Khdour Omar M, Bandyopadhyay Indrajit, Visavadiya Nishant P, Roy Chowdhury Sandipan, Hecht Sidney M
Biodesign Center for BioEnergetics , Arizona State University , Tempe , AZ 85287 , USA . Email:
School of Molecular Sciences , Arizona State University , Tempe , AZ 85287 , USA.
Medchemcomm. 2018 Jul 26;9(9):1491-1501. doi: 10.1039/c8md00274f. eCollection 2018 Sep 1.
Friedreich's ataxia (FRDA) is a progressive neurodegenerative disease that is linked to transcriptional repression of the nuclear FXN gene encoding the essential mitochondrial protein frataxin (FXN). Compounds that increase frataxin levels may enable effective therapeutic intervention for blunting disease progression. Recently, we showed that lipophilic methylene violet (MV) and methylene blue (MB) analogues both conferred benefit to cultured FRDA cells in several regards, including ROS suppression, maintenance of mitochondrial membrane potential and increased ATP production. Some of the MB analogues were also shown to promote increased frataxin levels and mitochondrial biogenesis. Presently, we report that two of the MV analogues studied previously ( and ) also increased frataxin levels and mitochondrial biogenesis significantly. Because the substitution pattern in the two series of compounds was not the same, we also prepared new MV derivatives having the same substitution pattern as the original MB derivatives studied to enable a more direct comparison. Two of the new MV compounds, and , exhibited enhanced antioxidant capability, increased frataxin levels and mitochondrial biogenesis, and improved aconitase activity. These encouraging findings demonstrated that the MV analogues had better overall activity with less cytotoxicity.
弗里德赖希共济失调（FRDA）是一种进行性神经退行性疾病，与编码必需线粒体蛋白铁调素（FXN）的核FXN基因的转录抑制有关。增加铁调素水平的化合物可能有助于有效治疗干预以减缓疾病进展。最近，我们发现亲脂性亚甲紫（MV）和亚甲蓝（MB）类似物在多个方面对培养的FRDA细胞有益，包括抑制活性氧（ROS）、维持线粒体膜电位和增加ATP生成。一些MB类似物还显示可促进铁调素水平升高和线粒体生物发生。目前，我们报告之前研究的两种MV类似物（ 和 ）也显著提高了铁调素水平和线粒体生物发生。由于这两类化合物的取代模式不同，我们还制备了具有与之前研究的原始MB衍生物相同取代模式的新MV衍生物，以便进行更直接的比较。两种新的MV化合物， 和 ，表现出增强的抗氧化能力、升高的铁调素水平和线粒体生物发生，以及改善的乌头酸酶活性。这些令人鼓舞的发现表明，MV类似物具有更好的整体活性且细胞毒性较小。
