Bis[pyrrolyl Ru(ii)] triads: a new class of photosensitizers for metal–organic photodynamic therapy

A new family of ten dinuclear Ru(ii) complexes based on the bis[pyrrolyl Ru(ii)] triad scaffold, where two Ru(bpy)(2) centers are separated by a variety of organic linkers, was prepared to evaluate the influence of the organic chromophore on the spectroscopic and in vitro photodynamic therapy (PDT) properties of the compounds. The bis[pyrrolyl Ru(ii)] triads absorbed strongly throughout the visible region, with several members having molar extinction coefficients (ε) ≥ 10(4) at 600–620 nm and longer. Phosphorescence quantum yields (Φ(p)) were generally less than 0.1% and in some cases undetectable. The singlet oxygen quantum yields (Φ(Δ)) ranged from 5% to 77% and generally correlated with their photocytotoxicities toward human leukemia (HL-60) cells regardless of the wavelength of light used. Dark cytotoxicities varied ten-fold, with EC(50) values in the range of 10–100 μM and phototherapeutic indices (PIs) as large as 5400 and 260 with broadband visible (28 J cm(–2), 7.8 mW cm(–2)) and 625 nm red (100 J cm(–2), 42 mW cm(–2)) light, respectively. The bis[pyrrolyl Ru(ii)] triad with a pyrenyl linker (5h) was especially potent, with an EC(50) value of 1 nM and PI > 27 000 with visible light and subnanomolar activity with 625 nm light (100 J cm(–2), 28 mW cm(–2)). The lead compound 5h was also tested in a tumor spheroid assay using the HL60 cell line and exhibited greater photocytotoxicity in this more resistant model (EC(50) = 60 nM and PI > 1200 with 625 nm light) despite a lower dark cytotoxicity. The in vitro PDT effects of 5h extended to bacteria, where submicromolar EC(50) values and PIs >300 against S. mutans and S. aureus were obtained with visible light. This activity was attenuated with 625 nm red light, but PIs were still near 50. The ligand-localized (3)ππ* state contributed by the pyrenyl linker of 5h likely plays a key role in its phototoxic effects toward cancer cells and bacteria.