Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 56, Issue 3, Pages 1007-1022Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm301485d
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Funding
- NIH/NHLBI [T32-HL007260-36]
- National Center for Research Resources [5P20RR024485-02]
- National Institute of General Medical Sciences,National Institutes of Health [8P20GM103542-02]
- South Carolina Clinical and Translational Research Institute [UL1RR029882]
- American Cancer Society
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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 neuro-degenerative 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.
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