Effect of relative configuration of TEMPO-type nitroxides on ascorbate reduction
Effect of relative configuration of TEMPO-type nitroxides on ascorbate reduction
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DOI：
10.1016/j.freeradbiomed.2022.11.033
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发表时间：
2022-12-05
影响因子：
7.4
通讯作者：
Mukai, Takahiro
中科院分区：
文献类型：
--
作者：
Azuma, Risa;Yamasaki, Toshihide;Mukai, Takahiro
2，2，6，6-四甲基哌啶-N-氧基（克里思）型氮氧自由基易被生物还原，导致自由基性质的损失。虽然已经报道了氮氧自由基的N-O部分周围的空间和电子环境影响还原，但氮氧自由基衍生物的相对构型如何改变尚不清楚。在这项研究中，我们研究了非对映异构体对C2-和C4-二取代TEMPO型氮氧自由基性质的影响。我们首次成功地分离了所研究的氮氧自由基的非对映异构体。此外，我们比较了在C2和C4位置上具有不同取代基的氮氧衍生物对抗坏血酸还原的反应性。发现C_2和C_4上的大取代基以及C_4上的电子效应影响异构体的还原。将C2-和C4-二取代的氮氧自由基给予小鼠进行电子自旋共振成像，以评估脑中的生物还原。与体外还原反应类似，在脑组织中观察到非对映异构体生物还原的差异。我们的研究表明，生物还原可以通过改变相对构型来控制，这可以用于设计氮氧化合物的生物应用。
2,2,6,6-Tetramethylpiperidin-N-oxyl (TEMPO)-type nitroxides are susceptible to bioreduction, leading to a loss of radical properties. Although it has been reported that the steric and electronic environments around the N-O moiety of nitroxides affect the reduction, how the relative configuration of nitroxide derivatives alters it is unclear. In this study, we investigated the effect of diastereomers on the radical properties of C2-and C4-disubstituted TEMPO-type nitroxides. We succeeded in isolating the diastereomers of the studied nitroxides for the first time. In addition, we compared the reactivities of nitroxide derivatives with different substituents at the C2 and C4 positions toward ascorbate reduction. We found that the bulky substituents at both C2 and C4 and the electronic effect of C4 affected the reduction of the isomers. C2-and C4-disubstituted nitroxides were administered to mice for electron spin resonance imaging to assess bioreduction in the brain. Similar to the reactivity to reduction in vitro, a difference in the bioreduction of diastereomers was observed in brain tissues. Our research strongly indicates that bioreduction can be controlled by changing the relative configuration, which can be used in the design of nitroxide derivatives for biological applications.