Date of Award

Spring 2016

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Chemistry and Biochemistry

Committee Director

Alvin A. Holder

Committee Member

Stephen J. Beebe

Committee Member

John B. Cooper

Committee Member

Guijun Wang

Committee Member

Lesley H. Greene

Abstract

Transition metal complexes have played a critical role in antitumor therapy with many complexes incorporating platinum, ruthenium, and lanthanum having been investigated in preclinical and clinical trials. The best known transition metal therapeutic is cisplatin, which is utilized in nearly 50% of all cancer therapies, despite its significant toxic side effects. The toxic side effects of current FDA approved platinum-based chemotherapeutics are often overlooked due to the “special status” granted to these drugs due to their ability to fight, what is often considered an incurable disease with life expectancies often measured in months. Oncology drug development has therefore now focused on developing new complexes with less toxicity and which inhibit cancer cell growth by different mechanisms of action when compared with platinum-based therapeutics.

Understanding exactly how a biological agent elicits its observed activity is perhaps the most critical step in drug discovery and is a question left unanswered by many. Take for instance NAMI-A and KP1019, both Ru(II)-based chemotherapeutics currently in clinical trials, despite their unsolved mechanisms of action. Detailed mechanistic investigations have the potential to inform the design of next generation chemotherapeutics. Therefore, in the first half of this thesis, we investigated the mechanisms of actions of some transition metal complexes incorporating Co(III), Ru(II), and/or V(IV) metal centers. Utilizing spectroscopic, biophysical, and molecular biological techniques such as UV-visible and fluorescence binding assays, isothermal titration calorimetry, and flow cytometry, we investigated the ability of these unique transition metal complexes to interact with CT DNA, inhibit cellular proliferation in mammary breast cancer cells, and modify cell signaling pathways. This information provides valuable insight into the potential mechanism of action of these compounds, which is expected to be different for each unique molecular structure. Additionally, a novel localized ablation technique involving a transition metal therapeutic and nanosecond pulsed electric field technology was developed and investigated. In the second half of this thesis, we focused attention on the development of new ligands and complexes which can be screened for their potential chemotherapeutic activity. Using simple, clean, and efficient organic and inorganic reactions small libraries of molecules were synthesized and characterized using a variety of spectroscopic techniques including: 1H, 13C, and 19F NMR spectroscopy, high resolution mass spectroscopy, and X-ray crystallography, where appropriate. From this work a new potential lead molecule(s) may be identified which may show enhanced chemotherapeutic activity. Additionally, structurally similar ligands and complexes will lead to structure-activity relationship studies which are also an integral part of drug discovery in lead optimization.

DOI

10.25777/469d-qs88

ISBN

9781339787671

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