Term | Value | Language |
---|---|---|
dc.contributor.advisor | DeRose, Victoria | |
dc.contributor.author | McDevitt, Christine | |
dc.date.accessioned | 2021-11-23T15:25:43Z | |
dc.date.issued | 2021-11-23 | |
dc.identifier.uri | https://scholarsbank.uoregon.edu/xmlui/handle/1794/26897 | |
dc.description.abstract | Platinum anti-cancer drugs are widely used in the United States being used in 10-20% of cancer therapy treatments today. These drugs have been in use for many years with cisplatin being in use for over 40 years. The mechanism of platinum compounds was believed to be through the DNA damage response pathway; however, recently it has been identified and confirmed that oxaliplatin causes cell death through ribosome biogenesis stress or nucleolar stress. Here we explore the structural and molecular level factors that influence why oxaliplatin causes nucleolar stress. Chapter II explores the structural characteristics of oxaliplatin that influence why this compound causes nucleolar stress. We identify new platinum compounds that also exploit this cell death pathway and find that there is a correlation between size and hydrophobicity but that the orientation of the ligand strongly influences whether compounds cause nucleolar stress. The orientation of the ligand can cause compounds with similar size and hydrophobicity to no longer cause nucleolar stress. Chapter III explores the properties of phenanthriplatin, another platinum compound reported to cause nucleolar stress, and other monofunctional platinum compounds. We found that no structural connection exists between oxaliplatin and phenanthriplatin that explain why both compounds cause stress and could indicate that they are working by two different binding events in cells to cause the same outcome. Chapter IV further explores the non-labile ligand of oxaliplatin (1,2-diaminocyclohexane) and finds that while the addition of a methyl to the scaffold is tolerated, the addition of an acetamide causes the compounds to no longer cause nucleolar stress. This further indicates that the interaction responsible for oxaliplatin causing nucleolar stress is highly selective and could work as a lock and key type mechanism. These structure studies are helpful to determine what the constraints for the interaction are but do not identify potential biomolecular targets of these compounds. In chapter V we report synthetic work towards two click-capable platinum compounds that can be used to directly probe the platinum atoms. A second generation click compound utilizing a cyclopropene-tetrazine bioorthogonal pair can be used for live cell imaging while an CuAAC oxaliplatin mimic could help to uncover the target of oxaliplatin that causes nucleolar stress. Chapter VI examines two types of binding that could occur, a bidentate adduct to a biomolecule such as a double strand of DNA and a mono adduct such as binding to NPM1, through computational modeling. These models illuminate the possibility of asymmetric molecules to exhibit flexibility at interfaces particularly when binding to biomolecules through a monoadduct. These studies help to illuminate the molecular factors that could influence platinum induced nucleolar stress and be used to further understand these platinum compounds and their activities as medicine. | en_US |
dc.language.iso | en_US | |
dc.publisher | University of Oregon | |
dc.rights | All Rights Reserved. | |
dc.subject | Cancer | en_US |
dc.subject | Cisplatin | en_US |
dc.subject | Nucleolar Stress | en_US |
dc.subject | Oxaliplatin | en_US |
dc.subject | Platinum | en_US |
dc.title | Platinum Induced Nucleolar Stress: A study of Molecular Level Factors | |
dc.type | Electronic Thesis or Dissertation | |
dc.description.embargo | 2022-10-11 | |
thesis.degree.name | Ph.D. | |
thesis.degree.level | doctoral | |
thesis.degree.discipline | Department of Chemistry and Biochemistry | |
thesis.degree.grantor | University of Oregon |