Department of Bio-functional Science, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Free Radic Biol Med. 2010 Dec 1;49(11):1703-9. doi: 10.1016/j.freeradbiomed.2010.08.027. Epub 2010 Sep 7.
Nitroxyl radicals (nitroxide) have great potential advantages as spin probes, antioxidants, contrast agents, and radiation-protecting agents. However, they are readily reduced by reductants in cells and lose their paramagnetic nature. Recently, tetraethyl-substituted nitroxyl radicals have been reported to have high stability toward reduction by ascorbic acid (AsA). We report the general considerations of tetraethyl nitroxyl radicals for in vivo application. The reason for the low reactivity to AsA reduction was the positive value of Gibbs energy between the tetraethyl nitroxyl radical and AsA. Further, these compounds had an inhibitory effect on lipid peroxidation despite having AsA resistance. They had low antiproliferative effects in HepG2 cells and HUVECs and did not have a lowering effect on blood pressure in animals. Further, after intravenous injection, the ESR signal intensities of tetraethyl-substituted piperidine nitroxyl radicals were very stable in mice over 20 min. These results suggest that tetraethyl-substituted nitroxyl radicals have stability against bioreduction with reductants such as AsA and confer onto them features as antioxidants and paramagnetic tracers/contrast agents. Hence, they will be useful in identifying the foci of oxidative stress in vivo using redox-based imaging approaches.
氮氧自由基（nitroxide）作为自旋探针、抗氧化剂、对比剂和辐射保护剂具有巨大的潜在优势。然而，它们很容易被细胞中的还原剂还原，从而失去顺磁性质。最近，报道了四乙基取代的氮氧自由基对抗坏血酸（AsA）还原具有很高的稳定性。我们报告了四乙基氮氧自由基用于体内应用的一般考虑因素。对 AsA 还原反应性低的原因是四乙基氮氧自由基和 AsA 之间的吉布斯自由能为正值。此外，尽管这些化合物具有抗 AsA 性，但它们对脂质过氧化仍具有抑制作用。它们在 HepG2 细胞和 HUVECs 中具有低的增殖抑制作用，并且在动物中没有降低血压的作用。此外，静脉注射后，四乙基取代哌啶氮氧自由基的 ESR 信号强度在小鼠体内 20 分钟以上非常稳定。这些结果表明，四乙基取代的氮氧自由基具有对还原剂（如 AsA）的生物还原的稳定性，并赋予它们抗氧化剂和顺磁示踪剂/对比剂的特性。因此，它们将有助于使用基于氧化还原的成像方法在体内识别氧化应激的焦点。
