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    Disulfide-Masked Prochelators to Target the Iron Metabolism of Cancer: Coordination Chemistry and Antiproliferative Activity in Malignant Cells

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    Name:
    azu_etd_17903_sip1_m.pdf
    Embargo:
    2023-05-12
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    2.534Mb
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    Author
    Utterback, Rachel
    Issue Date
    2020
    Advisor
    Tomat, Elisa
    
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    Publisher
    The University of Arizona.
    Rights
    Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction, presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
    Embargo
    Release after 05/12/2023
    Abstract
    Iron is the most abundant transition metal found in the human body, and it is essential for many biological processes, including oxygen transport, cellular respiration and DNA synthesis. Cancer cells have an increased demand for iron due to their higher proliferation rates, and this characteristic makes cancer cells more susceptible to iron deprivation. Thus, iron chelators have been studied for their use as chemotherapeutics for the treatment of cancer. Chapter 1 of this dissertation provides a brief summary of the roles of iron in cancer, as well as an overview of the different types of iron chelators that have been studied for the treatment of cancer. Chapter 2 focuses on a prochelation approach to improve the intracellular delivery of thiosemicarbazone, semicarbazone, and aroylhydrazone chelators for cancer applications. Specifically, these prochelators use a disulfide switch to mask a thiolate iron binding moiety so that these compounds can be activated intracellularly. These compounds show antiproliferative activity in cultured breast cancer cells and result in the intracellular formation of iron complexes that are not redox active. Further cell-based assays demonstrated that these chelators cause cell cycle arrest at the G1/S interface and induce apoptosis in cells. Chapter 3 focuses on one of our most biologically active prochelators, (AH1-S)2, and the characterization of its iron (III) complexes. The chelator AH1-SH binds iron in a 2:1 ligand-to-metal ratio, and the resulting complex features a low-spin Fe(III) center. Unlike our cationic thiosemicarbazone Fe(III) complexes, the Fe(III) complex of AH1-SH is neutral due to the ability of the aroyl hydrazone ligand to exhibit keto-enol tautomerization. The X-ray structure of this complex shows the AH1 ligand bound to the iron(III) center both in the keto form and in the enolate form. Further studies by EPR demonstrate that different protonation states of this complex exist in acidic, neutral, and basic media.
    Type
    text
    Electronic Dissertation
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Graduate College
    Chemistry
    Degree Grantor
    University of Arizona
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