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Matthew Ellis Dissertation pdf.pdf (9.73 MB)

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An Investigation Into the Fate of a C5'-Uridinyl Radical

Ellis, Matthew
http://rave.ohiolink.edu/etdc/view?acc_num=toledo1513355069432417

Abstract Details

2017, Doctor of Philosophy, University of Toledo, Medicinal Chemistry.
Constituents of the endogenous exposome include reactive oxygen species, which cause oxidative damage to nucleic acids, proteins, and lipids. It has been shown that such damage to RNA plays a role in the initiation of neurodegenerative diseases, such as Alzheimer’s. To investigate this phenomenon at the molecular level, the synthesis of a modified uridine was improved upon and subjected to photolytic activation, generating a C5'-uridinyl radical mimicking the hydrogen atom abstraction normally observed under conditions of oxidative stress. This was accomplished using a tert-butyl ketone at the C5' position, which undergoes Norrish Type I cleavage. Studies were performed under anaerobic conditions in the presence or absence of reductant at varying pH to emulate the diversity of the cellular environment, and it was found that the base release product uracil was predominant. Aerobic conditions were also utilized, which led to the formation of a C5' aldehyde. The C5'-uridinyl radical precursor was further derivatized for its incorporation into oligoribonucleotides. Development of a new automated RNA synthesis method in the 5' to 3' direction using 5' H-phosphonates was initiated. This included the synthesis of the building blocks required for the method development.
Amanda Bryant-Friedrich (Advisor)
Paul Erhardt (Committee Member)
Zahoor Shah (Committee Member)
Hermann von Grafenstein (Committee Member)
Peter Andreana (Committee Member)
102 p.
Chemistry; Organic Chemistry; Pharmacy Sciences
RNA Damage, Nucleotides, Oxidative Damage, Endogenous Exposome, RNA Synthesis, Organic Chemistry, Nucleic Acid Chemistry

Recommended Citations

Citations

  • Ellis, M. (2017). An Investigation Into the Fate of a C5'-Uridinyl Radical [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1513355069432417

    APA Style (7th edition)

  • Ellis, Matthew. An Investigation Into the Fate of a C5'-Uridinyl Radical . 2017. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=toledo1513355069432417.

    MLA Style (8th edition)

  • Ellis, Matthew. "An Investigation Into the Fate of a C5'-Uridinyl Radical ." Doctoral dissertation, University of Toledo, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1513355069432417

    Chicago Manual of Style (17th edition)

toledo1513355069432417
274
© 2017, all rights reserved.
This open access ETD is published by University of Toledo and OhioLINK.