Ruthenium (Ru) complexes with anticancer properties are a growing area of research with increasing promise since several Ru compounds have entered clinical trials, but few Ru anticancer compounds have been protic. The advantage of protic Ru compounds lies in the ability to perform fundamental studies to correlate structure with function. Removal of protons from a protic Ru complex represents an electronic change with minimal steric change. Therefore, it is interesting to investigate how proton removal impacts the photochemical properties of protic Ru complexes. We have designed several new complexes based upon the [(N,N)2Ru(n,n’-dhbp)]2+ scaffold where (N,N) is a bidentate diimine ligand and n = 4 or 6 in n,n’-dhbp (dihydroxybipyridine). When treated with visible light, these complexes can photodissociate to eject a ligand or they can react with air to generate singlet oxygen, with the extent to which each pathway dominates varying from compound to compound. In our studies, the protonation state of the ligand influences the photochemical pathway that dominates. We describe how these pathways and how cellular uptake and subcellular localization together leads to the resultant photocytotoxicity of the compounds. Several of the compounds described are light activated with our best compound achieving nanomolar EC50 values with phototoxicity indices as high as 200 vs. breast cancer cells.

Protic ruthenium anticancer compounds: Describing the role of ligand charge in both photodissociation and singlet oxygen production

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ACS Fall 2022

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