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

ABSTRACT: We report the synthesis and photochemical and biological characterization of Ru(II) complexes containing ?-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 (? = 46-50 ?s), consistent with efficient 1O2 production through population and subsequent decay of ligand-centered 3??* 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 ?-expansive ligands is not required to achieve photoactivated cell death.

SUBMITTER: Toupin NP 

PROVIDER: S-EPMC7539634 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature