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    Disulfide-Masked Prochelators Targeting the Iron Metabolism of Cancer: Design, Synthesis, and Biological Investigations

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    Author
    Akam, Eman Abureida
    Issue Date
    2016
    Keywords
    disulfide/thiol switch
    iron chelation
    prochelation
    reduction/activation
    cancer
    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 or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
    Embargo
    Release after 11-Jan-2019
    Abstract
    Iron is the most abundant transition metal found in living systems and plays a crucial role in DNA biosynthesis. To accommodate higher replication rates, cancer cells require higher amounts of iron compared to non-neoplastic counterparts. This higher demand for iron renders cancer cells susceptible to iron deprivation, and exposure to iron chelators leads to growth arrest and cell death. Iron chelation strategies employing a wide variety of iron-binding scaffolds are currently under investigation for use in cancer treatment. Although these chelation approaches are effective against several cancer cell types, their use is limited due to toxicity ascribed to indiscriminate metal sequestration and induction of oxidative stress. Prochelation strategies in which the chelating unit remains inactive until triggered by a disease-specific event are expected to increase the specificity of chelation-based therapeutics. Chapter 1 provides an overview of chelation and prochelation based therapies as well as disulfide-based approaches in the design of prodrugs. In Chapter 2, the reduction activation mechanism of disulfide-masked thiosemicarbazone prochelators is described. Whereas disulfide-masked prochelators do not bind iron, reduction of the disulfide bond upon cellular uptake produces active chelators that readily bind intracellular iron. These systems are not active extracellularly; rather, they target the intracellular labile iron pool. We found that the antiproliferative activity of these disulfide-masked prochelators is dependent on the intracellular redox environment, with enhanced toxicity in more reducing conditions. The iron complexes resulting from exposure of cultured cells to the chelation systems were detected intracellularly by electron paramagnetic resonance in intact frozen cells. The compounds in our first series do not engage in intracellular redox chemistry and do not cause oxidative stress. In Chapter 3, the synthesis and characterization of a larger series of disulfide-masked prochelators featuring several classes of tridentate ligands is described. We investigated the iron-binding efficacy of the corresponding chelators, their ability to induce oxidative stress and their cell-cycle effects. We found that these prochelator systems, regardless of the identity of the donor set of atoms, do not result in the intracellular generation of oxidative stress. We also found that treatment of cultured cancer cells with prochelators results in cell-cycle arrest at G1/0 in non-synchronized cells and G2/M in G2-synchronized cells. In addition, we found that all classes of prochelators exhibit antiproliferative effects likely through induction of apoptosis. In Chapter 4, the syntheses and biological evaluations of disulfide-masked prochelators that feature carbohydrate targeting units are described. The sugar conjugates present increased aqueous solubility, compete as effectively as D-glucose for transporter-mediated cellular uptake, and are 6 to 11-fold more selective towards colorectal cancer compared to an aglycone that does not contain a targeting unit. The design of more potent prochelator systems, as well as the design of systems with improved selectivity and aqueous solubility are discussed in Chapter 5.
    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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