ArticleChemical research in toxicology2014
Isotopic labeling experiments that elucidate the mechanism of DNA strand cleavage by the hypoxia-selective antitumor agent 1,2,4-benzotriazine 1,4-di-N-oxide.
Article in Chemical research in toxicology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 16 citations in OpenAlex.
- Deuteration of Six-Membered N-Heteroarenes: Chemistry and Applications.Chemistry (Weinheim an der Bergstrasse, Germany) · 2025Review
- Aerobic Cytotoxicity of AromaticInternational journal of molecular sciences · 2020Article
- Kinetics of Flavoenzyme-Catalyzed Reduction of Tirapazamine Derivatives: Implications for Their Prooxidant Cytotoxicity.International journal of molecular sciences · 2019Article
- Nanoparticles for nucleic acid delivery: Applications in cancer immunotherapy.Cancer letters · 2019Review
- Complexation of thorium with pyridine monocarboxylate-N-oxides: Thermodynamic and computational studies.The Journal of chemical thermodynamics · 2018Article
- Hypoxia-activated prodrugs and redox-responsive nanocarriers.International journal of nanomedicine · 2018Review
- Application of Suzuki-Miyaura and Buchwald-Hartwig Cross-coupling Reactions to the Preparation of Substituted 1,2,4-Benzotriazine 1-Oxides Related to the Antitumor Agent Tirapazamine.Journal of heterocyclic chemistry · 2017Article
- N-H⋯O versus O-H⋯O: density functional calculation and first principle molecular dynamics study on a quinoline-2-carboxamide N-oxide.Journal of molecular modeling · 2015Article
- Toward hypoxia-selective DNA-alkylating agents built by grafting nitrogen mustards onto the bioreductively activated, hypoxia-selective DNA-oxidizing agent 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine).The Journal of organic chemistry · 2014Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
The 1,2,4-benzotriazine 1,4-dioxides are an important class of potential anticancer drugs that selectively kill the low-oxygen (hypoxic) cells found in solid tumors. These compounds undergo intracellular one-electron enzymatic reduction to yield an oxygen-sensitive drug radical intermediate that partitions forward, under hypoxic conditions, to generate a highly reactive secondary radical that causes cell killing DNA damage. Here, we characterized bioreductively activated, hypoxia-selective DNA-strand cleavage by 1,2,4-benzotriazine 1,4-dioxide. We found that one-electron enzymatic activation of 1,2,4-benzotriazine 1,4-dioxide under hypoxic conditions in the presence of the deuterium atom donor methanol-d4 produced nondeuterated mono-N-oxide metabolites. This and the results of other isotopic labeling studies provided evidence against the generation of atom-abstracting drug radical intermediates and are consistent with a DNA-damage mechanism involving the release of hydroxyl radical from enzymatically activated 1,2,4-benzotriazine 1,4-dioxides.
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