ArticleThe Journal of organic chemistry2014
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).
Article in The Journal of organic chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
What it found
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The trial behind it
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Who cites it
9 citing papers in PubMed.
- Tumor-Selective and Chemical Activation Strategies for Nitrogen Mustard Prodrugs.Chemistry (Weinheim an der Bergstrasse, Germany) · 2026Review
- Development of a cobalt(iii)-based ponatinib prodrug system.Inorganic chemistry frontiers · 2021Article
- Not-So-Innocent Anions Determine the Mechanism of Cationic Alkylators.Chemistry (Weinheim an der Bergstrasse, Germany) · 2021Article
- Hypoxia-targeted drug delivery.Chemical Society reviews · 2019Review
- Hypoxia-activated prodrugs and redox-responsive nanocarriers.International journal of nanomedicine · 2018Review
- Hydrogen peroxide activated quinone methide precursors with enhanced DNA cross-linking capability and cytotoxicity towards cancer cells.European journal of medicinal chemistry · 2017Article
- 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
- Simple, High-Yield Syntheses of DNA Duplexes Containing Interstrand DNA-DNA Cross-Links Between an N(4) -Aminocytidine Residue and an Abasic Site.Current protocols in nucleic acid chemistry · 2016Article
- Novel delivery approaches for cancer therapeutics.Journal of controlled release : official journal of the Controlled Release Society · 2015Review
Corrections and comments
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Authors and funding
4 authors.
Funding
Abstract
Tirapazamine (3-amino-1,2,4-benzotriazine 1,4-dioxide) is a heterocyclic di-N-oxide that undergoes enzymatic deoxygenation selectively in the oxygen-poor (hypoxic) cells found in solid tumors to generate a mono-N-oxide metabolite. This work explored the idea that the electronic changes resulting from the metabolic deoxygenation of tirapazamine analogues might be exploited to activate a DNA-alkylating species selectively in hypoxic tissue. Toward this end, tirapazamine analogues bearing nitrogen mustard units were prepared. In the case of the tirapazamine analogue 18a bearing a nitrogen mustard unit at the 6-position, it was found that removal of the 4-oxide from the parent di-N-oxide to generate the mono-N-oxide analogue 17a did indeed cause a substantial increase in reactivity of the mustard unit, as measured by hydrolysis rates and DNA-alkylation yields. Hammett sigma values were measured to quantitatively assess the magnitude of the electronic changes induced by metabolic deoxygenation of the 3-amino-1,2,4-benzotriazine 1,4-dioxide heterocycle. The results provide evidence that the 1,2,4-benzotiazine 1,4-dioxide unit can serve as an oxygen-sensing prodrug platform for the selective unmasking of bioactive agents in hypoxic cells.
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