The development of new metal anticancer compounds is a challenge for inorganic chemists. We have to face the fact that four decades of research in this field have only produced a small number of clinically used compounds, most often developed through serendipity rather than through rational chemical design. Nevertheless, by virtue of the wealth of knowledge acquired in these years, medicinal inorganic chemistry is probably mature for making significant steps forward and there are great expectations for future developments. With the aim of contributing to the rationalization of this field, we suggest here a categorization of metal anticancer compounds into five classes based on their mode of action: (i) the metal has a functional role, i.e. it must bind to the biological target; (ii) the metal has a structural role, i.e. it is instrumental in determining the shape of the compound and binding to the biological target occurs through non-covalent interactions; (iii) the metal is a carrier for active ligands that are delivered in vivo; (iv) the metal compound is a catalyst; and (v) the metal compound is photoactive and behaves as a photo-sensitizer. Selected examples for each category are given. The few metal anticancer drugs that are in clinical use are all believed to be functional compounds. Our classification, that is clearly focused on the metal compound and is independent from the nature of its bio-target(s)—most often still unknown—has the purpose of providing an intellectual tool that might be helpful in the rational development of new drugs.

Two ruthenium compounds, namely [ImH]trans-[RuCl4(Im)(dmso-S)] (NAMI-A, Im = imidazole) and [IndH] trans-[RuCl4(Ind)2] (KP1019, Ind = indazole) have already completed phase I clinical trials as anticancer agents. They both have properties different from platinum anticancer drugs: for example, NAMI-A is selectively active against metastases of solid tumors. They show that in the field of anticancer metal drugs a new approach, based on targeted therapies, is possible. After a concise history of ruthenium anticancer compounds, this contribution will focus on ruthenium-dmso complexes and, in particular, on NAMI-A. Particular emphasis is given on the challenges that are inherent to this field: how to develop new anticancer ruthenium compounds and how to select new active compounds that manifest their anticancer activity through non-conventional mechanisms.

In this study, we have developed a series of new monofunctional Ru(II) complexes of the general formula mer-[Ru(Cl-Ph-tpy)(N-N)Cl]Cl in which Cl-Ph-tpy is 4'-(4-chlorophenyl)-2,2':6',2″-terpyridine, N-N is a bidentate chelating ligand (1,2-diaminoethane (en, 1), 1,2-diaminocyclohexane (dach, 2) or 2,2'-bipyridine (bpy, 3)). All complexes were fully characterized by elemental analysis and spectroscopic techniques (IR, UV-Vis, 1D and 2D NMR). Their chemical behavior in aqueous solution was studied by UV-Vis and NMR spectroscopy showing that all compounds are relatively labile leading to the formation of the corresponding aqua species 1aq-3aq. Their DNA binding ability was evaluated by UV-Vis spectroscopy, fluorescence quenching measurements and viscosity measurements. Competitive studies with ethidium bromide (EB) showed that the complexes can displace DNA-bound EB, suggesting strong competition with EB (Ksv=1.1-2.7×104M-1). These experiments show that the ruthenium complexes interact with DNA via intercalation. The complexes bind to serum protein albumin displaying relatively high binding constants (Ksv=104-105M-1). Compound 3 displayed from high to moderate cytotoxicity against two cancer cell lines HeLa and A549 (with IC50ca. 12.7μM and 53.8μM, respectively), while complexes 1 and 2 showed only moderate cytotoxicity (with IC50ca. 84.8μM and 96.3μM, respectively) against HeLa cells. The cell cycle analysis (by flow cytometry) of HeLa and A549 cells treated with complex 3 shows minor changes on the cell cycle phase distribution.