CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, 4169-007, Portugal.
CNC - Center for Neuroscience and Cell Biology, UC-Biotech Building, Biocant Park -University of Coimbra, Cantanhede, 3060-197, Portugal.
Sci Rep. 2017 Jul 28;7(1):6842. doi: 10.1038/s41598-017-07272-y.
Oxidative stress and mitochondrial dysfunction have been associated with metabolic and age-related diseases. Thus, the prevention of mitochondrial oxidative damage is nowadays a recognized pharmacological strategy to delay disease progression. Epidemiological studies suggested an association between the consumption of polyphenol-rich diet and the prevention of different pathologies, including diseases with a mitochondrial etiology. The development of mitochondrial-targeted antioxidants based on dietary antioxidants may decrease mitochondrial oxidative damage. Herein, we report the design and synthesis of two new mitochondriotropic antioxidants based on hydroxybenzoic acids (AntiOxBENs). The results obtained showed that the novel antioxidants are accumulated inside rat liver mitochondria driven by the organelle transmembrane electric potential and prevented lipid peroxidation, exhibiting low toxicity. Some of the observed effects on mitochondrial bioenergetics resulted from an increase of proton leakage through the mitochondrial inner membrane. The new derivatives present a higher lipophilicity than the parent compounds (protocatechuic and gallic acids) and similar antioxidant and iron chelating properties. AntiOxBENs are valid mitochondriotropic antioxidant prototypes, which can be optimized and used in a next future as drug candidates to prevent or slow mitochondrial oxidative stress associated to several pathologies.
氧化应激和线粒体功能障碍与代谢和年龄相关的疾病有关。因此，预防线粒体氧化损伤是当今公认的延缓疾病进展的药理学策略。流行病学研究表明，富含多酚的饮食与预防包括线粒体病因在内的多种疾病之间存在关联。基于膳食抗氧化剂开发靶向线粒体的抗氧化剂可能会减少线粒体氧化损伤。在此，我们报告了两种基于羟基苯甲酸的新型线粒体靶向抗氧化剂（AntiOxBENs）的设计和合成。结果表明，新型抗氧化剂在跨膜电势的驱动下在大鼠肝线粒体中积累，并可防止脂质过氧化，其毒性较低。观察到的一些对线粒体生物能学的影响源于通过线粒体内膜的质子泄漏增加。新衍生物的亲脂性高于母体化合物（原儿茶酸和没食子酸），且具有相似的抗氧化和铁螯合特性。AntiOxBENs 是有效的靶向线粒体抗氧化剂原型，可在未来进行优化并用作预防或减缓与多种疾病相关的线粒体氧化应激的候选药物。
