DEVELOPMENT OF COBALT AND RHENIUM ANTICANCER AGENTS TARGETING THE TUMOR MICROENVIRONMENT

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Abstract

This work details the development of metal-based anticancer agents specifically tailored to target aspects of the tumor microenvironment. Cancerous tumors receive decreased blood and nutrient supplies relative to healthy tissues, which leads to low O2 content, decreased pH, and increased levels of protein misfolding and DNA damage. Therapeutics may be designed to target these aspects of the tumor microenvironment, leading to increased selectivity for cancer cells over healthy cells. In particular, this work describes efforts to target two aspects of the tumor microenvironment: decreased O2 content and higher levels of endoplasmic reticulum (ER) stress. The first chapter outlines recent advances in complexes that exploit the increased rates of protein misfolding in tumors by disrupting ER function. This chapter includes a description of the relevant pathways involved in ER stress, a summary of metal complexes that kill cancer cells via ER stress, and a wholistic analysis of trends and similarities in metal complexes that share this mechanistic feature. Chapters 2 and 3 describe the development of Co(III) complexes of biologically active ligands that may be selectively reduced to yield cytotoxic species. Chapter 2 focuses on the development of Co(III)-bis(thiosemicarbazone) complexes with powerful anticancer activity. Chapter 3 details the synthesis of Co(III) complexes bearing Schiff base ligands, and it includes a thorough study of the ligand exchange pathways and redox reactions that lead to activation of these compounds. Chapter 4 describes the development and mechanistic investigation of the first rhenium complex that kills cancer cells via ER stress. Chapter 5 details the expansion of the original lead complex from Chapter 4 into a library of derivatives with variable activity and the investigation of the lead compound’s activity in vivo. Finally, Chapter 6 describes ongoing efforts to develop conjugated rhenium complexes for molecular targeting and pull-down experiments. Together, these results provide a description of metal complexes that target the tumor microenvironment and outline a template for the development of anticancer metal complexes from synthesis to physical characterization to mechanistic studies of their anticancer activity.

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433 pages
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2020-05
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Keywords
Anticancer; Cobalt; Endoplasmic; Hypoxia; Microenvironment; Rhenium
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Wilson, Justin J.
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Wolczanski, Peter T.
Lancaster, Kyle M.
Degree Discipline
Chemistry and Chemical Biology
Degree Name
Ph. D., Chemistry and Chemical Biology
Degree Level
Doctor of Philosophy
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Government Document
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Attribution-NoDerivatives 4.0 International
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dissertation or thesis
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