Redox-activated, hypoxia-selective DNA cleavage by quinoxaline 1,4-di-N-oxide.
Quinoxaline 1,4-dioxide (4) is the historical prototype for modern heterocyclic N-oxide antitumor agents such as 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine, 1) and 3-amino-2-quinoxalinecarbonitrile 1,4-dioxide (11). Early experiments in bacterial cell lines suggested that enzymatic, single-electron reduction of quinoxaline 1,4-dioxides under low-oxygen (hypoxic) conditions leads to DNA damage. Here the ability of quinoxaline 1,4-dioxide to cleave DNA has been explicitly characterized using in vitro assays. The hypoxia-selective DNA-cleaving properties of 4 reported here may provide a chemical basis for understanding the cytotoxic and mutagenic activities of various quinoxaline 1,4-dioxide antibiotics.
Ganley
B
B
Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211, USA.
Chowdhury
G
G
Bhansali
J
J
Daniels
J S
JS
Gates
K S
KS
D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D006868:Hydrolysis / Q000187:drug effects; D000860:Hypoxia; D010084:Oxidation-Reduction; D010957:Plasmids / Q000187:drug effects / Q000378:metabolism; D011810:Quinoxalines / Q000378:metabolism / Q000494:pharmacology*; D019820:Xanthine / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D011810:Quinoxalines; D019820:Xanthine; D004247:DNA; C003282:quindoxin; D014969:Xanthine Oxidase