Dual Triggering of DNA Binding and Fluorescence via Photoactivation of a Dinuclear Ruthenium(II) Arene Complex Steven W. Magennis,* ,² Abraha Habtemariam, ‡ Olga Novakova, § John B. Henry, ‡ Samuel Meier, ‡ Simon Parsons, ‡ Iain D. H. Oswald, ‡ Viktor Brabec, § and Peter J. Sadler* ,‡ School of Physics and the CollaboratiVe Optical Spectroscopy, Micromanipulation and Imaging Centre (COSMIC), The UniVersity of Edinburgh, King’s Buildings, Edinburgh EH9 3JZ, U.K., School of Chemistry, The UniVersity of Edinburgh, King’s Buildings, Edinburgh EH9 3JJ, U.K., and Institute of Biophysics, Academy of Sciences of the Czech Republic, V.i.i. KraloVopolska 135, CZ-61265 Brno, Czech Republic Received November 6, 2006 The dinuclear Ru II arene complexes [{(η 6 -arene)RuCl} 2 (µ-2,3-dpp)](PF 6 ) 2 , arene ) indan (1), benzene (2), p-cymene (3), or hexamethylbenzene (4) and 2,3-dpp ) 2,3-bis(2-pyridyl)pyrazine, have been synthesized and characterized. Upon irradiation with UVA light, complexes 1 and 2 readily underwent arene loss, while complexes 3 and 4 did not. The photochemistry of 1 was studied in detail. In the X-ray structure of [{(η 6 -indan)RuCl} 2 (µ-2,3-dpp)](PF 6 ) 2 (1), 2,3-dpp bridges two Ru II centers 6.8529(6) Å apart. In water, aquation of 1 in the dark occurs with replacement of chloride with biexponential kinetics and decay constants of 100 ± 1 min -1 and 580 ± 11 min -1 . This aquation was suppressed by 0.1 M NaCl. UV or visible irradiation of 1 in aqueous or methanolic solution led to arene loss. The fluorescence of the unbound arene is ∼40 times greater than when it is complexed. Irradiation of 1 also had a significant effect on its interactions with DNA. The DNA binding of 1 is increased after irradiation. The non-irradiated form of 1 preferentially formed DNA adducts that only weakly blocked RNA polymerase, while irradiation of 1 transformed the adducts into stronger blocks for RNA polymerase. The efficiency of irradiated 1 to form DNA interstrand cross-links was slightly greater than that of cisplatin in both 10 mM NaClO 4 and 0.1 M NaCl. In contrast, the interstrand cross-linking efficiency of non-irradiated 1 in 10 mM NaClO 4 was relatively low. An intermediate amount of cross-linking was observed when the sample of DNA already modified by non-irradiated 1 was irradiated. DNA unwinding measurements supported the conclusion that both mono- and bifunctional adducts with DNA can form. These results show that photoactivation of dinuclear Ru II arene complexes can simultaneously produce a highly reactive ruthenium species that can bind to DNA and a fluorescent marker (the free arene). Importantly, the mechanism of photoreactivity is also independent of oxygen. These complexes, therefore, have the potential to combine both photoinduced cell death and fluorescence imaging of the location and efficiency of the photoactivation process. Introduction Anticancer treatments that use site-selective photoinduced cytotoxicity have the potential to eliminate the unwanted side effects of conventional chemotherapy by avoiding damage to healthy cells. Photoactivation may also allow new and more toxic reaction pathways to be accessed. Photodynamic therapy (PDT), which involves the use of drugs (usually porphyrins or related molecules) that absorb light and subsequently react with cellular components to produce cytotoxic species, has received the most attention to date. 1 The most widely used drug, Photofrin, is an ill-defined mixture of up to 60 different substances and remains in the body for six to eight weeks, resulting in prolonged skin sensitivity. Photofrin requires oxygen for its mechanism of toxicity in PDT, even though tumors often have poor oxygen * To whom correspondence should be addressed. E-mail: s.magennis@ ed.ac.uk (S.W.M.); p.j.sadler@ed.ac.uk (P.J.S.). ² School of Physics and Collaborative Optical Spectroscopy, Microma- nipulation and Imaging Centre (COSMIC), The University of Edinburgh. ‡ School of Chemistry, The University of Edinburgh. § Institute of Biophysics, Academy of Sciences of the Czech Republic. (1) Dolmans, D. E. J. G. J.; Fukumura, D.; Jain, R. K. Nat. ReV. Cancer 2003, 3, 380-387. Inorg. Chem. 2007, 46, 5059-5068 10.1021/ic062111q CCC: $37.00 © 2007 American Chemical Society Inorganic Chemistry, Vol. 46, No. 12, 2007 5059 Published on Web 05/12/2007