Lloyd R V, Duling D R, Rumyantseva G V, Mason R P, Bridson P K
Laboratory of Molecular Biophysics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Mol Pharmacol. 1991 Sep;40(3):440-5.
The drug SR 4233 (3-amino-1,2,4-benzotriazine 1,4-dioxide) is under pharmacological study as the lead compound in a new series of hypoxia-activated drugs, the benzotriazine N-oxides. However, the stable two- and four-electron-reduced metabolites of SR 4233, formed by the successive loss of the two oxygen atoms, are not pharmacologically active. In order to evaluate the possibility of an initial one-electron intermediate as the active species, we have used microsomal reduction and EPR spectroscopy to identify the first free radical reduction product. The unpaired electron is primarily centered on the 1-nitrogen, and the radical is best described as a nitroxide. Results with spin-trapping experiments show that reduction of SR 4233 to a free radical is followed by its air oxidation, resulting in the formation of the superoxide radical. Experiments with specific inhibitors suggest that the drug is being reduced by microsomal NADPH-cytochrome P-450 reductase.
药物SR 4233（3-氨基-1,2,4-苯并三嗪1,4-二氧化物）作为一系列新型缺氧激活药物——苯并三嗪N-氧化物中的先导化合物，正在进行药理研究。然而，SR 4233通过连续失去两个氧原子形成的稳定的双电子和四电子还原代谢产物没有药理活性。为了评估初始单电子中间体作为活性物种的可能性，我们使用微粒体还原和电子顺磁共振光谱来鉴定第一个自由基还原产物。未成对电子主要集中在1-氮上，该自由基最好描述为一个氮氧自由基。自旋捕获实验结果表明，SR 4233还原为自由基后会被空气氧化，导致超氧自由基的形成。使用特定抑制剂的实验表明，该药物正被微粒体NADPH-细胞色素P-450还原酶还原。
