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).
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.
authors.affiliation: Departments of †Chemistry and ‡Biochemistry, University of Missouri , 125 Chemistry Building, Columbia, Missouri 65211, United States.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Johnson
authors.forename: Zachary D
authors.initials: ZD
authors.lastname: Parsons
authors.forename: Charles L
authors.initials: CL
authors.lastname: Barnes
authors.forename: Kent S
authors.initials: KS
authors.lastname: Gates
mesh_terms: D000477:Alkylating Agents / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D003497:Cyclic N-Oxides / Q000737:chemistry*; D004249:DNA Damage / Q000187:drug effects*; D008401:Gas Chromatography-Mass Spectrometry; D000860:Hypoxia / Q000139:chemically induced; D008466:Mechlorethamine / Q000737:chemistry*; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000737:chemistry* / Q000494:pharmacology*; D000077704:Tirapazamine; D014227:Triazines / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000477:Alkylating Agents; D000970:Antineoplastic Agents; D003497:Cyclic N-Oxides; D011355:Prodrugs; D014227:Triazines; D000077704:Tirapazamine; C067327:3-amino-1,2,4-benzotriazine; D008466:Mechlorethamine