Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
J Med Chem. 2013 Feb 14;56(3):1007-22. doi: 10.1021/jm301485d. Epub 2013 Jan 30.
Historically known for its role in blood coagulation and bone formation, vitamin K (VK) has begun to emerge as an important nutrient for brain function. While VK involvement in the brain has not been fully explored, it is well-known that oxidative stress plays a critical role in neurodegenerative diseases. It was recently reported that VK protects neurons and oligodendrocytes from oxidative injury and rescues Drosophila from mitochondrial defects associated with Parkinson's disease. In this study, we take a chemical approach to define the optimal and minimum pharmacophore responsible for the neuroprotective effects of VK. In doing so, we have developed a series of potent VK analogues with favorable drug characteristics that provide full protection at nanomolar concentrations in a well-defined model of neuronal oxidative stress. Additionally, we have characterized key cellular responses and biomarkers consistent with the compounds' ability to rescue cells from oxidative stress induced cell death.
在历史上，维生素 K（VK）以其在血液凝固和骨骼形成中的作用而闻名，现已开始成为大脑功能的重要营养物质。尽管 VK 在大脑中的作用尚未得到充分探索，但众所周知，氧化应激在神经退行性疾病中起着关键作用。最近有报道称，VK 可保护神经元和少突胶质细胞免受氧化损伤，并可使果蝇免受与帕金森病相关的线粒体缺陷的影响。在这项研究中，我们采用化学方法来确定 VK 的神经保护作用的最佳和最小药效团。为此，我们开发了一系列具有有利药物特性的强效 VK 类似物，它们在神经元氧化应激的明确定义模型中以纳摩尔浓度提供完全保护。此外，我们还对关键的细胞反应和生物标志物进行了表征，这些反应和标志物与化合物能够从氧化应激诱导的细胞死亡中拯救细胞的能力一致。
