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Modified Nucleosides Part A: A Platform for the Chemical Tagging of Ribonucleic Acids for Analysis by Mass Spectrometry Part B: Base-Modified Thymidines Exhibiting Cytotoxicity towards Cancer Cells

Borland, Kayla
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1530269297179685

Abstract Details

2019, PhD, University of Cincinnati, Arts and Sciences: Chemistry.
This dissertation is focused on modified nucleosides. Part A focuses on method development for multiplex analysis of modified oligonucleosides while part B is a medicinal chemistry perspective of modified nucleosides as potential anti-cancer therapeutics. Part A uses mass spectrometry (MS) as an enabling technology for the characterization of post-transcriptionally modified nucleosides within ribonucleic acids (RNAs). These modified RNAs tend to be more challenging to completely characterize using conventional genomic-based sequencing technologies. As with many biological molecules, information relating to the presence or absence of a particular compound (i.e., qualitative measurement) is only one step in sample characterization. Additional useful information is found by performing quantitative measurements on the levels of the compound of interest in the sample. To unlock this information within RNA samples, previously reported duplex-based strategies to characterize modified RNAs in two different samples have been examined. Here is reported the use of poly adenosine polymerase (PAP), which – under optimized conditions – can add one 2’ azido modified nucleotide to the 3’-terminus of modified RNA. The addition of this azido-modified nucleotide can allow for the use of click chemistry to uniquely tag each sample. One sample is labeled with an unisotopically labeled alkyne while the other samples are reacted with an isotopically labeled alkyne. The two samples can easily be compared to one another based on doublet separate by difference in isotopic label mass. In part B modified nucleoside are synthesized because, current FDA-approved anti-cancer modified nucleosides elicit severe side effects warranting their improvement. Therefore, a series of compounds with a mechanism of action focused on inhibiting DNA replication was designed. Compound were inspired by the previous discovery that 5-(a-substituted-2-nitrobenzyloxy)methyluridine-5’-triphosphates terminate DNA synthesis. Thus, a library of thymidine analogs were synthesized and evaluated using a cell viability assay in MCF7 breast cancer cells, which were chosen because they had the greatest susceptibility to these nucleosides. The structure-activity relationship study lead to a compounds having a-tert-butyl-2-nitro-4-(phenyl)alkynylbenzyloxy; it caused 50% of MCF7 cell death at 9 ± 1 µM concentration.
Patrick Limbach, Ph.D. (Committee Chair)
Ruxandra Dima, Ph.D. (Committee Member)
Edward Merino, Ph.D. (Committee Member)
301 p.
Pharmaceuticals
modified nucleosides; RNA oligonucleotides; anti-cancer agents; LC-MS; multiplexing

Recommended Citations

Citations

  • Borland, K. (2019). Modified Nucleosides Part A: A Platform for the Chemical Tagging of Ribonucleic Acids for Analysis by Mass Spectrometry Part B: Base-Modified Thymidines Exhibiting Cytotoxicity towards Cancer Cells [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1530269297179685

    APA Style (7th edition)

  • Borland, Kayla. Modified Nucleosides Part A: A Platform for the Chemical Tagging of Ribonucleic Acids for Analysis by Mass Spectrometry Part B: Base-Modified Thymidines Exhibiting Cytotoxicity towards Cancer Cells. 2019. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1530269297179685.

    MLA Style (8th edition)

  • Borland, Kayla. "Modified Nucleosides Part A: A Platform for the Chemical Tagging of Ribonucleic Acids for Analysis by Mass Spectrometry Part B: Base-Modified Thymidines Exhibiting Cytotoxicity towards Cancer Cells." Doctoral dissertation, University of Cincinnati, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1530269297179685

    Chicago Manual of Style (17th edition)

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This open access ETD is published by University of Cincinnati and OhioLINK.