Amphiphilic Amide Nitrones: A New Class of Protective Agents Acting as Modifiers of Mitochondrial Metabolism
Amphiphilic Amide Nitrones: A New Class of Protective Agents Acting as Modifiers of Mitochondrial Metabolism
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DOI：
10.1021/jm100212x
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发表时间：
2010-07-08
影响因子：
7.3
通讯作者：
Pucci, Bernard
中科院分区：
文献类型：
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作者：
Durand, Gregory;Poeggeler, Burkhard;Pucci, Bernard
我们的小组已经证明，α-苯基-N-叔丁基硝酮基试剂的两亲性是决定其生物活性和抗氧化毒性的关键特征。本文报道了一类新的两亲性酰胺硝酮的合成。用ABTS竞争法和ABTS（中心点+）还原法分别测定了它们的羟自由基清除活性和自由基还原能力。循环伏安法被用来研究它们的氧化还原行为，和取代的PBN上的硝酰基原子的电荷密度，电子亲和势和电离电位的影响进行了计算合理化。两亲性酰胺硝酮在暴露于氧化毒素的细胞培养物中的保护作用大大超过了母体化合物PBN所产生的保护作用。在纳摩尔浓度下，它们降低了离体大鼠脑线粒体中的电子和质子泄漏以及过氧化氢的形成。它们还显著增强线粒体膜电位。最后，多巴胺诱导的抑制复合物I的活性拮抗预处理与这些代理商。这些研究结果表明，两亲性酰胺硝酮不仅仅是自由基清除抗氧化剂，但可能作为一类新的生物能源代理直接对线粒体电子和质子的运输。
Our group has demonstrated that the amphiphilic character of alpha-phenyl-N-tert-butyl nitrone based agents is a key feature in determining their bioactivity and protection against oxidative toxicity. In this work, we report the synthesis of a new class of amphiphilic amide nitrones. Their hydroxyl radical scavenging activity and radical reducing potency were shown using ABTS competition and ABTS(center dot+) reduction assays, respectively. Cyclic voltammetry was used to investigate their redox behavior, and the effects of the substitution of the PBN on the charge density of the nitronyl atoms, the electron affinity, and the ionization potential were computationally rationalized. The protective effects of amphiphilic amide nitrones in cell cultures exposed to oxidotoxins greatly exceeded those exerted by the parent compound PBN. They decreased electron and proton leakage as well as hydrogen peroxide formation in isolated rat brain mitochondria at nanomolar concentration. They also significantly enhanced mitochondrial membrane potential. Finally, dopamine-induced inhibition of complex I activity was antagonized by pretreatment with these agents. These findings indicate that amphiphilic amide nitrones are much more than just radical scavenging antioxidants but may act as a new class of bioenergetic agents directly on mitochondrial electron and proton transport.