DNA Intercalating RuII Polypyridyl Complexes as Effective Photosensitizers in Photodynamic Therapy

Six substitutionally inert [RuII(bipy)2dppz]2+ derivatives (bipy=2,2′‐bipyridine, dppz=dipyrido[3,2‐a:2′,3′‐c]phenazine) bearing different functional groups on the dppz ligand [NH2 (1), OMe (2), OAc (3), OH (4), CH2OH (5), CH2Cl (6)] were synthesized and studied as potential photosensitizers (PSs) in photodynamic therapy (PDT). As also confirmed by DFT calculations, all complexes showed promising 1O2 production quantum yields, well comparable with PSs available on the market. They can also efficiently intercalate into the DNA double helix, which is of high interest in view of DNA targeting. The cellular localization and uptake quantification of 1–6 were assessed by confocal microscopy and high‐resolution continuum source atomic absorption spectrometry. Compound 1, and especially 2, showed very good uptake in cervical cancer cells (HeLa) with preferential nuclear accumulation. None of the compounds studied was found to be cytotoxic in the dark on both HeLa cells and, interestingly, on noncancerous MRC‐5 cells (IC50>100 μM). However, 1 and 2 showed very promising behavior with an increment of about 150 and 42 times, respectively, in their cytotoxicities upon light illumination at 420 nm in addition to a very good human plasma stability. As anticipated, the preferential nuclear accumulation of 1 and 2 and their very high DNA binding affinity resulted in very efficient DNA photocleavage, suggesting a DNA‐based mode of phototoxic action. Fear the reaper: Six RuII polypyridyl complexes were fully characterized and evaluated as potential photosensitizers for photodynamic therapy applications. Two displayed impressive phototoxic activity upon irradiation at 420 nm and extremely competitive phototoxic indexes. The good cellular uptake, together with preferential nuclear accumulation and very efficient light induced DNA cleavage suggest a DNA‐based mode of phototoxic action.