Author ORCID Identifier

https://orcid.org/0000-0003-1164-009X

Year of Publication

2022

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Arts and Sciences

Department/School/Program

Chemistry

First Advisor

Dr. Samuel Gorman Awuah

Abstract

Site-selective modifications of target proteins using specially designed small molecules is a powerful tool that has been extensively utilized in biomedicine. Small molecules can modify proteins either covalently or non-covalently depending on their structures and intrinsic chemical reactivity. Covalent chemical modification presents a more stable and often irreversible interaction with target proteins; unlike non-covalent binders, which form weak, reversible interactions with protein. Therefore, covalent modifiers represent an effective class of therapeutics due to their stability and irreversibility once bound to target proteins of interest. I hypothesized that tuning biocompatible, high-valent gold(III) complexes toward nucleophile-induced reductive elimination will lead to covalent protein modification by arylation. While most proteins are expressed amongst all cell types; protein overexpression is a common phenomenon in several cancer types due to their rapid proliferative phenotype and mutations compared to healthy non-cancerous cells. The nucleophilic amino acid side chains in proteins can be used as reactive handles for covalent modifications. Amongst the naturally occurring amino acids; cysteine, the most intrinsically nucleophilic, contains a highly reactive thiol functional group. This innate nucleophilicity provides a framework for covalent modification with electrophiles, which include but are not limited to electron-deficient metal centers (e.g., Au and Pd).

Although there are previous reports successfully identifying transition metals as suitable chemical modifiers, specifically, tuning gold(III) complexes for selective binding offers a unique strategy for chemotherapeutics. Gold(III) metal centers are innately acidic and react with softer bases such as phosphorus and sulfur unlike other late transition metals of d8 configuration. Secondly, gold(III) complexes are known to target proteins over DNA, unlike complexes of common transition metals such as platinum and ruthenium. Combining the innate ability of gold(III) complexes to interact with proteins and the high affinity for cysteine thiols, rational design of highly selective protein modifiers and efficient chemotherapeutics is possible.

My work focused on tuning the reactivity of cyclometalated gold(III) complexes for cysteine arylation and ligand-directed bioconjugation using metal-mediated ligand affinity chemistry (MLAC), - a new strategy to modify proteins covalently via a proximity guided approach to improve selectivity. In this work, MLAC was used to target the undruggable protein target, KRAS (G12C) mutant and can be broadly applied to other recalcitrant proteins. While developing cyclometalated gold(III) complexes discussed herein, a unique class of chiral gold(III) complexes bearing diamine or phosphine ligands led to other applications including improved anticancer activity in comparison to first generation gold(III) complexes. A key highlight is the development of stable organometallic gold(III) macrocycles with potent in vitro and promising in vivo anticancer action in aggressive cancer types including triple negative breast cancer (TNBC).

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2022.110

Funding Information

This study was supported by the National Institute of Health/ National Cancer Institute grant (NIH/NCI R01CA258421-01) in 2021-present and Centers of Biomedical Research Excellence (COBRE) P20 GM grant in 2020-2021

Available for download on Sunday, April 28, 2024

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