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Author ORCID Identifier
0009-0004-6553-6022
Date Available
8-5-2028
Year of Publication
2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
College
Arts and Sciences
Department/School/Program
Chemistry
Faculty
Samuel G. Awuah
Faculty
Kenneth Graham
Abstract
Gold(I) complexes have traditionally been limited to linear two-coordinate geometries (L-Au-L), exemplified by the clinically approved gold drug, auranofin. Although ligand engineering offers opportunities to expand the coordination environment of Au(I), the therapeutic potential of three-coordinate gold(I) complexes remains largely unexplored. This dissertation tests the hypothesis that rational ligand design can modulate the coordination geometry of Au(I), thereby directing its biological activity and expanding the utility of gold-based therapeutics. To address this challenge, a diverse library of three-coordinate Au(I) complexes with the general formula [X^X]-Au-L where both X groups are bidentate and bound to the center gold was designed, synthesized, and structurally characterized using a combination of spectroscopic and crystallographic techniques. Systematic variation of the bidentate ancillary ligands produced complexes with distinct degrees of structural distortion and asymmetry around the Au(I) center, enabling investigation of how coordination geometry influences biological function. Coordination of phenanthroline-derived ligands generated distorted trigonal planar complexes with varying structural asymmetry, whereas incorporation of N-heterocyclic carbene (NHC) ligands shifted the coordination environment toward a distorted linear geometry. These findings demonstrate that subtle ligand modifications provide a powerful strategy for controlling the structural and electronic properties of Au(I) complexes.
The biological consequences of these structural variations were evaluated across multiple cancer models. The Au(I)-NHC complexes exhibited potent activity against glioblastoma, an aggressive primary brain cancer, and induced pronounced disruption of mitochondrial dynamics, consistent with previous observations that mitochondria represent a vulnerable target of three-coordinate Au(I) complexes. In contrast, three-coordinate Au(I) complexes incorporating biaryl dialkyl phosphine ligands largely retained distorted trigonal planar geometries while exhibiting distinct biological behavior. Structure–activity relationship studies in triple-negative breast cancer models revealed that these phosphine-containing complexes preferentially activated endoplasmic reticulum stress pathways with comparatively limited effects on mitochondrial function. These results demonstrate that ligand architecture can redirect the cellular mechanism of action of three-coordinate Au(I) complexes, highlighting coordination geometry as an important determinant of organelle-selective therapeutic activity. The underlying biological mechanisms were further investigated through comprehensive in vitro and in vivo studies. Disruption of mitochondrial dynamics and activation of the unfolded protein response following endoplasmic reticulum stress converged on apoptotic cell death, establishing two complementary mechanisms through which three-coordinate Au(I) complexes exert anticancer activity. These findings provide mechanistic insight into how structural modification of the coordination sphere governs cellular responses and therapeutic efficacy.
To further expand the chemical diversity of this platform, phosphine-functionalized carborane ligands (DPPCb) were synthesized and incorporated into three-coordinate Au(I) complexes. The incorporation of electron-delocalized carborane scaffolds introduces a versatile ligand framework with unique steric and electronic properties, providing new opportunities for the development of structurally diverse gold therapeutics.
Collectively, this work establishes a comprehensive framework for the rational design of three-coordinate gold(I) complexes by linking ligand architecture, coordination geometry, and biological mechanism. These studies significantly expand the chemical space of Au(I)-based therapeutics and demonstrate that precise modulation of the metal coordination environment can generate mechanistically distinct anticancer agents targeting mitochondrial function or endoplasmic reticulum stress. More broadly, this dissertation provides fundamental design principles for the development of next-generation gold-based medicines and advances the application of coordination chemistry in chemical biology and cancer therapy.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2026.400
Archival?
Archival
Funding Information
This research was supported by the following grants:
National Science Foundation-Chemistry Life Processes (CHE-2203559)
National Science Foundation (CHE-997738)
National Institute of Health (P20GM130456)
National Institute of Health/National Cancer Institute (P30 CA177558)
National Institute of Health/National Cancer Institute (R01CA258421-01)
National Science Foundation (CHE-1625732)
National Institute of Health (P20 GM130456)
Recommended Citation
Greif, Charles IV, "Developing Synthetic Strategies for Three-Coordinate Gold(I) Complexes as Anticancer Agents" (2026). University of Kentucky Doctoral Dissertations. 870.
https://uknowledge.uky.edu/gradschool_diss/870
