Interactions of Metal-Metal-Bonded Antitumor Active Complexes with DNA Fragments and DNA HELEN T. CHIFOTIDES AND KIM R. DUNBAR* Department of Chemistry, Texas A&M University, College Station, Texas 77843 Received September 1, 2004 ABSTRACT This Account summarizes the DNA binding properties of anticancer active dinuclear Rh, Re, and Ru compounds. The combined results of NMR spectroscopy, X-ray crystallography, and various biochemi- cal tools provide incontrovertible evidence that dinuclear com- plexes are favorably poised to bind to purine nucleobases, DNA fragments, and double-stranded DNA. Moreover, direct DNA photocleavage in vitro is effected by dirhodium compounds in the presence of electron acceptors in solution or directly attached to the dirhodium core. This research has provided valuable insight in the interactions of dinuclear compounds with DNA, knowledge that is an excellent backdrop for rational design of promising dinuclear drugs. Introduction The medicinal properties of inorganic compounds are well-known, dating to ancient times, with the earliest recognition being traced back to the Egyptians who used copper to sterilize water in 3000 B.C. Presently, metal compounds that exhibit antiarthritic, antibacterial, anti- cancer, antidepressant, and anti-hypertensive properties are in routine clinical use. Interest in metal antitumor compounds stems from the extraordinary effectiveness of cisplatin (cis-[Pt(NH 3 ) 2 Cl 2 ] or cis-DDP) 1-3 and related complexes for the treatment of ovarian, testicular, head, neck, esophageal, and lung carcinomas, with a cure rate greater than 90% in the case of testicular cancer. Extensive investigations of this potent antitumor agent have estab- lished DNA as its primary intracellular target. The intras- trand d(GpG) head-to-head (H-H) cross-links that are formed contribute to a cascade of events, including transcription inhibition and repair shielding of cisplatin- DNA lesions, which lead to cell death. 1-3 The success of cisplatin notwithstanding, it is important to continue the search for new anticancer active metal compounds with different activities and resistances as well as lower tox- icities. Among the recognized non-platinum antitumor agents are dinuclear carboxylate species of rhodium (Rh), 4 rhe- nium (Re), 5,6 and ruthenium (Ru). 7 The basic paddlewheel structure of these compounds, which consists of a metal- metal-bonded fragment with at least two bridging ligands (Chart 1), appears to defy most of the accepted guidelines for metal anticancer agents. The recognition of the anticancer activity of tetracarboxylate compounds spawned a number of investigations in the 1970s regarding plau- sible cellular targets, 8,9 but research in this area steadily declined, in part, because the compounds did not surpass the anticancer activity of cisplatin. The revival of this research field in our laboratories over the past decade has been directed towards elucidating the biological activity of metal-metal-bonded systems vis-a `-vis interactions with DNA, which is the primary target of platinum antican- cer agents. Our findings provide valuable insight in the viable substitution pathways and binding modes of di- metal units with DNA and pave the way for rational design of promising anticancer and photochemotherapeutic candidates. Prior to highlighting our results, a brief overview of the biological activity of each class of com- pounds is presented. Biological Activity of the Compounds Dirhodium. Studies of the biological activity of dirhodium complexes conducted in the 1970s support the conclusion that tetracarboxylate compounds Rh 2 (μ-O 2 CR) 4 (R ) Me, Et, Pr) exhibit significant in vivo antitumor activity against L1210 tumors, 10 Ehrlich ascites, 8,9,11,12 sarcoma 180, and P388 tumor lines. 4 Although the precise antitumor mech- anism of dirhodium carboxylate compounds has not been elucidated, it is known that they bind to DNA 8,9,13-15 and inhibit DNA replication and protein synthesis 16-18 in a manner akin to cisplatin. A systematic variation of the axial (ax) and equatorial (eq) ligands has shed light on the structure-activity relationships in this family of compounds. Of particular note is the fact that the antitumor activity increases in the series Rh 2 (μ-O 2 CR) 4 (R ) Me, Et, Pr) (Chart 1, struc- ture a) with the lipophilicity of the R group. 8,10,11 The compounds Rh 2 (μ-O 2 CCF 3 ) 4 (Chart 1, structure a) and Rh 2 (μ-HNCOCF 3 ) 4 (Chart 1, structure b) have been re- ported to significantly increase the survival rate of mice bearing Ehrlich ascites cells and have LD 50 values on the same order as that of cisplatin. 19,20 The most active member of the methoxyphenylphosphine series is the * To whom correspondence should be addressed. E-mail: dunbar@mail.chem.tamu.edu. Kim R. Dunbar was born in Mount Pleasant, PA, and received a B.S. from Westminster College in 1980 and a Ph.D. from Purdue University in 1984. She joined the faculty of Michigan State University in 1987 and moved to Texas A&M University in 1999 where she holds the position of Davidson Chair of Science. Her research interests span topics in synthetic and structural inorganic chemistry with a focus on materials and bioinorganic chemistry. She has been named a Fellow of the Alfred P. Sloan Foundation and the American Association for the Advancement of Science and a Camille and Henry Dreyfus Teacher -Scholar. She is an Associate Editor for the journal Inorganic Chemistry and Secretary of the ACS Division of Inorganic Chemistry. Helen T. Chifotides was born in Providence, RI, and received her B.S. and Ph.D. degrees in Chemistry from the University of Athens, Greece. After a NATO Postdoctoral Fellowship at Michigan State University (1994-1995), she was appointed as a Lecturer in Chemistry at Oregon State University (1995-1997). She held a senior staff scientist position in the Biochemistry Laboratory of the Pulmonary Hospital ‘Sotiria’ in Athens, Greece, until 2001. Currently, she is a Senior Research Associate at Texas A&M University. Her research interests focus on the interactions of mononuclear and dinuclear metal complexes with DNA and other biologically active molecules. Acc. Chem. Res. 2005, 38, 146-156 146 ACCOUNTS OF CHEMICAL RESEARCH / VOL. 38, NO. 2, 2005 10.1021/ar0302078 CCC: $30.25  2005 American Chemical Society Published on Web 02/15/2005