Title: 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).
Authors: Johnson, Kevin M; Parsons, Zachary D; Barnes, Charles L; Gates, Kent S
Published In J Org Chem, (2014 Aug 15)
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.
PubMed ID: 25029663
MeSH Terms: Alkylating Agents/chemistry; Alkylating Agents/pharmacology*; Antineoplastic Agents/chemistry*; Antineoplastic Agents/pharmacology*; Cyclic N-Oxides/chemistry*; DNA Damage/drug effects*; Gas Chromatography-Mass Spectrometry; Hypoxia/chemically induced; Mechlorethamine/chemistry*; Molecular Structure; Oxidation-Reduction; Prodrugs/chemistry*; Prodrugs/pharmacology*; Triazines/chemistry*; Triazines/pharmacology*