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Natural Product Inhibitors of Hsp90: Potential Leads for Drug Discovery
Amolins, Michael Wayne
Amolins, Michael Wayne
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Abstract
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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Date
2009-07-09
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Publisher
University of Kansas
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Keywords
Pharmaceutical chemistry, Chemistry, Biochemistry, Organic chemistry, Cancer, Flavone, Heat shock proteins, Molecular modeling, Naphthoquinone, Neuroprotection