Year of Award

2013

Document Type

Dissertation

Degree Type

Doctor of Philosophy (PhD)

Degree Name

Biomedical Sciences

Department or School/College

Department of Biomedical and Pharmaceutical Sciences

Committee Chair

Howard Beall

Commitee Members

Douglas Coffin, Keith Parker, Mark Pershouse, Kent Sugden

Keywords

Antitumor agents, Cancer, Targeted drug discovery

Abstract

Cancer is a common, complex, and oftentimes fatal disease. Despite extensive research in the field of cancer drug discovery, there are still improvements to be made in the design of effective anticancer agents. This project involved three separate but related studies that fall under the category of anticancer drug discovery as a whole. The overall goal of this project was to design and investigate the mechanisms of action of new antitumor agents to be used against solid tumors. First, we developed a series of anthracenyl isoxazole amides (AIMs) designed to bind to G-quadruplex DNA and inhibit telomerase. Results from this study demonstrated an alternative mitochondrial mechanism of action of the AIMs not yet fully described in the literature. Investigation of lead compound AIM 1 showed localization of the AIM in mitochondria with resulting induction of apoptosis, generation of mitochondrial superoxide, disruption of mitochondrial membrane potential, and activation of caspase-9. The second goal of this project was to assay a series of 4-isoxazolyl-1,4-dihydropyridines (IDHPs) that function as P-gp inhibitors to determine their contribution to enhanced cytotoxicity of the AIMs when co-dosed together in vitro. Because so many anticancer agents are substrates for P-gp and are therefore limited in their ability to reach intended targets, the development of P-gp inhibitors is an important area of research. Results from this study indicate that IDHPs are a viable class of P-gp inhibitors that can be co-dosed with P-gp substrates to increase substrate cytotoxicity. The third goal of this study was to determine the NQO1 substrate potential of a series of lavendamycin derivative quinolinequinones and assess their corresponding antitumor potential. Surprisingly, few of the quinolinequinones tested showed preferential specificity for NQO1-expressing cells compared to NQO1-null cells. However, in our series of aryl-substituted quinolinequinones, the active molecules appear to be the quinone derivatives and not derivatives of hydroquinones or semiquinones. These data suggest a mode of action that differs from that of previously studied lavendamycin analogues that are activated by NQO1 reduction. While this project focused on the general targeting of solid tumors, the type of tumor explicitly studied varied from brain cancer to breast cancer and encompassed multiple drug targets. Collectively the results of this study are expansive and offer much to the field of anticancer drug discovery.

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© Copyright 2013 Alison King Kearns