Natural Product Inhibitors of Hsp90: Potential Leads for Drug Discovery
Issue Date
2009-07-09Author
Amolins, Michael Wayne
Publisher
University of Kansas
Format
121 pages
Type
Thesis
Degree Level
M.S.
Discipline
Medicinal Chemistry
Rights
This item is protected by copyright and unless otherwise specified the copyright of this thesis/dissertation is held by the author.
Metadata
Show full item recordAbstract
This thesis represents a discussion of the advancements made in the area of Hsp90 therapeutics, and the development of a novel Hsp90 inhibitory scaffold of natural product origin. Through utilization of a recently reported firefly luciferase assay, our group was able to conduct a high-throughput screen that resulted in the identification of several Hsp90 inhibitors that contained a 1,4-naphthoquinone scaffold. From this, a library of naphthoquinones was synthesized. To further probe structure-activity relationships, a comparative molecular field analysis was performed, and a second generation of 1,4-naphthoquinones was developed. Although the results were promising, concerns arose regarding the nature of the scaffold itself. It is well documented that quinone-based scaffolds exert cytotoxicity through Michael reaction chemistry or redox activity. To circumvent this concern, the core scaffold was changed from a 1,4-naphthoquinone core to a structurally similar flavone. This was completed through utilization of molecular modeling and Western Blot analyses.
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- Medicinal Chemistry Dissertations and Theses [80]
- Theses [3901]
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