Photophysical and Biological Investigations of Rhenium-Based Anticancer Agents

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Abstract
Despite significant advances over the last fifty years, cancer remains one of the leading causes of death worldwide. Among the most effective and well-studied class of chemotherapeutic agents are the FDA- approved platinum-based drugs cisplatin, carboplatin, and oxaliplatin. Given the clinical success of the platinum-based compounds, extensive research efforts have been directed towards investigating the anticancer activity of complexes of alternative metal ions, with the hopes that these inorganic complexes can overcome some of the challenges with current chemotherapy regimens. In Chapter 1 we summarize recent investigations of anticancer agents comprising the elements, rhenium, osmium, and iridium. We then explore a subset of rhenium(I) tricarbonyl complexes bearing varying axial ligands for their anticancer cancer and photoluminescent imaging properties (Chapter 2). After which, we focus our attention on mainly rhenium(I) tricarbonyl complexes that utilize light as a mechanism for cancer cell targeting (Chapter 3). A novel tricarbonyl rhenium isonitrile polypyridyl (TRIP) complex was investigated and found to have potent anticancer activity in a variety of cancer cell lines and exhibit a distinct mechanism of cell death from that of platinum-based drugs, specifically endoplasmic reticulum stress due to accumulation of misfolded proteins (Chapter 4). Due to the interesting mechanism of cell death of the TRIP complex, we explored the in vivo activity of TRIP other derivatives of TRIP and determined that they have the same biological phenotype as the parent complex, as well high anticancer activity that is dictated by the donor strength of the equatorial polypyridyl ligand (Chapter 5). A TRIP-resistant ovarian cancer cell was developed and its resistance phenotype was thoroughly investigated and its resistance was found to be a consequence of overexpression of the efflux transporter P-glycoprotein and the metal detoxifying protein metallothionine (Chapter 6). Lastly, novel rhenium(I) tricarbonyl complexes bearing organelle- targeting ligands were explored for their ability to produce toxic singlet oxygen as photodynamic therapeutic agents (Chapter 7). In the final chapter, we switch focuses and we highlight outreach activities for middle and high school students that helps teach students about radioactivity (Chapter 8). In appendix A, we show the biological activity of platinum complexes bearing azobenzene ligands.
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652 pages
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2020-05
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Wilson, Justin
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Lin, Hening
Lancaster, Kyle
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Chemistry and Chemical Biology
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Ph. D., Chemistry and Chemical Biology
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Doctor of Philosophy
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dissertation or thesis
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