Synthetic Analogues of Redox-Enabled Natural Products

Fash, David Michael, Department of Chemistry, University of Virginia
Hecht, Sidney, Department of Chemistry, University of Virginia
Cafiso, David, Department of Chemistry, University of Virginia

Dysfunctional mitochondria are a major source of intracellular reactive oxygen species (ROS) and are, therefore, potentially vulnerable to oxidative stress. When ROS production exceeds the capacity for detoxification, oxidative damage to proteins, DNA, and phospholipids can occur, potentially leading to impairment of cell function and death. Accordingly, mitochondrial ROS production and oxidative damage are attractive targets for pharmacological intervention. An efficient synthesis has provided access to novel quinone analogues of the antioxidants idebenone and -tocopherol. An olefin metathesis reaction was used to introduce various straight chains which were then coupled to a Diels-Alder adduct at the quinone. In other cases, a Heck reaction was employed to synthesize certain idebenone analogues. -Tocopherol quinone derivatives were obtained through key reactions such as a Sharpless asymmetric epoxidation and a Sonogashira coupling. Certain analogues have shown to suppress the levels of reactive oxygen species in cultured cells, quench peroxidation of mitochondrial membranes, and increase ATP synthesis. By supplementing endogenous ubiquinone in the electron transport chain, these analogues have the potential to treat mitochondrial diseases such as Friedreich's ataxia.

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PHD (Doctor of Philosophy)
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