DNA intercalating Ru(II) polypyridyl complexes as effective photosensitizers in photodynamic therapy.

Six substitutionally inert [Ru(II) (bipy)2 dppz](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), CH2 OH (5), CH2 Cl (6)] were synthesized and studied as potential photosensitizers (PSs) in photodynamic therapy (PDT). As also confirmed by DFT calculations, all complexes showed promising (1) O2 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.

Mari C ，Pierroz V ，Rubbiani R ，Patra M ，Hess J ，Spingler B ，Oehninger L ，Schur J ，Ott I ，Salassa L ，Ferrari S ，Gasser G ... -  《-》

Evaluation of the Medicinal Potential of Two Ruthenium(II) Polypyridine Complexes as One- and Two-Photon Photodynamic Therapy Photosensitizers.

Two [Ru(phen)2 dppz]2+ derivatives (phen=1,10-phenantroline, dppz=dipyrido[3,2-a:2',3'-c]phenazine) with different functional groups on the dppz ligand [dppz-7,8-(OMe)2 (1), dppz-7,8-(OH)2 (2)] have been synthesized, characterized and investigated as photosensitizers (PSs) for photodynamic therapy (PDT) against cancer. Both complexes showed intense red phosphorescence and promising singlet oxygen (1 O2 ) quantum yields of 75 % (1) and 54 % (2) in acetonitrile. Complex 1 (logPo/w =-0.52, 2.4 nmol Ru per mg protein) was found to be more lipophilic, having also a higher cellular uptake efficiency compared to 2 (logPo/w =-0.20, 0.9 nmol Ru per mg protein). Complex 1 localized evenly in HeLa cells whereas 2, was mainly visualized in the cell membrane by confocal microscopy. In the dark, complex 1 (IC50 =36.5 μm) was found to be more toxic than complex 2 (IC50 >100 μm) on a HeLa cells monolayer. Importantly, in view of PDT applications, both complexes were found to be non-toxic in the dark towards multicellular HeLa spheroids (IC50 >100 μm). Upon one-photon irradiation (420 nm, 9.27 J cm-2 ), 1 exhibited higher phototoxicity (IC50 =3.1 μm) than 2 (IC50 =16.7 μm) on HeLa cell monolayers. When two-photon irradiation (800 nm, 9.90 J cm-2 ) was applied, only 1 (IC50 =9.5 μm) was found to be active toward HeLa spheroids. This study demonstrates that the functional group on the intercalative ligand has a strong influence on the cellular localization and anticancer activity of RuII polypyridyl complexes.

Hess J ，Huang H ，Kaiser A ，Pierroz V ，Blacque O ，Chao H ，Gasser G ... -  《-》

Critical Overview of the Use of Ru(II) Polypyridyl Complexes as Photosensitizers in One-Photon and Two-Photon Photodynamic Therapy.

Heinemann F ，Karges J ，Gasser G 《-》

Aryl-Substituted Ruthenium(II) Complexes: A Strategy for Enhanced Photocleavage and Efficient DNA Binding.

Abreu FD ，Paulo TF ，Gehlen MH ，Ando RA ，Lopes LGF ，Gondim ACS ，Vasconcelos MA ，Teixeira EH ，Sousa EHS ，de Carvalho IMM ... -  《-》

Luminescent ruthenium polypyridyl complexes with extended 'dppz' like ligands as DNA targeting binders and cellular agents.

Poulsen BC ，Estalayo-Adrián S ，Blasco S ，Bright SA ，Kelly JM ，Williams DC ，Gunnlaugsson T ... -  《-》