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Derivation of Hydroquinone to Produce Selective, Oxidatively Activated Chemotherapeutic Agents

Bell-Horwath, Tiffany R.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1397736839

Abstract Details

2014, PhD, University of Cincinnati, Arts and Sciences: Chemistry.
DNA modifying agents are stalwarts of chemotherapeutic cancer treatments, but require vital design improvements to improve selectivity, lower side effects, and continue their widespread use. A key problem for DNA modifying agents is lack of specificity. To address this issue, our lab designs novel molecular scaffolds which are activated by a hallmark of some cancers: increased oxidative stress cause by reactive oxygen species (ROS). Oxidative stress, as measured by levels of ROS, oxidized biomolecules, and enzyme activity, is a hallmark of certain cancer cells. My work focuses on a potential path forward in the design of DNA modifying agents by exploiting the increased ROS into a pro-drug approach. Elevation of ROS has been linked to oncogenesis and has been found in several aggressive cancers, including renal cell carcinoma, melanoma, and leukemia. ROS occurs in four major endogenous forms within the cell: superoxide, hydrogen peroxide, singlet oxygen, and hydroxyl radical. ROS occur in cells via two discrete mechanisms; first, as a byproduct of metabolism. For example, mitochondria generate superoxide via complex I and III during oxidative phosphorylation. Secondly, ROS are known to derive from several enzymes. Especially important are NADPH oxidases that regulate the function of several tyrosine kinases involved in cell growth and survival. Amplified ROS results in increased DNA damage and mutation, tumor heterogeneity, the ability to self-replicate, and angiogenesis. In turn, these mutations cause enhanced activation of oncogenes. Consequently, it is no surprise that levels of ROS-induced DNA damage correlates with cancer prognosis. We utilize a design strategy wherein the pro-drug is stable, but upon ROS activation a reactive molecule is formed. This leads to more reactive forms of the molecule being present in cancer cells. Thus reactivity, and not uptake, is controlled to induce cytotoxicity more specifically in cancer cells and lower off-target reactions.
Edward Merino (Committee Chair)
David Smithrud (Committee Member)
Pearl Tsang (Committee Member)
1110 p.
Biochemistry
Reactive Oxygen Species; AML; ROS; Anti-Cancer Agent; Drug Design; Acute Myeloid Leukemia

Recommended Citations

Citations

  • Bell-Horwath, T. R. (2014). Derivation of Hydroquinone to Produce Selective, Oxidatively Activated Chemotherapeutic Agents [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1397736839

    APA Style (7th edition)

  • Bell-Horwath, Tiffany. Derivation of Hydroquinone to Produce Selective, Oxidatively Activated Chemotherapeutic Agents. 2014. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1397736839.

    MLA Style (8th edition)

  • Bell-Horwath, Tiffany. "Derivation of Hydroquinone to Produce Selective, Oxidatively Activated Chemotherapeutic Agents." Doctoral dissertation, University of Cincinnati, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1397736839

    Chicago Manual of Style (17th edition)

ucin1397736839
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© 2014, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.