Author ORCID Identifier
Date Available
4-24-2025
Year of Publication
2023
Degree Name
Doctor of Philosophy (PhD)
Document Type
Doctoral Dissertation
College
Arts and Sciences
Department/School/Program
Chemistry
First Advisor
Dr. Edith C. Glazer
Abstract
Platinum(Pt)-based agents are used in approximately 50% of all cancers that are treated with chemotherapy. Unfortunately, the dose-limiting toxicity of these agents remains problematic for patients undergoing treatment. Additionally, Pt(II) therapeutics suffer from transporter-dependent uptake, limited chemical functionalization, and high susceptibility to inactivation by free thiols within the cytosol. Developing small molecules with non-canonical mechanisms of action is one strategy that can be employed to circumvent these limitations. Utilization of coordination complexes with ruthenium(Ru) metal centers is one attractive strategy. Ru(II) compounds are often octahedral, facilitating greater accessibility for chemical diversity; Ru(II) complexes use passive transport and transferrin-mediated transport for cellular uptake; Ru(II) is a harder Lewis acid than Pt(II), facilitating reduced thiol coordination, which results in reduced inactivation. Herein, we investigate several Ru(II) scaffolds that display non-canonical mechanisms. They are able to preferentially induce ribosome biogenesis stress and mitochondrial membrane uncoupling. Complementary to this work, we investigated the mechanism of action for photoactive chemotherapeutics (PACTs) and photodynamic therapeutics (PDTs). Despite the fact that reactive oxygen species (ROS) generated by PDTs can oxidize nucleobases, cellular bioenergetic pathways are effectively shut down before DNA damage could be recognized by DNA damage repair (DDR) machinery, suggesting that, unlike Pt(II) therapeutics, DNA damage is not the cause of cell death for these compound.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2023.069
Funding Information
This work was supported by the National Institutes of Health Grant (GM107586) from 2018 to 2020 and the National Science Foundation Grant (MCB-1453168) from 2018 to 2022
Recommended Citation
Mitchell, Richard Joseph, "Investigating Ru(II) Anticancer Agents with Non-Canonical Mechanisms of Action" (2023). Theses and Dissertations--Chemistry. 176.
https://uknowledge.uky.edu/chemistry_etds/176
