Potentiation of the cytotoxicity of the anticancer agent tirapazamine by benzotriazine N-oxides:: The role of redox equilibria
Potentiation of the cytotoxicity of the anticancer agent tirapazamine by benzotriazine N-oxides:: The role of redox equilibria
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DOI：
10.1021/ja0559101
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发表时间：
2006-01-11
影响因子：
15
通讯作者：
Denny, WA
中科院分区：
文献类型：
--
作者：
Anderson, RF;Shinde, SS;Denny, WA
替拉帕明(3-氨基-1，2，4-苯并三嗪-1，4-二氧化物)是一种对肿瘤缺氧细胞具有选择性毒性的铅生物还原药物，被认为是通过还原酶生成具有高单电子还原电位的活性氧化自由基E(L)来发挥作用的。它具有双重作用机制，既产生DNA自由基，在其单电子还原后，随后氧化这些DNA自由基，通过转移0原子形成不稳定的阳离子或可水解的内酯，导致DNA链断裂。这些平行的二次反应也被认为是由其两电子还原的代谢物1-氧化物引发的。我们用脉冲辐解方法证明了3-(N，N-二甲基-1，2-乙二胺)类似物3-(N，N-二甲基-1，2-乙二胺)的苯并三氮基能够氧化替拉帕明本身。我们发现替拉帕胺和1-氧化物都与它们各自的苯并三氮基保持平衡，较高浓度的更易溶的1-氧化物保持了较高浓度的更具活性的氧化自由基替帕扎明。测定了1-氧化物及其相关化合物的单电子还原电位E(1)，并与替拉扎明和2-硝基咪唑辐射增敏剂咪唑咪唑的E(1)值一起预测了已发表的电子转移百分数。这项自由基化学研究揭示了DNA中报道的自由基损伤增强的机制，这是电子亲和化合物低氧细胞毒性的基础。苯并三嗪类化合物的苯并三氮基的E(1)值决定了氧化还原平衡的位置，而氧化还原平衡决定了初始自由基损伤量。1，4-氧化物和1-氧化物化合物的E(1)值控制着初始自由基损伤一旦形成时的增强程度。
Tirapazamine (3-amino-1,2,4-benzotriazine 1,4-dioxide), the lead bioreductive drug with selective toxicity for hypoxic cells in tumors, is thought to act by forming an active oxidizing radical of high one-electron reduction potential, E(l), when reduced by reductases. It has a dual mechanism of action, both generating DNA radicals, following its one-electron reduction and subsequently oxidizing these DNA radicals to form labile cations or hydrolyzable lactones through transferring an 0 atom, resulting in DNA strand breaks. These parallel secondary reactions have been proposed to be also initiated by its two-electron reduced metabolite, the 1-oxide. We have used pulse radiolysis to show that the benzotriazinyl radical of a highly soluble analogue of tirapazamine, the 3-(N,N-dimethyl-1,2-ethanediamine) analogue, is able to oxidize tirapazamine itself. We have found that both tirapazamine and the 1-oxides are in equilibrium with their respective benzotriazinyl radicals, with high concentrations of the more soluble 1-oxide maintaining a high concentration of the more reactive oxidizing radical of tirapazamine. The one-electron reduction potentials, E(1), of the 1-oxides and related compounds have been measured and, together with the E(1) values of tirapazamine and the 2-nitroimidazole radiosensitizer, misonidazole, are shown to predict the published percentages of electron transfer. This radical chemistry study gives an insight into the mechanisms of the potentiation of radical damage, reported for DNA, that underlies the hypoxic cytotoxicity of electron affinic compounds. The E(1) values of the benzotriazinyl radicals of the benzotriazine compounds govern the position of the redox equilibria, which determine the amount of initial radical damage. The E(1) values of the 1,4-dioxides and 1-oxide compounds govern the degree of potentiation of the initial radical damage once formed.