Date of Award
Doctor of Philosophy (PhD)
Boron neutron capture therapy (BNCT) is a binary radiotherapeutic modality for cancer treatment, in which delivery agents containing 10B atoms are transported into tumor cells and then irradiated with low-energy thermal neutrons. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that are involved in the remodeling and degradation of all components of the extracellular matrix (ECM). Overexpressed levels of MMP activity have been implicated in several disease states including tumor growth and metastasis. We have appended a borane-rich carborane cluster onto MMP-targeting pharmacophores to enable delivery of 10B atoms to a tumor. Herein, we describe the molecular docking experiments and synthesis of series of BNCT ligands based on the broad spectrum MMP inhibitors SC-77964 and CGS-27023A.The extensive use of antibiotics has exacerbated the emergence of drug-resistant strains in most human pathogens, a global problem with devastating implications for the treatment of infectious diseases and classes of commercially available antibiotics. In order to combat the ongoing challenge of antibiotic resistance, we have identified two attractive and underexplored bacterial targets for the development of novel classes of antibiotics, the dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE, EC 184.108.40.206) enzyme and the sodium dependent NADH: Ubiquinone oxidoreductase (Na+-NQR) respiratory enzyme. Inhibition of DapE and Na+-NQR should be selectively toxic to bacteria but not the human host, since both enzymes are absent in mammals. Our work has focused on identification and synthesis of lead compounds, lead optimization via structure-activity relationships (SAR), and further testing of a library of small molecule inhibitors of DapE and Na+-NQR as novel broad-spectrum antibiotics.
Flieger, Sebastian, "Design and Synthesis of Novel Antibiotics and Anticancer Agents Targeting Pharmaceutically Relevant Enzymes" (2023). Dissertations. 4018.
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Copyright © 2023 Sebastian Flieger
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