2003
DOI: 10.1016/s1044-0305(03)00334-9
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A mass spectrometry study of tirapazamine and its metabolites: Insights into the mechanism of metabolic transformations and the characterization of reaction intermediates

Abstract: Tandem mass spectrometry methods were used to study the sites of protonation and for identification of 3-amino-1,2,4-benzotriazine 1,4-dioxide (1, tirapazamine), and its metabolites (3-amino-1,2,4-benzotriazine 1-oxide (3), 3-amino-1,2,4-benzotriazine 4-oxide (4), 3-amino-1,2,4-benzotriazine (5), and a related isomer 3-amino-1,2,4-benzotriazine 2-oxide (6). Fragmentation pathways of 3 and 5 indicated the 4-N-atom as the most likely site of protonation. Among the N-oxides studied, the 4-oxide (4) showed the hig… Show more

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Cited by 36 publications
(38 citation statements)
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“…Redox-activated DNA cleavage by 5 is substantially inhibited (60–90%) by classical radical-scavenging agents15 such as ethanol, methanol, t -butanol, DMSO, and mannitol (500 mM, Figure 4). Overall, the data indicate that one-electron reduction of 5 under anoxic conditions leads to direct DNA strand cleavage via radical mechanisms such as those characterized previously for TPZ 2224,26,29…”
Section: Resultssupporting
confidence: 71%
“…Redox-activated DNA cleavage by 5 is substantially inhibited (60–90%) by classical radical-scavenging agents15 such as ethanol, methanol, t -butanol, DMSO, and mannitol (500 mM, Figure 4). Overall, the data indicate that one-electron reduction of 5 under anoxic conditions leads to direct DNA strand cleavage via radical mechanisms such as those characterized previously for TPZ 2224,26,29…”
Section: Resultssupporting
confidence: 71%
“…Under hypoxic conditions TZP undergoes intracellular one-electron reduction to a radical anion that is converted to either a highly toxic hydroxyl radical or to an oxidizing radical by the elimination of water [94][95][96]. These radicals cause DNA-ssbs, base damage and DPCs which stall and collapse replication forks, which in turn are repaired by the HR pathway [91].…”
Section: Consequences For Tumor Resistance and Treatmentmentioning
confidence: 99%
“…There is evidence that TPZ is reduced under hypoxic conditions via a one electron enzymic reduction to a reactive intermediate (TPZ • ), which produces hydroxyl radicals (HO • ) [73][74][75] or benzotriazinyl radicals (BTZ • ) [76]. These radicals are then able to abstract a hydrogen atom from DNA and cause DNA fragmentation [24,77].…”
Section: N-oxide-based Bioreductive Agentsmentioning
confidence: 99%