Graduate Thesis Or Dissertation
 

Mandelalides as Potent Mitochondrial ATP Synthase Inhibitors : From Discovery of New Analogs to Function-Oriented Synthetic Studies

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  • Our quest for pharmaceutically important marine natural products led to re-isolation of known mandelalides A-D and identification of new congeners E-L from re-collected South African Lissoclinum tunicate specimens. Mandelalides A, B, and L were characterized as selective cancer cell toxins, with an unusual activity profile influenced by their glycosylation / acylation status and assay cell density. Real-time measurement of the respiratory capacity of living mammalian cells indicated that mandelalides A and B are inhibitors of mitochondrial function acting in a manner similar to the known mitochondrial ATP synthase inhibitor oligomycin A. Based on our current results we concluded that sensitivity of cancer cell lines to mandelalides A and B is more likely related to the oxidative phenotype and compromised adaptive survival response of the cell lines. After evaluation of the structure-activity profile of all natural and synthetic mandelalides, we hypothesized that the southern hemisphere of mandelalide A is more likely to be important for transport to the intracellular site of action, and perhaps binding to its molecular target, while the C₁₆-C₂₄ segment of the macrocycle may serve mainly as a spacer domain which remotely controls the conformational stability of the southern hemisphere. As part of our recent ongoing studies and to test our hypothesis we initiated the function-oriented stereoselective synthesis of simplified analogs of mandelalide A that retain the biological activity of the natural product. The highlight of our synthetic strategy is a catalytic asymmetric hetero Diels-Alder (HDA) cycloaddition to construct the tetrahydropyran moiety of the southern hemisphere.
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  • 2017-08-10 to 2019-04-13

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