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- All Subjects: Natural Products
- All Subjects: Quinone
- Creators: Skibo, Edward
Description
It has been well established that mitochondria play a critical role in the pathology of Friedreich's Ataxia. This disease is believed to be caused by a deficiency of frataxin, which research suggests is responsible for iron sulfur cluster assembly. This incomplete assembly of iron sulfur clusters is believed to be linked with dysfunctional complexes in the mitochondrial respiratory chain, increased oxidative stress, and potential cell death. Increased understanding of the pathophysiology of this disease has enabled the development of various therapeutic strategies aimed at restoring mitochondrial respiration. This thesis contains an analysis of the biological activity of several classes of antioxidants against oxidative stress induced by diethyl maleate in Friedreich's Ataxia lymphocytes and CEM leukemia cells. Analogues of vitamin E α-tocopherol have been shown to protect cells under oxidative stress. However, these same analogues show various levels of inhibition towards the electron transport chain complex I. Bicyclic pyridinols containing a ten carbon substituent provided favorable cytoprotection. N-hydroxy-4-pyridone compounds were observed to provide little protection. Similarly, analogues of CoQ10 in the form of pyridinol and pyrimidinol compounds also preserved cell viability at low concentrations.
ContributorsJaruvangsanti, Jennifer (Author) / Hecht, Sidney (Thesis advisor) / Woodbury, Neal (Committee member) / Skibo, Edward (Committee member) / Arizona State University (Publisher)
Created2012
Description
Throughout time, compounds from natural sources have provided humans with medicines, and recently become the structural inspiration for semisynthetic drugs. One arena that has benefited greatly from the use of these natural products is the discovery of novel antibacterial agents. Methicillin-resistant Staphylcoccus aureus (MRSA) continues to plague the United States as well as throughout the world, at least in part because of increasing antibiotic resistance. Therefore, scientists continue to scour natural products as potential leads, either directly or indirectly, for antibiotics to treat MRSA. The structure of the indole sesquiterpene, polyalthenol, was discovered in 1976 and recent work shows a 4µg/mL minimum inhibitory concentration (MIC) against a variety of strains of MRSA. Given the unique framework of this natural product and its biological activity against MRSA, the total synthesis becomes the next logical step. Presently a racemic synthesis has successfully afforded an indole ketone with the correct relative stereochemistry of polyalthenol, however, the completion of the total synthesis of polyalthenol presents several challenges. Herein, the work towards the synthesis is described in addition to the proposed completion of the synthesis.
ContributorsReichenberg, Erynn Wright (Author) / Madar, David J (Thesis advisor) / Skibo, Edward (Committee member) / Miller, William (Committee member) / Arizona State University (Publisher)
Created2012