RESUMO
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.
Assuntos
Ciências da Nutrição , Quinonas/química , Vitamina E/química , Animais , Células CHO , Cricetinae , Cães , Relação Dose-Resposta a Droga , Desenho de Fármacos , Fibroblastos/metabolismo , Ataxia de Friedreich/metabolismo , Humanos , Hidrolases/química , Camundongos , Testes para Micronúcleos , Modelos Químicos , NAD(P)H Desidrogenase (Quinona)/metabolismo , Oxirredução , Estresse Oxidativo , Ratos , Vitamina E/análogos & derivados , Vitamina E/metabolismo , Vitamina E/farmacologia , alfa-Tocoferol/metabolismoRESUMO
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.
Assuntos
Envelhecimento/efeitos dos fármacos , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Benzoquinonas/química , Benzoquinonas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Envelhecimento/fisiologia , Animais , Antioxidantes/química , Células Cultivadas , Cães , Relação Dose-Resposta a Droga , Humanos , Camundongos , Estrutura Molecular , Ratos , Tocotrienóis , Vitamina E/análogos & derivados , Vitamina E/química , Vitamina E/farmacologiaRESUMO
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%.
