ABSTRACT
We report on the synthesis, biological and pharmacological activity of the tocoquinone natural product, α-tocopherol quinone (ATQ); an oxidative metabolite of α-tocopherol. ATQ is a potent cellular protectant against oxidative stress, whose biological activity is dependent upon its ability to undergo reversible two-electron redox cycling. ATQ is orally bioavailable, with a favorable pharmacokinetic profile and has demonstrated a beneficial clinical response in patients with Friedreich's ataxia. ATQ is a member of a broader class of vitamin E derived quinone metabolites which may be ascribable in whole or in part to the activity of vitamin E.
Subject(s)
Nutritional Sciences , Quinones/chemistry , Vitamin E/chemistry , Animals , CHO Cells , Cricetinae , Dogs , Dose-Response Relationship, Drug , Drug Design , Fibroblasts/metabolism , Friedreich Ataxia/metabolism , Humans , Hydrolases/chemistry , Mice , Micronucleus Tests , Models, Chemical , NAD(P)H Dehydrogenase (Quinone)/metabolism , Oxidation-Reduction , Oxidative Stress , Rats , Vitamin E/analogs & derivatives , Vitamin E/metabolism , Vitamin E/pharmacology , alpha-Tocopherol/metabolismABSTRACT
We report that α-tocotrienol quinone (ATQ3) is a metabolite of α-tocotrienol, and that ATQ3 is a potent cellular protectant against oxidative stress and aging. ATQ3 is orally bioavailable, crosses the blood-brain barrier, and has demonstrated clinical response in inherited mitochondrial disease in open label studies. ATQ3 activity is dependent upon reversible 2e-redox-cycling. ATQ3 may represent a broader class of unappreciated dietary-derived phytomolecular redox motifs that digitally encode biochemical data using redox state as a means to sense and transfer information essential for cellular function.
Subject(s)
Aging/drug effects , Antioxidants/metabolism , Antioxidants/pharmacology , Benzoquinones/chemistry , Benzoquinones/pharmacology , Oxidative Stress/drug effects , Aging/physiology , Animals , Antioxidants/chemistry , Cells, Cultured , Dogs , Dose-Response Relationship, Drug , Humans , Mice , Molecular Structure , Rats , Tocotrienols , Vitamin E/analogs & derivatives , Vitamin E/chemistry , Vitamin E/pharmacologyABSTRACT
The most efficient synthesis reported to date of ubiquinone (CoQ10) is described. A sequence consisting of six operations is involved which leads to crystalline material in an overall yield of >64%.
