Natural Product Inhibitors of Hsp90: Potential Leads for Drug Discovery

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

Synthesis and Preliminary Evaluation Steroidal AntiestrogenGeldanamycin Conjugates

Three novel steroidal antiestrogen-geldanamycin conjugates were prepared using a convergent strategy. The antiestrogenic component utilized the 11β-(4-functionalized-oxyphenyl) estradiol scaffold, while the geldanamycin component was derived by replacement of the 17-methoxy group with an appropriately functionalized amine. Ligation was achieved in high yield using azide alkyne cyclization reactions. Evaluation of the products against two breast cancer cell lines indicated that the conjugates retained significant antiproliferative activity