Light Activated Protic Ruthenium(II) Compounds: Structure Function Relationships and Determining Which Factors Influence Cytotoxicity

Cancer is a significant health challenge that has been difficult to treat. There is a continuous search for treatments with fewer side effects. The study of metallodrugs with antitumor properties has increased since the discovery and clinical approval of the Pt(II) drug, cisplatin, to treat many cancerous tumors. Photodynamic therapy (PDT) is a clinically approved targeted cancer treatment. Ru(II) polypyridyl complexes have gained attention over the years for their photochemical and photophysical properties, which can be harnessed for PDT. Ru(II) polypyridyl complexes have electronic properties that make their excited state properties tunable by ligand and charge modification. Many Ru(II) compounds have been studied as PDT agents, but only a few have been protic. The research in this dissertation is focused on the synthesis of diprotic Ru(II) polypyridyl compounds and fundamental studies of how ligand modifications influence lipophilicity, singlet oxygen generation, emission energies, luminescence quantum yields, luminescence lifetimes, and cytotoxicity of light-activated protic Ru(II) compounds. The diprotic ligands allow investigation into the influence of Ru-N strain and the electronic effects of protonation and deprotonation of the diprotic ligands on the photoexcited state properties and the photoexcited state reaction of Ru(II) polypyridyl compounds. For this dissertation, diprotic Ru(II) polypyridyl compounds have been synthesized and studied using three protic polypyridyl ligands with varying π-conjugation and hydroxyl group substitution. To investigate the impact of lipophilicity and ligand substitution on diprotic Ru(II) compounds, two new lipophilic bathophenanthroline compounds with 4,4′-dhbp and 6,6′-dhbp ligands were synthesized and investigated. The compound with the 6,6′-dhbp has a Ru-N strain and photodissociates because of the thermal accessibility of the antibonding triplet excited state. The compound with 4,4′-dhbp ligand has no Ru-N strain, does not photodissociate, and was the most photocytotoxic of the two compounds against the breast cancer cell line, MCF7. To probe the effect of (de)protonation events on the excited state properties and excited state reactions of diprotic Ru(II) compounds, eight compounds were synthesized using the 6,6′-dhbp and the 4,4′-dhbp, from which eight doubly deprotonated Ru(II) compounds were isolated. Studies showed that deprotonation quenches excited state properties, and only diprotic Ru(II) compounds of the 4,4′-dhbp have long-lived luminescence (ƮEm), high photoluminescence quantum yield (ɸPL), and high singlet oxygen quantum yield (ɸΔ). Going forward, the use of 6,6′-dhbp ligand was discontinued, and a new ligand, 4,7-dhphen, which is similar to but more conjugated than the 4,4′-dhbp ligand, was introduced.To study the impact of π-expansion of diprotic ligands on the photocytotoxicity of Ru(II) compounds, five new compounds were synthesized using the 4,4′-dhbp and 4,7-dhphen ligands. Photoactivation studies of these compounds against human skin melanoma cells (SK-MEL-28), breast cancer cells (MCF7), and triple-negative breast cancer cells (MDA-MB-231) show that, in most cases, the Ru(II) compounds of the 4,7-dhphen ligand are not as photocytotoxic as the Ru(II) compounds of 4,4′-dhbp. These studies show that extensive conjugation does not necessarily enhance the photocytotoxicity of the diprotic Ru(II) compounds in this dissertation.