Date of Degree

2009

Document Type

PhD diss.

Degree Name

PhD (Doctor of Philosophy)

Department

Pharmacology

First Advisor

Raymond J. Hohl

Abstract

Several members of the schweinfurthin family are potent and selective inhibitors of cancer cell growth in the NCI 60-cell cancer screen. The schweinfurthins display unique activity in this screen which suggests that these compounds have a previously unexploited target. This activity encourages development of the schweinfurthins as anti-cancer agents; however, the scarcity of the natural products has hindered biological evaluation. For this reason, a program was initiated to synthesize the natural products and analogues thereof. These efforts have made 5 natural product schweinfurthins and over 60 analogues available for biological evaluation.

Studies presented herein evaluate the biological activity, intracellular localization, and potential protein interactions of schweinfurthins analogues. To investigate the potent and differential effects of these compounds, a two-cell line screen was developed incorporating a sensitive cell (SF-295) and insensitive cell line (A549). The structure-function data obtained from this screen identified a schweinfurthin site amenable to modification. Based on this finding, fluorescent schweinfurthins were designed and synthesized. These compounds retain schweinfurthin-like potency and activity which is critical for their study. The intracellular localization of these schweinfurthins was investigated using fluorescence microscopy. These studies identified the lysosomes and peri-nuclear organelles as potential sites of schweinfurthin activity. Additionally, we describe the attachment of a fluorescent schweinfurthin to a solid support, which was utilized to identify protein-schweinfurthin interactions. This approach identified vimentin as a potential target of schweinfurthin activity.

Pages

xii, 155

Bibliography

139-155

Copyright

Copyright 2009 Craig Heath Kuder

Included in

Pharmacology Commons

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