Cisplatin is currently employed as the first step in treating a variety of cancers, including metastatic breast and ovarian tumours,[1] and it achieves its toxicity by irreversibly creating intrastrand DNA cross-links, provoking a cellular DNA damage response and ultimately leading to programmed cell death or cell cycle arrest.[2] However, acquired drug resistance represents a key challenge in platinum-based chemotherapy and there remains a significant need for therapeutic strategies that address the emergence of cisplatin resistance in tumours.[3] Since the observation that [Ru (bpy) 2 (dppz)] 2+(bpy: 2, 2’-bipyridine; dppz: dipyrido [3, 2-a: 2’, 3’-c] phenazine) and [Ru-(phen) 2 (dppz)] 2+(phen: 1, 10-phenanthroline) function as “light switches” upon reversibly binding to DNA—they display quenched luminescence in aqueous media but emission from a 3 MLCT (metal-to-ligand charge transfer) excited state as a result of intercalation [4]—there has been a burgeoning interest in d6 transition metal polypyridyl coordination complexes that reversibly bind to DNA. Such work has particularly centred on structure-and site-specific DNA probes [5] but more recently there has been growing attention on further developing these complexes for application as imaging agents in living biological systems [6] while cytotoxicity studies on these systems have shown the importance of ancillary and intercalating ligand to be apparent in the overall toxicity.[7] In this context, the biological activity of RuII “light switch” systems is of great interest and, conceptually, the therapeutic application is particularly attractive, as light switch complexes bind to DNA by an entirely different mechanism to cisplatin (through reversible interactions—usually intercalation—rather than irreversible coordination), and so cytotoxic metallo-intercalators are predicted to remain active against cells with acquired cisplatin resistance. Here, we report the successful cellular uptake of two [Ru (L) 2-(tpphz)] 2+ intercalating systems into live cancer cells (tpphz: tetrapyrido [3, 2-a: 2’, 3’-c: 3’’, 2’’-h: 2’’’, 3’’’-j] phenazine; 1L: bpy; 2L: phen; Scheme 1). These complexes are multifunctional in cellulo imaging probes and also display cytotoxicity. Using their properties as imaging agents, their ability to bind to cellular DNA in live and fixed cells was confirmed by confocal laser scanning microscopy (CLSM) and transmission electron microscopy (TEM), and we found their cytotoxic potency towards cancer cells to be similar in magnitude to cisplatin. Strikingly, this toxicity is retained even with cisplatin resistant cancer cells.

Complexes 1 and 2 were prepared as described previously,[8] and although the in vitro DNA binding properties of 1 have been previously reported,[9] corresponding data for 2 have not been reported. Optical absorption and emission response of 2 to the addition of calf thymus DNA (CT-DNA) in addition to viscosity studies showed that this complex binds to DNA through intercalation and displays an in vitro DNA light-switch effect (Figure 1 and Figure S1 in the Supporting Information). By fitting the emission data to the McGhee–von Hippel model for binding to an isotropic lattice,[10] the equilibrium binding constant, Kb, was estimated to be 3.0 105 MÀ1, a similar order of