Ortial Stéphanie, Durand Grégory, Poeggeler Burkhard, Polidori Ange, Pappolla Miguel A, Böker Jutta, Hardeland Rüdiger, Pucci Bernard
Laboratoire de Chimie BioOrganique et des Systèmes Moléculaires Vectoriels, Faculté des Sciences, Université d'Avignon et des Pays de Vaucluse, 84000 Avignon, France.
J Med Chem. 2006 May 4;49(9):2812-20. doi: 10.1021/jm060027e.
The use of classical antioxidants is limited by their low bioavailabilities, and therefore, high doses are usually required to display significant protective activity. In a recent article (J. Med. Chem. 2003, 46, 5230) we showed that the ability of the alpha-phenyl-N-tert-butylnitrone (PBN) to restore the viability of ATPase-deficient human skin fibroblasts was greatly enhanced by grafting it on a fluorinated amphiphilic carrier. With the aim of extending this concept to other antioxidants, we present here the design, the synthesis, and the physicochemical measurements of a new series of fluorinated amphiphilic antioxidant derivatives. The hydroxyl radical scavenging activity and the radical reducing potency of these newly designed compounds were respectively demonstrated in an ABTS competition and an ABTS(*+) reduction assay. We also showed that the protective effects of amphiphilic antioxidants derived from PBN, Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) or lipoic acid (5-[1,2]-dithiolan-3-ylpentanoic acid) in primary cortical mixed cell cultures exposed to oxidotoxins are greatly improved compared to their parent compounds in the following rank-order: (1) PBN, (2) Trolox, and (3) lipoic acid. In contrast, the protective activity of indole-3-propionic acid was slightly decreased by grafting it on the amphiphilic carrier. Similar observations were made in in vivo experiments using aquatic invertebrate microorganisms, called rotifers, which were exposed to lethal concentrations of nonselective (H(2)O(2)) and mitochondria-selective (doxorubicin) oxidotoxins. The conclusion of these studies is that fluorinated amphiphilic PBN, Trolox, and lipoic acid derivatives exhibit very potent protective activities in in vitro and in vivo experiments. The findings demonstrated herein therefore strongly suggest that the amphiphilic character enhances the bioavailability of the antioxidants and allows for a selective targeting of mitochondria.
传统抗氧化剂的应用因其低生物利用度而受到限制，因此通常需要高剂量才能展现出显著的保护活性。在最近一篇文章（《药物化学杂志》，2003年，第46卷，第5230页）中，我们表明，通过将α-苯基-N-叔丁基硝酮（PBN）接枝到氟化两亲性载体上，其恢复ATP酶缺陷型人类皮肤成纤维细胞活力的能力得到了极大增强。为了将这一概念扩展到其他抗氧化剂，我们在此展示了一系列新型氟化两亲性抗氧化剂衍生物的设计、合成及物理化学测量。在ABTS竞争实验和ABTS(+)还原实验中分别证明了这些新设计化合物的羟自由基清除活性和自由基还原能力。我们还表明，与它们的母体化合物相比，源自PBN、Trolox（6-羟基-2,5,7,8-四甲基苯并二氢吡喃-2-羧酸）或硫辛酸（5-[1,2]-二硫杂环戊烷-3-基戊酸）的两亲性抗氧化剂在暴露于氧化毒素的原代皮质混合细胞培养物中的保护作用在以下排序中得到了极大改善：（1）PBN，（2）Trolox，（3）硫辛酸。相比之下，吲哚-3-丙酸接枝到两亲性载体上后其保护活性略有下降。在使用水生无脊椎微生物（称为轮虫）的体内实验中也得到了类似的观察结果，这些轮虫暴露于致死浓度的非选择性（H₂O₂）和线粒体选择性（阿霉素）氧化毒素中。这些研究的结论是，氟化两亲性PBN、Trolox和硫辛酸衍生物在体外和体内实验中表现出非常强的保护活性。因此本文所展示的研究结果强烈表明，两亲性特征增强了抗氧化剂的生物利用度，并允许对线粒体进行选择性靶向。
