism, were not detected.Conclusions/significanceOur data is indicative of a major role of the thiol binding capacity of Bzn reduction products in the mechanism of Bzn toxicity against T. cruzi.

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“…For example, it was suggested that the corresponding hydroxylamine derivative obtained by the reduction is the active form of the drug. 64 In this context, it should be noted that the nitro group can be eliminated in the reduction of Met ronidazole. [63][64][65] For instance, it is known that the electrolysis of Met ronidazole affords nitrite ions in high yield; 65 the reduc tion of the drug in solution in the presence of thiols and divalent iron ions gives complexes containing iron ions, molecules of thio derivatives, and nitric oxide.…”

Section: Scheme 70mentioning

confidence: 99%

“…64 In this context, it should be noted that the nitro group can be eliminated in the reduction of Met ronidazole. [63][64][65] For instance, it is known that the electrolysis of Met ronidazole affords nitrite ions in high yield; 65 the reduc tion of the drug in solution in the presence of thiols and divalent iron ions gives complexes containing iron ions, molecules of thio derivatives, and nitric oxide. 66 It should be emphasized that N substituted 5 nitro 2 styrylimidazoles in alkaline media (pH > 10) undergo the cleavage accompanied by the opening of the imidazole ring and elimination of the nitro group as the nitrite an ion.…”

Section: Scheme 70mentioning

confidence: 99%

Biotransformations of drugs belonging to nitrogen heterocycles

Граник

2010

Russ Chem Bull

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The present review covers general aspects related to the metabolism of organic compounds, primarily, of biologically active azaheterocycles used as drugs. Compounds of this type occupy a dominant place among known drugs. Data on the main chemical processes determining the pathways of principal biotransformations, such as redox reactions, hydrolysis, alkylation, acy lation, various conjugations, isomerizations, and condensations, are summarized. The metabo lisms of heterocycles is considered based on the ring size of the substrate.

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Studies on the action of nitroimidazole drugs

Cited by 59 publications

References 24 publications

7-Nitro-4-(phenylthio)benzofurazan is a potent generator of superoxide and hydrogen peroxide

7-Nitro-4-(phenylthio)benzofurazan is a potent generator of superoxide and hydrogen peroxide

Benznidazole Biotransformation and Multiple Targets in Trypanosoma cruzi Revealed by Metabolomics

Biotransformations of drugs belonging to nitrogen heterocycles

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