Chowdhury Goutam, Kotandeniya Delshanee, Daniels J Scott, Barnes Charles L, Gates Kent S
Department of Chemistry, University of Missouri-Columbia, Columbia, Missouri 65211, USA.
Chem Res Toxicol. 2004 Nov;17(11):1399-405. doi: 10.1021/tx049836w.
The compound 3-amino-2-quinoxalinecarbonitrile 1,4-dioxide (4) displays potent hypoxia-selective cytotoxicity in cell culture. This compound is structurally similar to the known hypoxia-selective DNA-damaging agent tirapazamine (1, TPZ), but the ability of 4 to cause DNA damage under low-oxygen conditions has not previously been characterized. The results presented here provide the first evidence that 4 causes reductively activated DNA damage under hypoxic conditions. The findings indicate that one-electron reduction of 4 by NADPH:cytochrome P450 reductase yields an oxygen-sensitive intermediate (5). This activated intermediate is rapidly destroyed by reaction with O2 under aerobic conditions, but goes forward to cause DNA damage under low-oxygen conditions. Analysis of the DNA damage indicates that reductive activation of 4 leads to production of a highly reactive, freely diffusible oxidizing radical that causes sequence-independent cleavage of the deoxyribose backbone and oxidative damage to the heterocyclic bases in duplex DNA. On the basis of the experiments reported here, the chemical nature of the DNA damage caused by redox-activated 4 is analogous to that reported previously for TPZ.
化合物3-氨基-2-喹喔啉甲腈1,4-二氧化物（4）在细胞培养中表现出强大的低氧选择性细胞毒性。该化合物在结构上与已知的低氧选择性DNA损伤剂替拉扎明（1，TPZ）相似，但此前尚未对4在低氧条件下引起DNA损伤的能力进行表征。此处呈现的结果首次证明4在低氧条件下会导致还原激活的DNA损伤。研究结果表明，NADPH：细胞色素P450还原酶对4的单电子还原产生一种对氧敏感的中间体（5）。这种活化中间体在有氧条件下会与O2反应迅速被破坏，但在低氧条件下会继续导致DNA损伤。对DNA损伤的分析表明，4的还原激活会导致产生一种高活性、可自由扩散的氧化自由基，该自由基会导致脱氧核糖主链的非序列依赖性切割以及双链DNA中杂环碱基的氧化损伤。基于此处报道的实验，氧化还原激活的4所导致的DNA损伤的化学性质与先前报道的替拉扎明类似。
