Studies Toward the Syntheses of Antiarrythmic, Anti-Virulence, and Anticancer Small Molecules
| dc.contributor.advisor | Kürti, László | en |
| dc.contributor.committeeMember | Falck, John R. | en |
| dc.contributor.committeeMember | Chen, Chuo | en |
| dc.contributor.committeeMember | Corey, David R. | en |
| dc.creator | Adebesin, Adeniyi Michael | en |
| dc.date.accessioned | 2018-01-04T21:11:52Z | |
| dc.date.available | 2018-01-04T21:11:52Z | |
| dc.date.created | 2015-12 | |
| dc.date.issued | 2015-11-23 | |
| dc.date.submitted | December 2015 | |
| dc.date.updated | 2018-01-04T21:05:23Z | |
| dc.description.abstract | This work is comprised of three projects: a) the development of antiarrythmic analogs of 17(R),18(S)-epoxyeicosatetraenoic acid for the treatment of atrial fibrillation, b) the development of potent inhibitors of QseC mediated virulence gene expression, and c) studies toward a biomimetic total synthesis of nigricanoside A. Antiarrhythmic analogs of 17(R),18(S)-epoxyeicosatetraenoic acid (17(R),18(S)-EEQ): Arrhythmias such as atrial and ventricular fibrillation are a leading cause of death in the United States of America. However, the available drugs for the treatment of these deadly conditions can paradoxically induce proarrhythmic effects, amongst other side effects, and are individually insufficient for treatment. Through a neonatal rat cardiomyocyte assay, 17(R),18(S)-EEQ was found to possess negative chronotropic effects, a characteristic of antiarrhythmic activity. My work on this project led to the development of potent and metabolically robust analogs of 17(R),18(S)-EEQ, which are currently being developed by OMEICOS Therapeutics GmbH, an early stage drug development company, for the treatment of atrial fibrillation. Inhibitors of QseC mediated virulence gene expression: Quorum sensing E. coli regulator C (QseC), a membrane-bound histidine sensor kinase, mediates the expression of various virulence genes in Gram-negative bacteria such as Escherichia coli (EHEC), Salmonella typhimurium, and Francisella tularensis which are pathogenic to humans. Therefore, QseC is a potential target of anti-virulence antibacterial strategies. In collaboration with the Sperandio laboratory, my work on this project led to the development of novel inhibitors of QseC mediated virulence gene expression. Some of the analogs synthesized in this project are currently being investigated by GlaxoSmithKline as anti-virulence agents. Studies toward a biomimetic total synthesis of nigricanoside A: Nigricanoside A, a novel ether-linked glycoglycerolipid with 7 unassigned stereocenters, was reported to possess potent (IC50 ≈ 3 nM) antimitotic activity against MCF-7 and HCT-116 cancer cell lines. However, the rarity of the natural product precluded further structural and biological studies. With the aid of biomimetic hypotheses and literature precedents, the Falck laboratory reduced the stereochemical uncertainty associated with the structure elucidation of the nigricanosides. Furthermore, one of the biomimetic hypotheses inspired the development of a novel stereocontrolled distal epoxidation of conjugated dienols. Armed with this methodology, my work on this project led to the synthesis of the three major fragments of a nigricanoside. | en |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.oclc | 1017760142 | |
| dc.identifier.uri | https://hdl.handle.net/2152.5/4460 | |
| dc.language.iso | en | en |
| dc.subject | Anti-Bacterial Agents | en |
| dc.subject | Gram-Negative Bacteria | en |
| dc.subject | Protein Kinase Inhibitors | en |
| dc.subject | Protein Kinases | en |
| dc.subject | Quorum Sensing | en |
| dc.subject | Sulfonamides | en |
| dc.title | Studies Toward the Syntheses of Antiarrythmic, Anti-Virulence, and Anticancer Small Molecules | en |
| dc.type | Thesis | en |
| dc.type.material | text | en |
| thesis.degree.department | Graduate School of Biomedical Sciences | en |
| thesis.degree.discipline | Biological Chemistry | en |
| thesis.degree.grantor | UT Southwestern Medical Center | en |
| thesis.degree.level | Doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |