DNA has a strong affinity for many heterocyclic aromatic dyes, such as acridine 
and its derivatives. Lerman in 1961 first proposed intercalation as the source 
of this affinity, and this mode of DNA binding has since attracted considerable 
research scrutiny. Organic intercalators can inhibit nucleic acid synthesis in 
vivo, and they are now common anticancer drugs in clinical therapy. The covalent 
attachment of organic intercalators to transition metal coordination complexes, 
yielding metallointercalators, can lead to novel DNA interactions that influence 
biological activity. Metal complexes with σ-bonded aromatic side arms can act as 
dual-function complexes: they bind to DNA both by metal coordination and through 
intercalation of the attached aromatic ligand. These aromatic side arms 
introduce new modes of DNA binding, involving mutual interactions of functional 
groups held in close proximity. The biological activity of both cis- and 
trans-diamine Pt(II) complexes is dramatically enhanced by the addition of 
σ-bonded intercalators. We have explored a new class of organometallic 
"piano-stool" Ru(II) and Os(II) arene anticancer complexes of the type 
[(η(6)-arene)Ru/Os(XY)Cl](+). Here XY is, for example, ethylenediamine (en), and 
the arene ligand can take many forms, including tetrahydroanthracene, biphenyl, 
or p-cymene. Arene-nucleobase stacking interactions can have a significant 
influence on both the kinetics and thermodynamics of DNA binding. In particular, 
the cytotoxic activity, conformational distortions, recognition by DNA-binding 
proteins, and repair mechanisms are dependent on the arene. A major difficulty 
in developing anticancer drugs is cross-resistance, a phenomenon whereby a cell 
that is resistant to one drug is also resistant to another drug in the same 
class. These new complexes are non-cross-resistant with cisplatin towards cancer 
cells: they constitute a new class of anticancer agents, with a mechanism of 
action that differs from the anticancer drug cisplatin and its analogs. The 
Ru-arene complexes with dual functions are more potent towards cancer cells than 
their nonintercalating analogs. In this Account, we focus on recent studies of 
dual-function organometallic Ru(II)- and Os(II)-arene complexes and the methods 
used to detect arene-DNA intercalation. We relate these interactions to the 
mechanism of anticancer activity and to structure-activity relationships. The 
interactions between these complexes and DNA show close similarities to those of 
covalent polycyclic aromatic carcinogens, especially to N7-alkylating 
intercalation compounds. However, Ru-arene complexes exhibit some new features. 
Classical intercalation and base extrusion next to the metallated base is 
observed for {(η(6)-biphenyl)Ru(ethylenediamine)}(2+) adducts of a 14-mer 
duplex, while penetrating arene intercalation occurs for adducts of the 
nonaromatic bulky intercalator 
{(η(6)-tetrahydroanthracene)Ru(ethylenediamine)}(2+) with a 6-mer duplex. The 
introduction of dual-function Ru-arene complexes introduces new mechanisms of 
antitumor activity, novel mechanisms for attack on DNA, and new concepts for 
developing structure- activity relationships. We hope this discussion will 
stimulate thoughtful and focused research on the design of anticancer 
chemotherapeutic agents using these unique approaches.