Analytical Biochemistry and Mass Spectrometry Core Facility, Department of Pharmacy, University of Groningen, The Netherlands.
Analyst. 2012 Oct 21;137(20):4698-702. doi: 10.1039/c2an35388a.
Electrochemistry in combination with mass spectrometry has shown promise as a versatile technique not only in the analytical assessment of oxidative drug metabolism, but also for small-scale synthesis of drug metabolites. However, electrochemistry is generally limited to reactions initiated by direct electron transfer. In the case of substituted-aromatic compounds, oxidation proceeds through a Wheland-type intermediate where resonance stabilization of the positive charge determines the regioselectivity of the anodic substitution reaction, and hence limits the extent of generating drug metabolites in comparison with in vivo oxygen insertion reactions. In this study, we show that the electrocatalytic oxidation of hydrogen peroxide on a platinum electrode generates reactive oxygen species, presumably surface-bound platinum-oxo species, which are capable of oxygen insertion reactions in analogy to oxo-ferryl radical cations in the active site of Cytochrome P450. Electrochemical oxidation of lidocaine at constant potential in the presence of hydrogen peroxide produces both 3- and 4-hydroxylidocaine, suggesting reaction via an arene oxide rather than a Wheland-type intermediate. No benzylic hydroxylation was observed, thus freely diffusing radicals do not appear to be present. The results of the present study extend the possibilities of electrochemical imitation of oxidative drug metabolism to oxygen insertion reactions.
电化学与质谱联用已显示出作为一种多功能技术的潜力，不仅在氧化药物代谢的分析评估中，而且在药物代谢物的小规模合成中也是如此。然而，电化学通常仅限于直接电子转移引发的反应。在取代芳香族化合物的情况下，氧化通过 Wheland 型中间体进行，其中正电荷的共振稳定决定了阳极取代反应的区域选择性，因此与体内氧插入反应相比，限制了生成药物代谢物的程度。在这项研究中，我们表明，在铂电极上过氧化氢的电催化氧化会产生活性氧物种，推测是表面结合的铂-氧物种，它们能够进行类似于细胞色素 P450 活性位点中氧代铁酰基阳离子的氧插入反应。在存在过氧化氢的情况下，通过恒电位电化学氧化利多卡因可同时生成 3-和 4-羟基利多卡因，这表明反应是通过芳基氧化物而不是 Wheland 型中间体进行的。未观察到苄基羟化，因此似乎不存在自由扩散的自由基。本研究的结果将电化学模拟氧化药物代谢的可能性扩展到氧插入反应。
