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

被引:139
作者
Ganley, B
Chowdhury, G
Bhansali, J
Daniels, JS
Gates, KS [1 ]
机构
[1] Univ Missouri, Dept Chem, Columbia, MO 65211 USA
[2] Univ Missouri, Dept Biochem, Columbia, MO 65211 USA
关键词
D O I
10.1016/S0968-0896(01)00163-8
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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. (C) 2001 Elsevier Science Ltd. All rights reserved.
引用
收藏
页码:2395 / 2401
页数:7
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