Brandt U, Schubert J, Geck P, von Jagow G
Universitätsklinikum Frankfurt, Zentrum der Biologischen Chemie, Frankfurt am Main, Germany.
Biochim Biophys Acta. 1992 Jul 6;1101(1):41-7. doi: 10.1016/0167-4838(92)90464-o.
The physico-chemical properties and uncoupling activity of eight derivatives of N-phenyl-2-pyridinamines related to the fungicide fluazinam were analyzed using rat liver mitochondria. The uncoupling activity of these compounds relies on the deprotonable secondary amino group. One of the derivatives tested (B-3) was slightly more efficient than fluazinam. By phase-distribution analysis we could show that the N-phenyl-2-pyridinamines are chemicals with moderate hydrophobicity. Deprotonation of the compound reduces the water/octanol partition coefficient by about one order of magnitude. The pKA value of the deprotonable group is affected equally by electron withdrawing substituents of the phenyl- and the pyridinyl-ring, and could be predicted simply from the sum of the Hammett coefficients. The uncoupling efficiency was not dependent on the hydrophobicity of the compound, but appeared to be governed by the pKA of the deprotonable group. This structure/uncoupling characteristic is different from that of the generally more hydrophobic uncouplers of the salicylanilide-type. The pKA resulting in the most efficient uncoupling was found to lie in the range of the pH of the reaction medium. A model based on a solution complexation mechanism, which describes this behaviour, is presented. We conclude that the N-phenyl-2-pyridinamines uncoupled the mitochondria by a simple protonophoric cycle involving protonation/deprotonation in the bulk phase, and that the kinetics of uncoupling were primarily governed by the total concentration of the limiting uncoupler species.
使用大鼠肝脏线粒体分析了与杀真菌剂氟啶胺相关的8种N-苯基-2-吡啶胺衍生物的物理化学性质和解偶联活性。这些化合物的解偶联活性依赖于可去质子化的仲氨基。所测试的一种衍生物（B-3）比氟啶胺略有效。通过相分布分析，我们可以表明N-苯基-2-吡啶胺是具有中等疏水性的化学物质。化合物的去质子化使水/辛醇分配系数降低约一个数量级。可去质子化基团的pKA值同样受到苯基和吡啶基环的吸电子取代基的影响，并且可以简单地从哈米特系数的总和预测。解偶联效率不依赖于化合物的疏水性，而是似乎由可去质子化基团的pKA决定。这种结构/解偶联特性不同于通常疏水性更强的水杨酰苯胺型解偶联剂。发现导致最有效解偶联的pKA位于反应介质pH值范围内。提出了一种基于溶液络合机制描述这种行为的模型。我们得出结论，N-苯基-2-吡啶胺通过涉及本体相中质子化/去质子化的简单质子载体循环使线粒体解偶联，并且解偶联动力学主要由限制性解偶联剂物种的总浓度控制。
