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dc.contributor.authorKing, Arthur Paden
dc.date.accessioned2020-08-10T20:23:52Z
dc.date.available2020-08-10T20:23:52Z
dc.date.issued2020-05
dc.identifier.otherKing_cornellgrad_0058F_11984
dc.identifier.otherhttp://dissertations.umi.com/cornellgrad:11984
dc.identifier.urihttps://hdl.handle.net/1813/70382
dc.description433 pages
dc.description.abstractThis 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.
dc.language.isoen
dc.rightsAttribution-NoDerivatives 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nd/4.0/
dc.subjectAnticancer
dc.subjectCobalt
dc.subjectEndoplasmic
dc.subjectHypoxia
dc.subjectMicroenvironment
dc.subjectRhenium
dc.titleDEVELOPMENT OF COBALT AND RHENIUM ANTICANCER AGENTS TARGETING THE TUMOR MICROENVIRONMENT
dc.typedissertation or thesis
thesis.degree.disciplineChemistry and Chemical Biology
thesis.degree.grantorCornell University
thesis.degree.levelDoctor of Philosophy
thesis.degree.namePh. D., Chemistry and Chemical Biology
dc.contributor.chairWilson, Justin J.
dc.contributor.committeeMemberWolczanski, Peter T.
dc.contributor.committeeMemberLancaster, Kyle M.
dcterms.licensehttps://hdl.handle.net/1813/59810
dc.identifier.doihttps://doi.org/10.7298/haxj-sd14


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