Redox-activated, hypoxia-selective DNA cleavage by quinoxaline 1,4-di-N-oxide

Quinoxaline 1,4-dioxide (4) is the historical prototype for modern heterocy clic N-oxide antitumor agents such as 3-amino-1,2,4-benzotriazine 1,4-dioxi de (tirapazamine, 1) and 3-amino-2-quinoxalinecarbonitrile 1,4-dioxide (11) . Early experiments in bacterial cell lines suggested that enzymatic, singl e-electron reduction of quinoxaline 1,4-dioxides under low-oxygen (hypoxic) conditions leads to DNA damage. Here the ability of quinoxaline 1,4-dioxid e to cleave DNA has been explicitly characterized using in vitro assays. Th e hypoxia-selective DNA-cleaving properties of 4 reported here may provide a chemical basis for understanding the cytotoxic and mutagenic activities o f various quinoxaline 1,4-dioxide antibiotics. (C) 2001 Elsevier Science Lt d. All rights reserved.