Biodesign Center for BioEnergetics, and School of Molecular Sciences, Arizona State University, Tempe, AZ 85287, USA.
Biodesign Center for BioEnergetics, and School of Molecular Sciences, Arizona State University, Tempe, AZ 85287, USA.
Bioorg Med Chem. 2018 Jul 23;26(12):3359-3369. doi: 10.1016/j.bmc.2018.05.005. Epub 2018 May 4.
Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disorder resulting from reduced expression of the protein frataxin (FXN). Although its function is not fully understood, frataxin appears to help assemble iron sulfur clusters; these are critical for the function of many proteins, including those needed for mitochondrial energy production. Finding ways to increase FXN levels has been a major therapeutic strategy for this disease. Previously, we described a novel series of methylene violet analogues and their structural optimization as potential therapeutic agents for neurodegenerative and mitochondrial disorders. Presently, a series of methylene blue analogues has been synthesized and characterized for their in vitro biochemical and biological properties in cultured Friedreich's ataxia lymphocytes. Favorable methylene blue analogues were shown to increase frataxin levels and mitochondrial biogenesis, and to improve aconitase activity. The analogues were found to be good ROS scavengers, and able to protect cultured FRDA lymphocytes from oxidative stress resulting from inhibition of complex I and from glutathione depletion. The analogues also preserved mitochondrial membrane potential and augmented ATP production. Our results suggest that analogue 5, emerging from the initial structure of the parent compound methylene blue (MB), represents a promising lead structure and lacks the cytotoxicity associated with the parent compound MB.
弗里德里希共济失调（FRDA）是一种常染色体隐性神经退行性疾病，由蛋白质 frataxin（FXN）表达减少引起。尽管其功能尚未完全了解，但 frataxin 似乎有助于组装铁硫簇；这些对于许多蛋白质的功能至关重要，包括线粒体能量产生所需的蛋白质。寻找增加 FXN 水平的方法一直是治疗这种疾病的主要策略。以前，我们描述了一系列新型亚甲紫类似物及其作为神经退行性和线粒体疾病潜在治疗剂的结构优化。目前，已经合成了一系列亚甲蓝类似物，并对其在培养的 FRDA 淋巴细胞中的体外生化和生物学特性进行了表征。结果表明，有利的亚甲蓝类似物能够增加 frataxin 水平和线粒体生物发生，并改善顺乌头酸酶活性。这些类似物被发现是良好的 ROS 清除剂，能够保护培养的 FRDA 淋巴细胞免受复合物 I 抑制和谷胱甘肽耗竭引起的氧化应激。类似物还能保持线粒体膜电位并增加 ATP 产生。我们的研究结果表明，母体化合物亚甲蓝（MB）的初始结构中出现的类似物 5 代表了一种很有前途的先导结构，并且缺乏与母体化合物 MB 相关的细胞毒性。
