J. Daniels, T. Chatterji, L. MacGillivray
Dec 1, 1998
Citations
0
Influential Citations
22
Citations
Journal
Journal of Organic Chemistry
Abstract
The compound 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine, WIN 59075, SR4233, 1), currently undergoing phase II and III clinical trials as an antitumor agent, is thought to derive its therapeutic activity by selectively damaging DNA in oxygen-poor (hypoxic) tumor cells.1,2 DNA damage by 1 is triggered by enzymatic reduction of the heterocycle.2 It is commonly suggested1,2 that the one-electron reduced form of the drug (2) reacts directly with DNA, although recent studies have provided evidence that 2 undergoes fragmentation to yield the potent DNA-damaging agent hydroxyl radical (Scheme 1).3 The selective cytotoxicity of 1 toward hypoxic cells probably is due to the fact that, in the presence of molecular oxygen, 2 is readily oxidized by molecular oxygen, thereby regenerating 1 and producing superoxide radical (O2), whose cytotoxicity is mitigated by cellular enzymes such as superoxide dismutase, glutathione peroxidase, and catalase.5 During the course of previous investigations, we observed light-dependent DNA cleavage by 1. We further investigated this phenomenon because light-dependent formation of reactive species can be a medicinally important process.6-8 In addition, we recognized that heterocyclic N-oxides are known to be rich in photochemistry9-13 but that the photochemistry of benzotriazine N-oxides was virtually unexplored.