Author ORCID Identifier
https://orcid.org/0000-0003-3076-264X
Date Available
5-23-2026
Year of Publication
2024
Document Type
Doctoral Dissertation
Degree Name
Doctor of Philosophy (PhD)
College
Arts and Sciences
Department/School/Program
Chemistry
Advisor
Dr. Samuel Awuah
Abstract
Despite notable advancements in the design and synthesis of novel chemotherapeutic drugs, cancer continues to be a leading cause of death in the United States. Metallodrugs, especially Au complexes, have played a prominent role in the search for the next generation of chemotherapeutic agents. Herein, I report on the synthetic strategies towards the rational design of stable Au (Au)-based agents, study their reactivity in biological environment, and offer insights into the cytotoxic mechanism of action in cancer. Chemotherapeutic Au compounds exist mainly in +I or +III oxidation states. Repurposing of the Au(I) FDA approved auranofin for the treatment of diseases including cancer has ignited a lot of research excitement for Au(I) anticancer. Despite being isoelectronic to cisplatin, Au(III) complexes exhibit different chemistry, reactivity, and molecular targets compared to cisplatin which could be exploited in the development of new metallodrugs. The challenges in developing Au(III) complexes with potent anticancer activities arise from their stability and solubility, physicochemical barriers that need to be overcome to prevent drug degradation and off-target effects. By rational ligand tuning, I developed Au(III) agents with kinetic inertness and redox stability to biological nucleophiles and exhibit potent cytotoxic activities in cancer cells. This was achieved by synthesizing Au(III) complexes with different degree of cyclometalation (C^N or C^C cyclometalation). C^N cyclometalated Au(III) bearing chiral phosphine ligands have been studied previously as potent anticancer agents, although there is no report to the best of my knowledge on their speciation on reacting with biological nucleophiles. My work studied for the first time the adducts formed on reacting cytotoxic C^N cyclometalated chiral Au(III)-bisphosphine with L-glutathione. Furthermore, to improve the stability of cyclometalated Au(III) complexes, I rationalized that the presence of two strong sigma-donating carbon atoms bonded to Au could increase the stability of this class of compounds. Hence, a series of C^C cyclometalated Au(III) compounds bearing diverse bisphosphine ligands were synthesized from di-μ-chlorido biphenyl digold(III) starting material . These complexes displayed improved physiological stability in both L-glutathione and serum from mice in a UV-Vis, APCI-MS and LCMS study. Also, this class of compounds showed in vitro cytotoxicity in a panel of triple negative breast cancer (TNBC) and glioblastoma cancer cells. Further mechanistic study showed that compared to cisplatin, these complexes can act as mild mitochondria uncoupler comparable to other protonophores such as FCCP. To the best of my knowledge, this is the first Au(III) mitochondria uncoupling agent. Additionally, challenges regarding Au(III) complex solubility and bioaccumulation were resolved via protein nanodelivery. I hypothesized that encapsulation of lipophilic Au complexes with a biodegradable protein bovine serum albumin will improve the physicochemical properties and anticancer efficacy. Using lipophilic long alkyl chain Au(III) dithiocarbamate with different degrees of cyclometalation (phenylpyridine [C^N] or biphenyl [C^C]), the physiological stability and antiproliferative activity in cancer cells indicates decrease in solubility and anticancer activity with an increase alkyl chain. Therefore, longer alkyl chain Au(III) dithiocarbamate complexes were encapsulated with bovine serum albumin and this resulted in a significant increase in solubility, stability and anticancer activity. Overall, this report provides a framework of synthetic strategies to access Au based compounds with improved redox stability that could be beneficial in many fields of science such as medicine, catalysis, and functional materials.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2024.261
Recommended Citation
Arojojoye, Adedamola, "SYNTHETIC STRATEGIES TOWARD THE DEVELOPMENT OF STABLE GOLD-BASED ANTICANCER AGENTS AND THEIR MECHANISTIC INSIGHT" (2024). Theses and Dissertations--Chemistry. 196.
https://uknowledge.uky.edu/chemistry_etds/196
