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NOVEL STRATEGIES FOR IMPROVING THE PHARMACOLOGICAL PROPERTIES OF PLATINUM-ACRIDINE ANTICANCER AGENTS

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abstract
Unlike traditional cisplatin-type platinum-based anticancer drugs, platinum-acridine hybrid agents were designed as dual platinating/intercalating DNA-targeted cytotoxics, which are able to cause cancer cell death at low-nanomolar concentrations. Unfortunately, the preclinical development of these agents has been hampered by their severe systemic toxicity. The goal of this dissertation was to devise strategies that improve the drug-like properties of platinum-acridines and allow their safe delivery. To achieve this, several classical and newly developed synthetic methodologies have been used to generate functionally unique hybrid agents. Several model systems, whole-cell assays, and animal studies have been used in this dissertation to validate their design and demonstrate their utility as anticancer agents. A modular screening platform was developed, based on a platinum-mediated amine-to-nitrile addition reaction, for rapid identification of functionalized platinum-acridine agents. These pre-screening assays produced functionalized “warheads” while providing insight into structure–activity relationships (SAR). Using several library members, we set out to explore synthetic approaches to construct platinum-acridine-based conjugates. A chemically robust azide-modified platinum-acridine was selected to validate the feasibility of copper-mediated and copper-free click chemistry as platinum-compatible conjugation reactions. This chemistry was used to attach fluorescent molecules to detect platinum-acridines in cancer cells by confocal microscopy. Both fluorophore tagging prior to incubation with cells and post-labeling methods were explored. In addition, a hydroxyl-modified warhead was conjugated with endoxifen via a chemically stable carbamate bond to produce a highly active hybrid agent in estrogen receptor positive (ER+) breast cancer. In another study, lipophilic ester-based prodrugs of platinum–acridines were generated showing improved drug-like properties (e. g., partition coefficients, logD). Two distinct pathways by which the target compounds can be activated have been confirmed by LC-ESMS and/or NMR techniques: (i) a platinum-assisted, self-immolative ester cleavage in a low-chloride environment, and (ii) enzymatic cleavage by human carboxylesterase-2 (hCES-2). Highly efficient amide coupling reactions in platinum complexes were also developed. This modular approach can be used to assemble a diverse library of platinum-acridines containing other bioactive components, such as molecularly targeted therapies, targeted ligands, and chemosensitizers. Finally, liposomal encapsulation of platinum-acridine was achieved, and the formulations were evaluated in A549 lung cancer xenograft models in mice. Improved anticancer efficacy of one of the liposomal formulations compared with the free drug was observed in this assay. In conclusion, the research in this dissertation has laid the foundation for the future preclinical development of platinum-acridines as oncology drugs by devising new synthetic methodology and providing proof-of-concept data in clinically relevant models of cancer.
subject
contributor
Ding, Song (author)
Bierbach, Ulrich (committee chair)
Guthold, Martin (committee member)
King, Bruce S (committee member)
Dos Santos, Patricia C (committee member)
Welker, Mark E (committee member)
date
2016-01-11T09:35:19Z (accessioned)
2017-01-10T09:30:11Z (available)
2015 (issued)
degree
Chemistry (discipline)
embargo
2017-01-10 (terms)
identifier
http://hdl.handle.net/10339/57423 (uri)
language
en (iso)
publisher
Wake Forest University
title
NOVEL STRATEGIES FOR IMPROVING THE PHARMACOLOGICAL PROPERTIES OF PLATINUM-ACRIDINE ANTICANCER AGENTS
type
Dissertation

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