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NOVEL APPROACHES FOR CONTROLLING TARGET SELECTIVITY AND PHARMACOLOGICAL PROPERTIES OF PLATINUM-INTERCALATOR-BASED ANTICANCER AGENTS

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abstract
Traditional DNA-targeted anticancer agents, such as platinum-based therapies, have been a mainstay in the treatment of aggressive solid malignancies in the clinical setting. Unfortunately, due to multifactorial drug resistance and systemic toxicity the clinical efficacy of these drugs is severely limited. Platinum-acridine hybrid agents have proven to overcome multifactorial drug resistance in some of the most aggressive forms of cancer, in particular non-small-cell lung cancer (NSCLC). The remaining challenges with this generation of anticancer agents revolve around overcoming the dose-limiting toxicities caused by indiscriminate chromatin damage (genotoxicity) in malignant and healthy cells and improving the unfavorable pharmacokinetics (PK) caused by the poor drug-like properties of these agents. The goal of this dissertation was to devise a structurally minimalistic approach by which platinum-acridines can be tuned to simultaneously achieve both of these goals. In particular, a design was desired that minimizes platinum adduct formation in the double-stranded portion of genomic DNA but enhances the reactivity with G-quadruplex DNA, a preclinically validated anticancer target.
subject
Anticancer agents
Cancer
G-quadruplex
NSCLC
Platinum
contributor
Pickard, Amanda Jayne (author)
Bierbach, Ulrich (committee chair)
Pardee, Timothy S (committee member)
Jones, Paul B (committee member)
Salam, Akbar (committee member)
Welker, Mark E (committee member)
date
2014-09-10T08:35:21Z (accessioned)
2014-10-17T08:30:09Z (available)
2014 (issued)
degree
Chemistry (discipline)
identifier
http://hdl.handle.net/10339/39394 (uri)
language
en (iso)
publisher
Wake Forest University
title
NOVEL APPROACHES FOR CONTROLLING TARGET SELECTIVITY AND PHARMACOLOGICAL PROPERTIES OF PLATINUM-INTERCALATOR-BASED ANTICANCER AGENTS
type
Dissertation

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