Bis[Pyrrolyl Ru(II)] Triads: a New Class of Photosensitizers for Metal-Organic Photodynamic Therapy

Abstract

A new family of ten dinuclear Ru(II) complexes based on the bis[pyrrolyl Ru(II)] triad scaffold, where two Ru(bpy)<sub>2</sub> 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 (e) ≥10<sup>4</sup> at 600–620 nm and longer. Phosphorescence quantum yields were generally less than 0.1% and in some cases undetectable. The singlet oxygen quantum yields 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<sub>50</sub> values in the range of 10–100 µM and phototherapeutic indices (PIs) as large as 5,400 and 260 with broadband visible (28 J cm<sup>-2</sup>, 7.8 mW cm<sup>-2</sup>) and 625-nm red (100 J cm<sup>-2</sup>, 42 mW cm<sup>-2</sup>) light, respectively. The bis[pyrrolyl Ru(II)] triad with a pyrenyl linker (5h) was especially potent, with an EC50 value of 1 nM and PI >27,000 with visible light and subnanomolar activity with 625-nm light (100 J cm<sup>-2</sup>, 28 mW cm<sup>-2</sup>). The lead compound 5h was also tested in a tumor spheroid assay using the HL60 cell line and exhibited greater photocytotoxcicity in this more resistant model (EC<sub>50</sub>=60 nM and PI>1,200 with 625-nm light) despite a lower dark cytotoxicity. The in vitro PDT effects of 5h extended to bacteria, where submicromolar EC<sub>50</sub> values and PIs >300 against <i>S. mutans</i> and <i>S. aureus </i>were obtained with visible light. This activity was attenuated with 625-nm red light, but PIs were still near 50. The ligand-localized <sup>3</sup>ππ* state contributed by the pyrenyl linker of 5h likely plays a key role in its phototoxic effects toward cancer cells and bacteria.<br><br>

Unexpectedly Long Lifetime of the Excited State of Benzothiadiazole Derivative and Its Adducts with Lewis Acids

“…To the best of our knowledge, only two works have been reported on purely organic phosphorescent Br-substituted 2,1,3-benzothiadiazoles [ 44 , 45 ], and a few more works have been devoted to organic non-bromine 2,1,3-benzothiadiazoles showing microsecond lifetimes [ 46 , 47 , 48 ]. Metal-containing phosphorescent benzothiadiazoles are more abundant, but examples of metals are predominantly represented by precious Pt(II) [ 49 , 50 , 51 ], Au(III) [ 52 ], Au(I) [ 53 ], Ir(III) [ 54 , 55 ] and Ru(II) [ 56 ].…”