RADICAL-CATION INTERMEDIATES IN N-DEALKYLATION REACTIONS
RADICAL-CATION INTERMEDIATES IN N-DEALKYLATION REACTIONS
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DOI：
10.3109/00498259509061886
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发表时间：
1995-07-01
期刊：
影响因子：
1.8
通讯作者：
MACDONALD, TL
中科院分区：
文献类型：
--
作者：
GUENGERICH, FP;OKAZAKI, O;MACDONALD, TL
1. P450催化的N-脱烷基化存在许多可能的机理，并且多年来一直在考虑，包括C-和N-羟基化和顺序电子转移（SET）。对于过氧化物酶，证据强烈支持SET，并且可以检测到自由基。任何机制都必须解释P450没有将来自（H2O）-O-18的标记掺入产物中，以及在过氧化物酶催化的N-脱烷基化反应中观察到的高动力学氘同位素效应，但P450没有。几条证据支持SET在P450胺氧化中的作用，包括Hammett分析，二氢吡啶氧化产物和基于机制的抑制产物。假设认为P450通过碱催化作用使SET产生的铵自由基去质子化，因为pK（a）估计与9相似。二氢吡啶铵自由基具有低pK（a），（
1. A number of mechanistic possibilities exist for P450-catalysed N-dealkylation and have been considered over the years, including C- and N-hydroxylation and sequential electron transfer (SET). With peroxidases the evidence strongly favours SET and free radicals can be detected. Any mechanism must account for lack of incorporation of label from (H2O)-O-18 into product by P450s and the high kinetic deuterium isotope effects that are seen in N-dealkylation reactions catalysed by peroxidases but not P450s.2. Several lines of evidence support a role for SET in P450 amine oxidations, including Hammett analysis, products of dihydropyridine oxidations, and products of mechanism-based inhibition by strained cycloalkylamines.3. The hypothesis was considered that the P450s act via base catalysis to deprotonate the aminium radical generated by SET, since the pK(a), has been estimated to be similar to 9. Dihydropyridine aminium radicals have low pK(a), (