Laboratoire de Chimie BioOrganique et des Systemes Moleculaires Vectoriels, Universite d'Avignon et des Pays de Vaucluse, Faculte des Sciences, 33 Rue Louis Pasteur, 84000 Avignon, France.
J Med Chem. 2010 Jul 8;53(13):4849-61. doi: 10.1021/jm100212x.
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(+) 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.
我们的研究小组已经证明，基于α-苯基-N-叔丁基硝酮的两亲性是决定其生物活性和抗氧化毒性的关键特征。在这项工作中，我们报告了一类新型的两亲酰胺硝酮的合成。使用 ABTS 竞争和 ABTS(+)还原测定法分别显示了它们的羟基自由基清除活性和自由基还原能力。循环伏安法用于研究它们的氧化还原行为，并通过计算合理地解释了 PBN 取代对硝酮原子电荷密度、电子亲和力和电离势的影响。与母体化合物 PBN 相比，两亲酰胺硝酮在暴露于氧化毒素的细胞培养物中表现出更强的保护作用。它们以纳摩尔浓度显著降低了分离的大鼠脑线粒体中的电子和质子泄漏以及过氧化氢的形成。它们还显著增强了线粒体膜电位。最后，这些药物预处理可拮抗多巴胺诱导的复合物 I 活性抑制。这些发现表明，两亲酰胺硝酮不仅仅是自由基清除抗氧化剂，它们可能直接作用于线粒体电子和质子转运，成为一类新的生物能药物。
