Singlet Oxygen Formation vs Photodissociation for Light-Responsive Protic Ruthenium Anticancer Compounds: The Oxygenated Substituent Determines Which Pathway Dominates.

Ruthenium complexes bearing protic diimine ligands are cytotoxic to certain cancer cells upon irradiation with blue light. Previously reported complexes of the type [(,)Ru(6,6'-dhbp)]Cl with 6,6'-dhbp = 6,6'-dihydroxybipyridine and , = 2,2'-bipyridine (bipy) (), 1,10-phenanthroline (phen) (), and 2,3-dihydro-[1,4]dioxino[2,3-][1,10]phenanthroline (dop) () show EC values as low as 4 μM (for ) vs breast cancer cells upon blue light irradiation ( 2017, 56, 7519). Herein, subscript denotes the acidic form of the complex bearing OH groups, and denotes the basic form bearing O groups. This photocytotoxicity was originally attributed to photodissociation, but recent results suggest that singlet oxygen formation is a more plausible cause of photocytotoxicity. In particular, bulky methoxy substituents enhance photodissociation but these complexes are nontoxic ( 2018, 47, 15685). Cellular studies are presented herein that show the formation of reactive oxygen species (ROS) and apoptosis indicators upon treatment of cells with complex and blue light. Singlet oxygen sensor green (SOSG) shows the formation of O in cell culture for cells treated with and blue light. At physiological pH, complexes - are deprotonated to form - . Quantum yields for O (ϕ) are 0.87 and 0.48 for and , respectively, and these are an order of magnitude higher than the quantum yields for and . The values for ϕ show an increase with 6,6'-dhbp derived substituents as follows: OMe < OH < O. TD-DFT studies show that the presence of a low lying triplet metal-centered (MC) state favors photodissociation and disfavors O formation for and (OH groups). However, upon deprotonation (O groups), the MLCT state is accessible and can readily lead to O formation, but the dissociative MC state is energetically inaccessible. The changes to the energy of the MLCT state upon deprotonation have been confirmed by steady state luminescence experiments on - and their basic analogs, -. This energy landscape favors O formation for and and leads to enhanced toxicity for these complexes under physiological conditions. The ability to convert readily from OH to O groups allowed us to investigate an electronic change that is not accompanied by steric changes in this fundamental study.