Date of Award
2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (Ph.D.)
Department
Drug Discovery and Chemical Synthesis
First Advisor
Liang Xue, Ph.D.
First Committee Member
George Pantouris, Ph.D.
Second Committee Member
Andreas Franz, Ph.D.
Third Committee Member
Wade Russu, Ph.D.
Fourth Committee Member
Craig Vierra, Ph.D.
Abstract
Chemotherapy works by killing fast dividing cells. Unfortunately, these drugs are not specific to cancer tissue and can damage normal cells. Chemotherapy is like taking poison and hoping it kills the cancer cells before it kills you. As an alternative, many researchers have investigated the use of antigene therapy to selectively target cancer causing genes to avoid off target effects. Although promising, the theory is limited by the stability of the triplex structure. Here, we report the discovery of potent triplex binding ligands derived from the natural product quercetin. Chemical derivatives of 5-substituted 3, 3’, 4’, 7-tetramethoxyquercetin derivatives were characterized using several biophysical methods: thermal denaturation monitored by UV, circular dichroism, viscometry, differential scanning calorimetry, and isothermal titration calorimetry. The data revealed that these derivatives specifically stabilize triplex DNA and do not influence the stability of duplex DNA, triple RNA, or duplex RNA. Structurally, the amino containing side chains at the 5-position and the linker length are critical for the observed binding affinity and specificity. Two derivatives, 5 and 7, are comparable (if not better) to the triplex groove binder Neomycin. Our data confirm the binding mode as enthalpically driven intercalation. Piperidine or pyrrolidine 5-substituted 3, 3’, 4’, 7-tetramethoxyquercetin derivatives with a three-carbon linker are the lead compounds for development as a potential antigene enhancer.
Pages
154
Recommended Citation
Rangel, Vanessa Marie. (2023). THE DISCOVERY AND CHARACTERIZATION OF NOVEL POTENT 5-SUBSTITUTED 3, 3’, 4’, 7-TETRAMETHOXYFLAVONOID DNA TRIPLEX SPECIFIC BINDING LIGANDS. University of the Pacific, Dissertation. https://scholarlycommons.pacific.edu/uop_etds/3841
Included in
Medicinal-Pharmaceutical Chemistry Commons, Nucleic Acids, Nucleotides, and Nucleosides Commons, Organic Chemistry Commons
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