pubs.acs.org/Organometallics Published on Web 07/20/2010 r 2010 American Chemical Society 3632 Organometallics 2010, 29, 3632–3641 DOI: 10.1021/om100524x Ferrocene-Promoted Photoactivated DNA Cleavage and Anticancer Activity of Terpyridyl Copper(II) Phenanthroline Complexes Basudev Maity, † Mithun Roy, † Bhabatosh Banik, † Ritankar Majumdar, ‡ Rajan R. Dighe, ‡ and Akhil R. Chakravarty* ,† † Department of Inorganic and Physical Chemistry, ‡ Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India Received May 28, 2010 Ferrocene-appended copper(II) complexes [Cu(Fc-tpy)(B)](ClO 4 ) 2 (1-3) and [Cu(Ph-tpy)(dppz)]- (ClO 4 ) 2 (4) as control, where Fc-tpy is 4 0 -ferrocenyl-2,2 0 :6 0 ,2 00 -terpyridine, Ph-tpy is 4 0 -phenyl-2,2 0 :6 0 ,2 00 - terpyridine, and B is a phenanthroline base, viz., 1,10-phenanthroline (phen, 1), dipyridoquinoxaline (dpq, 2), and dipyridophenazine (dppz, 3), were prepared and structurally characterized, and their DNA binding, photoactivated DNA cleavage activity, and cytotoxic properties were studied [Fc = (η 5 - C 5 H 4 )Fe II (η 5 -C 5 H 5 )]. Complexes 1 and 3 as hexafluorophosphate salts were structurally characterized by X-ray crystallography. Molecular structures of [Cu(Fc-tpy)(phen)](PF 6 ) 2 (1a) and [Cu(Fc-tpy)(dppz)]- (PF 6 ) 2 3 MeCN (3a 3 MeCN) show a distorted square-pyramidal geometry at copper(II), with the Fc-tpy ligand and the phenanthroline base showing respective tridentate and bidentate binding modes. The phenanthroline base exhibits axial -equatorial bonding, while the Fc-tpy ligand binds at the basal plane. The complexes showed quasi-reversible cyclic voltammetric responses near 0.45 and -0.3 V vs SCE in aqueous DMF-0.1 M KCl assignable to the Fc þ -Fc and Cu(II)-Cu(I) redox couples, respectively. The complexes bind to DNA, giving K b values of 1.4  10 4 to 5.6  10 5 M -1 in the order 4 ∼ 3 > 2 > 1. Thermal denaturation and viscometric titration data suggest groove and/or partial intercalative mode of DNA binding of the complexes. The complexes showed chemical nuclease activity in the presence of 3-mercaptopropionic acid (0.5 mM) or H 2 O 2 (0.25 mM). Complexes 2-4 showed plasmid DNA cleavage activity in visible light, forming • OH radicals. The Fc-tpy complex 3 showed better DNA photocleavage activity than its Ph-tpy analogue. The ferrocene moiety in the dppz complex 3 makes it more photocytotoxic than the Ph-tpy analogue 4 in HeLa cells. Introduction Transition metal complexes showing anticancer activity have been extensively studied following the discovery of cisplatin and its analogues as transcription inhibitors. 1-8 The inherent dark toxicity and cellular resistivity have gener- ated subsequent interest to develop a new generation of platinum-based anticancer agents. Lippard and co-workers have recently reported Pt(IV) prodrugs that could generate cisplatin on intracellular reduction of the metal. 9 An alternate strategy could be to design organometallic compounds that are suitable as anticancer agents, as exemplified by titanocene dichloride, ferrocifen, and half-sandwich (arene)ruthenium complexes. 10-14 Ferrocene, with its significant lipophilicity, could result in better cell permeability and stability in biolo- gical aqueous medium, and its reversible redox property makes it suitable for designing ferrocene-based bioorganome- tallic species for therapeutic applications. 11,15-17 For exam- ple, the ferrocenyl moiety in ferrocifen, which is a ferrocene- conjugated tamoxifen, significantly augments the anticancer activity of tamoxifen. 11 Ferrocene itself is not cytotoxic, and it *To whom correspondence should be addressed. Fax: 91-80-23600683. E-mail: arc@ipc.iisc.ernet.in. (1) Rosenberg, B.; van Camp, L.; Trosko, J. E.; Mansour, V. H. Nature 1969, 222, 385–386. (2) Jung, Y.; Lippard, S. J. Chem. Rev. 2007, 107, 1387–1407. (3) Guo, Z.; Sadler, P. J. Angew. Chem., Int. Ed. 1999, 38, 1512–1531. (4) Reedijk, J. Eur. J. Inorg. Chem. 2009, 1303–1312. (5) Galanski, M.; Keppler, B. Anti-cancer Agents in Med. Chem. 2007, 7, 55–73. (6) Kelland, L. Nat. Rev. Cancer 2007, 7, 573–584. (7) Mao, J.; Zhang, Y.; Zhu, J.; Zhang, C.; Guo, Z. Chem. Commun. 2009, 908–910. (8) Singh, T. N.; Turro, C. Inorg. Chem. 2004, 43, 7260–7262. (9) (a) Dhar, S.; Lippard, S. J. Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 22199–22204. (b) Dhar, S.; Liu, Z.; Thomale, J.; Dai, H.; Lippard, S. J. J. Am. Chem. Soc. 2008, 130, 11467–11476. (c) Lovejoy, K. S.; Lippard, S. J. Dalton Trans. 2009, 10651–10659. (10) K€ opf-Maier, P. Anticancer Res. 1999, 19, 493–504. (11) Jaouen, G.; Top, S.; Vessires, A.; Leclercq, G.; McGlinchey, M. J. Curr. Med. Chem. 2004, 11, 2505–2517. (12) Peacock, A. F. A.; Sadler, P. J. Chem. Asian J. 2008, 3, 1890– 1899. (13) Bergamo, A.; Sava, G. Dalton Trans. 2007, 1267–1272. (14) (a) Allardyce, C. S.; Dorcier, A.; Scolaro, C.; Dyson, P. J. Appl. Organomet. Chem. 2005, 19,1–10. (b) Hartinger, C. G.; Dyson, P. J. Chem. Soc. Rev. 2009, 38, 391–401. (15) Van Staveren, D. R.; Metzler-Nolte, N. Chem. Rev. 2004, 104, 5931–5985. (16) Fouda, M. F. R.; Abd-Elzaher, M. M.; Abdelsamaia, R. A.; Labib, A. A. Appl. Organomet. Chem. 2007, 21, 613–625. (17) Swarts, J. C.; Vosloo, T. G.; Cronje, S. J.; Du Plessis, W. C.; Van Rensburg, C. E. J.; Kreft, E.; Van Lier, J. E. Anticancer Res. 2008, 28, 2781–2784.