Modulating Excited State Properties and Ligand Ejection Kinetics in Ruthenium Polypyridyl Complexes Designed to Mimic Photochemotherapeutics

Ruthenium(II) polypyridyl complexes have gained significant interest as photochemotherapeutics (PCTs) due to their synthetic viability, strong light absorption, well understood excited state properties, and high phototoxicity indexes. Herein, we report the synthesis, characterization, electrochemical, spectrochemical, and preliminary cytotoxicity analyses of three series of ruthenium(II) polypyridyl complexes designed to mimic PCTs. The three series have the general structure of Ru(bpy)2(N–N)2+ (Series 1), Ru(bpy)(dmb)(N–N)2+ (Series 2), and Ru(dmb)2(N–N)2+ (Series 3, where N–N is a bidentate polypyridyl ligand, bpy = 2,2′-bipyridine, and dmb = 6,6′-dimethyl-2,2′-bipyridine). In the three series, the N–N ligand was systematically modified to incorporate increased conjugation and/or electronegative heteroatoms to increase dπ-π* backbonding, red-shifting the lowest energy metal-to-ligand charge transfer (MLCT) absorptions from λmax = 454 to λmax = 580 nm, nearing the therapeutic window for PCTs (600–1100 nm). In addition, steric bulk was systematically introduced through the series, distorting the Ru(II) octahedra, making the dissociative 3dd* state thermally accessible at room and body temperatures. This resulted in a 4 orders of magnitude increase in photoinduced ligand ejection kinetics, and demonstrates the ability to modulate both the MLCT* and dd* manifolds in the complexes, which is critical in PCT drug design. Preliminary cell viability assays suggest that the increased steric bulk to lower the 3dd* states may interfere with the cytotoxicity mechanism, limiting photoinitiated toxicity of the complexes. This work demonstrates the importance of understanding both the MLCT* and dd* manifolds and how they impact the ability of a complex to act as a PCT agent.