Dual-Action Ru(II) Complexes with Bulky π‑Expansive Ligands: Phototoxicity without DNA Intercalation

We report the synthesis and photochemical and biological characterization of Ru­(II) complexes containing π-expansive ligands derived from dimethylbenzo­[i]­dipyrido­[3,2-a:2′,3′-c]­phenazine (Me₂dppn) adorned with flanking aryl substituents. Late-stage Suzuki couplings produced Me₂dppn ligands substituted at the 10 and 15 positions with phenyl (5), 2,4-dimethylphenyl (6), and 2,4-dimethoxyphenyl (7) groups. Complexes of the general formula [Ru­(tpy)­(L)­(py)]­(PF₆)₂ (8–10), where L = 4–7, were characterized and shown to have dual photochemotherapeutic (PCT) and photodynamic therapy (PDT) behavior. Quantum yields for photodissociation of monodentate pyridines from 8–10 were about 3 times higher than that of parent complex [Ru­(tpy)­(Me₂dppn)­(py)]­(PF₆)₂ (1), whereas quantum yields for singlet oxygen (¹O₂) production were ∼10% lower than that of 1. Transient absorption spectroscopy indicates that 8–10 possess long excited state lifetimes (τ = 46–50 μs), consistent with efficient ¹O₂ production through population and subsequent decay of ligand-centered ³ππ* excited states. Complexes 8–10 displayed greater lipophilicity relative to 1 and association to DNA but do not intercalate between the duplex base pairs. Complexes 1 and 8–10 showed photoactivated toxicity in breast and prostate cancer cell lines with phototherapeutic indexes, PIs, as high as >56, where the majority of cell death was achieved 4 h after treatment with Ru­(II) complexes and light. Flow cytometric data and rescue experiments were consistent with necrotic cell death mediated by the production of reactive oxygen species, especially ¹O₂. Collectively, this study confirms that DNA intercalation by Ru­(II) complexes with π-expansive ligands is not required to achieve photoactivated cell death.