Structure–Activity Relationship Study of Vitamin K Derivatives Yields Highly Potent Neuroprotective Agents

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 di...

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Bibliographic Details
Published inJournal of medicinal chemistry Vol. 56; no. 3; pp. 1007 - 1022
Main Authors Josey, Benjamin J, Inks, Elizabeth S, Wen, Xuejun, Chou, C. James
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 14.02.2013
Amer Chemical Soc
Subjects
Base Sequence
Cell Line
Chemistry, Medicinal
DNA Primers
Humans
Life Sciences & Biomedicine
Magnetic Resonance Spectroscopy
Mass Spectrometry
Neuroprotective Agents - chemistry
Neuroprotective Agents - pharmacology
Oxidative Stress - drug effects
Pharmacology & Pharmacy
Real-Time Polymerase Chain Reaction
Science & Technology
Structure-Activity Relationship
Vitamin K - chemistry
Vitamin K - pharmacology
MENAQUINONE-4
NEURONAL CELL-LINE
IN-VITRO
BRAIN-INJURY
DEPENDENT PROTEINS
OXIDATIVE GLUTAMATE TOXICITY
DEATH
STRESS
NEURODEGENERATIVE DISEASES
MITOCHONDRIAL FISSION
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Summary: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.
Bibliography:NIH RePORTER
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ISSN:0022-2623
1520-4804
DOI:10.1021/jm301485d