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Design and Development of Potential Therapeutic Agents for Use in Hormone Responsive Cancers

Jetson, Rachael Rene
http://rave.ohiolink.edu/etdc/view?acc_num=mco1384270219

Abstract Details

2013, Doctor of Philosophy in Medicinal Chemistry (Ph.D.), University of Toledo, College of Pharmacy.
This thesis describes medicinal chemistry methods aimed towards the understanding of estrogen receptors (ERs) and breast cancer. Breast cancer is the second most common cancer and the second leading cause of cancer fatalities in women in the United States. These devastating statistics are partially attributed to unreliable diagnosis, reoccurrence and drug resistance. Approximately 70% of these cancers express ERs, making them a relevant target for the development of new therapeutics and investigation into the mechanism of this disorder. A major portion of this project focuses on the design and synthesis of compound libraries directed towards ERs that will utilize natural products as their starting point. From a family of compounds called the flavonoids that contain estrogenic (glycinol) and anti-estrogenic (glyceollins) members, we devised new structures that are meant to exploit key binding interactions within the ER. Studies leading to these target compound libraries include the design and synthesis of `model’ compound libraries meant to mimic the target structure’s corresponding pharmacophores. By developing the model libraries we were able to explore synthetic methods that could be used for the synthesis of the targets. Additionally, one set of these libraries was also used to obtain initial biological data to develop structure-activity relationships that, in turn, contributed to final target selection. To further support our target design we studied our compound libraries (target and model) via ER docking paradigms derived from protein database starting points. To properly conduct these experiments we first determined an appropriate protein docking model for our natural product system. This docking model was designed in such a way as to best describe the biological profile of known agents and a group of our natural products. Using this protein docking model, we examined our compound libraries allowing for a more direct comparison between the two systems. Additional studies were directed toward the androgen receptor (AR) and prostate cancer. The rationale for these studies includes implications that androgens and ARs are involved in breast cancer. Furthermore, the glyceollin group from the flavonoid family has shown anti-androgen potential. Similar to the ER experiments, an X-ray derived protein docking model for the AR was devised to describe the biological profile of known agents and some of the glyceollins. This docking model was then used to study all the compound libraries. A final project was an investigation into the role of retinoic acid receptors (RARs) in breast cancer. Preliminary research implies that RARs may play a role in breast cancer drug resistance. In order to help address this hypothesis, we first synthesized a known agent to probe the RAR subtype involved in breast cancer, RARa. Secondly, we suggested other possible agents that may work as scaffolds for designing new, more specific probes. We devised a new synthetic route to these agents that ultimately led to higher yields, lower cost and decreased labor compared to that for the original standard. In this dissertation all of these topics are discussed in greater detail. Each chapter focuses on a different project and provides a synopsis of the methods utilized. Similarly, results from the methods and conclusions are given for each project including comments on their future directions.
Paul Erhardt (Advisor)
Amanda Bryant-Friedrich (Committee Member)
Viranga Tillekeratne (Committee Member)
Jill Trendel (Committee Member)
Frederick Williams (Committee Member)
353 p.
Biology; Chemistry; Organic Chemistry; Pharmacy Sciences
Breast cancer; Glyceollins; Estrogen Receptors; Retinoic Acid Receptors; Selective Estrogen Receptor Modulators

Recommended Citations

Citations

  • Jetson, R. R. (2013). Design and Development of Potential Therapeutic Agents for Use in Hormone Responsive Cancers [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1384270219

    APA Style (7th edition)

  • Jetson, Rachael. Design and Development of Potential Therapeutic Agents for Use in Hormone Responsive Cancers. 2013. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1384270219.

    MLA Style (8th edition)

  • Jetson, Rachael. "Design and Development of Potential Therapeutic Agents for Use in Hormone Responsive Cancers." Doctoral dissertation, University of Toledo, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=mco1384270219

    Chicago Manual of Style (17th edition)

mco1384270219
297
© 2013, some rights reserved.Creative Commons License Design and Development of Potential Therapeutic Agents for Use in Hormone Responsive Cancers by Rachael Rene Jetson is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.