DNA binding mode of ruthenium complexes and relationship to tumor cell toxicity
Transition-metal-based compounds constitute a discrete class of chemotherapeutics, widely used in the clinic as antitumor and antiviral agents. Examples of established antitumor metallodrugs, routinely used in the clinic, are cisplatin [cis-diamminedichloroplatinum(II)] and its analogues carboplatin and oxaliplatin. However, drug resistance and side effects have limited their clinical utility. These limitations have prompted a search for more effective and less toxic metal-based antitumor agents. Some of the efforts have been directed in the design of non-platinum, transition-metal-based antitumor agents and ruthenium complexes have attracted much interest as alternative drugs to cisplatin in cancer chemotherapy. Ruthenium complexes demonstrate similar ligand exchange kinetics to those of platinum(II) antitumor drugs already used in the clinic while displaying only low toxicity. This is in part due to the ability of ruthenium complexes to mimic the binding of iron to molecules of biological significance, exploiting the mechanisms that the body has evolved for transport of iron. In addition, the redox potential between the different accessible oxidation states occupied by ruthenium complexes enables the body to catalyze oxidation and reduction reactions, depending on physiological environment. The biochemical changes that accompany cancer alter physiological environment, enabling ruthenium complexes to be selectively activated in cancer tissues. Due to differing ligand geometry between their complexes, ruthenium compounds bind to DNA affecting its conformation differently than cisplatin and its analogues. In addition, nonnuclear targets, such as the mitochondrion and the cell surface, have also been implicated in the antineoplastic activity of some ruthenium complexes. Thus, ruthenium compounds offer the potential over antitumor platinum(II) complexes currently used in the clinic of reduced toxicity, a novel mechanism of action, the prospect of non-cross-resistance and a different spectrum of activity. In other words, some chemical properties make ruthenium compounds well suited for medicinal applications and as an alternative to platinum antitumor drugs in the treatment of cancer cells resistant to cisplatin. Although the pharmacological target for antitumor ruthenium compounds has not been unequivocally identified. there is a large body of evidence indicating that the cytotoxicity of many ruthenium complexes correlates with their ability to bind DNA although few exceptions have been reported. This review summarizes results demonstrating that several ruthenium compounds that exhibit antitumor effects different from cisplatin or its analogues bind DNA and modify it differently than cisplatin or its analogues. (c) 2006 Elsevier Ltd. All rights reserved.