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.

The conjugation of porphyrins to metal fragments is a strategy for making new compounds that are expected to combine the phototoxicity and the tumour-localization properties of the porphyrin chromophore with the cytotoxicity of the metal fragment for additive antitumour effect. We report here the preparation of new classes of porphyrin–ruthenium conjugates with potential bio-medical applications. Ruthenium was chosen because several Ru compounds have shown promising anticancer activity. The conjugation with the porphyrin moiety was accomplished either through peripheral pyridyl rings (e.g.meso-4′-tetrapyridylporphyrin, 4′TPyP) or through bpy units (e.g.meso-(p-bpy-phenyl)porphyrins, bpy_n-PPs, n = 1–4). The number of Ru fragments attached to the porphyrins ranges from 1 to 4 and the total charge of the conjugates from −4 to +8. Different types of peripheral fragments, both Ru(III) and Ru(II), have been used: in some cases they are structurally similar to established anticancer compounds. Examples are [Na]₄[4′TPyP{trans-RuCl₄(dmso-S)}₄] (2), that bears four NAMI-type Ru(III) fragments, or [4′TPyP{Ru([9]aneS3)(en)}₄][CF₃SO₃]₈ (3) and [bpy₄-PP{Ru([9]aneS3)(dmso-S)}₄][CF₃SO₃]₈ (9) (en = ethane-1,2-diamine, [9]aneS3 = 1,4,7-trithiacyclononane) that have four half-sandwich Ru(II) compounds. The Ru fragments may either contain one or more labile ligands, such as in 2 or in 9, or be coordinatively saturated and substitutionally inert, such as in 3 or in [bpy₄-PP{Ru([12]aneS4)}₄][CF₃SO₃]₈ (11) ([12]aneS4 = 1,4,7,10-tetrathiacyclododecane). Most of the ruthenium-porphyrin conjugates described in this work are soluble—at least moderately—in aqueous solution and are thus suitable for biological investigations, in particular for cytotoxicity and photo-cytotoxicity tests.