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Type of Document Dissertation Author Fleming, Kristen Nicole Author's Email Address knf1424@aol.com URN etd-04132004-132533 Title Total Synthesis of the Cytotoxic Natural Products Myriaporones 1, 3, and 4 and Related Analogues Degree Doctor of Philosophy Department Chemistry and Biochemistry Advisory Committee
Advisor Name Title Richard E. Taylor Committee Chair Bradley D. Smith Committee Member Marvin J. Miller Committee Member Paul Helquist Committee Member Keywords
- tedanolide
- diastereoselective
- epoxidation
- Evans aldol
Date of Defense 2004-04-06 Availability unrestricted Abstract This dissertation details the synthetic efforts that ultimately culminated in the first successful total synthesis of the cytotoxic marine natural products myriaporones 1, 3, and 4. Our interest in these molecules stemmed from their demonstrated antitumor activity, as well as their structural similarity to a highly potent class of natural products, the tedanolides. Although a number of groups have embarked on the total synthesis of tedanolide over the years, its complex architecture has prevented its completion and only one group has successfully completed 13-deoxytedanolide. Therefore, our ultimate goal is to determine whether the myriaporones and tedanolides share an identical biological receptor and have similar modes of action and, if so, then the myriaporones would represent structurally simplified tedanolide analogues.
At the time of isolation, the stereochemistry of two centers in the myriaporones (C5 and C6) was not assigned unambiguously. Through completion of the total syntheses and NMR comparisons with the natural products, the absolute stereochemistry of this class of natural products has now been determined. In addition to completing the myriaporones, their corresponding C5 epimers were formed as well and all have undergone extensive biological evaluation. Since bioavailability of these natural products is limited, their activities at the time of isolation were reported against only a single cancer cell line. The highly efficient synthetic approach discussed in this dissertation has allowed for production of a significant quantity of each target molecule and corresponding activities against a number of different cancer cell lines are presented here. These exciting results have only strengthened interest in the myriaporones as potential drug leads.
With the total synthesis of the myriaporones complete, focus has switched to generating analogues aimed at uncovering structure- and conformation-activity relationships for these molecules. By forming analogues that are biased toward specific conformations, we hope to maximize activity and learn more about the relationship between the myriaporones and tedanolides. Current synthetic efforts toward a number of analogues will demonstrate how very slight modifications to our established route will lead to the formation of a diverse array of new potential chemotherapeutic agents.
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