Green-Light-Activated Ru(II)-Anthraquinone Photocatalyst: Evaluation of Catalytic NADH/NADPH Photooxidation and Redox-Mediated Photocytotoxicity

Herein, we report the design, synthesis, and molecular characterization of a highly oxidative Ru(II)-based photocatalyst: [Ru(TPA)(qdppz)]PF 6 [Ru1], where TPA is tris(2-pyridylmethyl)amine and qdppz represents 12,17-dihydronaphtho-[2,3-h]dipyrido[3,2-a:2′,3′-c]-phenazine-12,17-dione. The MLCT band of [Ru1] complex at 485 nm enabled a green-light-induced photocatalytic chemotherapeutic modality. The conjugation of the quinone moiety to the [Ru(TPA)] core significantly enhances the lipophilicity of [Ru1], facilitating its cellular uptake. The photostable complex demonstrated good photocytotoxicity under green light irradiation with a high selectivity index (SI) against HepG2 cancer cells, with an IC 50 of 16.34 μM (SI = 7) in normoxia and an IC 50 of 45.68 μM (SI = 3) under hypoxic conditions. Furthermore, the [ Ru1 ] complex also presents anticlonogenic activity, as evidenced by the colony formation assay. ROS generation was identified in the HepG2 cell lines in the presence of green light and the [Ru1] complex, which was verified using an in vivo DCFDA assay. Mechanistic investigations reveal that, under green light irradiation, the [Ru1] complex exhibits synergistic Type I/II photosensitization and photocatalytically oxidizes NADH and NADPH to NAD + /NADP + in biological media (PBS) with high turnover frequencies (TOF) of 104.73 h –1 and 136.79 h –1, respectively. Overall, [Ru1] represents a promising new approach for developing efficient Ru(II)-based complexes for cancer photochemotherapy by inducing intracellular redox imbalance.