Spin Trapping of Radicals Other Than the •OH Radical upon Reduction of the Anticancer Agent Tirapazamine by Cytochrome P450 Reductase
Spin Trapping of Radicals Other Than the •OH Radical upon Reduction of the Anticancer Agent Tirapazamine by Cytochrome P450 Reductase
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DOI：
10.1021/ja906860a
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发表时间：
2009-10-14
影响因子：
15
通讯作者：
Anderson, Robert F.
中科院分区：
文献类型：
--
作者：
Shinde, Sujata S.;Hay, Michael P.;Anderson, Robert F.
用电子顺磁共振（EPR）谱研究了替拉扎明（3-氨基-1，2，4-苯并三嗪-1，4-二氧化物，TPZ）被富含细胞色素P-450还原酶的微粒体单电子还原后产生的自由基种类。用5，5 '-二甲基吡咯啉1-N-氧化物（DMPO）进行自旋捕获，得到了碳中心自由基和众所周知的DMPO-OH加合物的复合光谱。使用O-17-tabeted水导致EPR谱改变为DMPO-（OH）-O-17的EPR谱，表明该自由基物种是在溶剂参与下形成的，而不是从单电子还原TPZ释放的（OH）-O-中心点自由基。此外，使用密切相关的自旋陷阱5-二乙氧基磷酰基-5-甲基吡咯啉N-氧化物（DEPMPO）（比DMPO更不容易氧化），仅给出碳中心自由基光谱，没有任何（OH）-O中心点自由基的参与。还原TPZ的更可溶的类似物，在氧化还原：平衡与其1-氧化物衍生物，导致自旋捕获的碳中心的自由基和氮中心的自由基由N-叔丁基-α-苯基硝酮（PBN）。这种以氮为中心的自由基光谱的多中心性质为该类生物还原药物在单电子还原后形成苯并三嗪基自由基提供了支持。
The radical species produced following one-electron reduction of tirapazamine (3-amino-1,2,4-benzotriazine 1,4-dioxide, TPZ) by cytochrome P-450 reductase-enriched microsomes have been investigated using electron paramagnetic resonance (EPR) spectroscopy. Spin trapping with 5,5'-dimethylpyrroline 1-N-oxide (DMPO) gave a composite spectrum of a carbon-centered radical and the well-known DMPO-OH adduct. Using O-17-tabeted water resulted in a change in the EPR spectrum to that of DMPO-(OH)-O-17, indicating that this radical species is formed with solvent involvement and not from release of a (OH)-O-center dot radical from one-electron-reduced TPZ. Furthermore, using the closely related spin trap 5-diethoxyphosphoryl-5-methylpyrroline N-oxide (DEPMPO), which is less prone to oxidation than DMPO, gave only a carbon-centered radical spectrum without any involvement of a (OH)-O-center dot radical. Reduction of a more soluble analogue of TPZ, in redox: equilibrium with its 1-oxide derivative, led to spin trapping of both a carbon-centered radical and a nitrogen centered radical by N-tert-butyl-alpha-phenylnitrone (PBN). The multicentered nature of this nitrogen-centered radical spectrum provides support for the formation of a benzotriazinyl radical following one-electron reduction of this class of bioreductive drug.