Ruthenium-Arene Anticancer Drugs

The first report on the anticancer properties of ruthenium was published in 1976 when the Ru(III) compound /ac-[RuC13(NH3)3] (Fig. 11) was found to induce filamentous growth of Escherichia coli at concentrations comparable to those at which cisplatin generates similar effects (49). This Ru(III) complex and related compounds such as cis-[RuCl2(NH3)4]Cl illustrated the potential anticancer activity of ruthenium complexes, but insolubility prevented further pharmacological use. Since these initial studies, other Ru(III) complexes have been studied for potential anticancer activity, and two compounds, NAMI-A (50) and KP1019 (51), are currently undergoing clinical trials. Remarkably, 

Other active areas of research into the anticancer properties of ruthenium(II) complexes, include, amongst several other examples, the related work on RAPTA ruthenium-arene 

General Features of Ruthenium-Arene Anticancer Drugs 

General Structural Features. The general structure of halfsandwich ruthenium(II)-arene complexes is shown in Fig. 12. The structural, stereochemical and electronic features of metal-arene complexes have been discussed (63). A typical piano-stool geometry consists of an rj6-arene occupying three coordination sites of the pseudo-octahedral complex, leaving the three legs X, Y, and Z available for coordination. The sites X and Y can be taken up by two monodentate ligands, but are more commonly 

We have also recently explored some ruthenium-arene complexes that depart markedly from the general structure described above. For instance, full-sandwich ruthenium complexes have been synthesized, in which the positions X, Y, and Z are taken by an rj6-arene ring of a biologically active ligand, such as aspartame, to assess the influence of a metal complex as a modulating substituent on the properties of the bioactive ligand (66). 

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A. General Features of Ruthenium-Arene Anticancer Drugs 24... 

Ang WH, Daldini E, Scolaro C, Scopelliti R, Juillerat-Jeannerat L, Dyson PJ (2006) Development of organometallic ruthenium-arene anticancer drugs that resist hydrolysis. Inorg Chem 45 9006-9013... 

This work provides important evidence for elucidating the cytotoxic effect of the ruthenium-arene complexes and the influence of the arene thereon, for instance with respect to excision repair of DNA lesions and DNA destabilization. It also established two different classes of Ru(II) arene anticancer drugs, i.e. those bearing an arene that has the possibility to intercalate and those that do not. This distinction is important as we will see further differences in DNA binding interactions for these two classes (vide infra). 

Fig. 2. Ligand substitution as a prodrug strategy for metallochem-otherapeutics (a) general scheme of prodrug activation by ligand substitution hydrolysis of a metal—halide bond is a typical activation pathway of metal-based anticancer drugs, as exemplified by the activation of cisplatin (b) and a ruthenium—arene complex (c).

We started this section by stating that the advent of bioorganometallics provides the medicinal chemist with access to new types of reactivity and therefore with new opportunities for anticancer drug design. Our studies on the ruthenium-arene... 

Dale LD, Tocher JH, Dyson TM, Edwards DI, Tocher DA (1992) Studies on DNA damage and induction of SOS repair by novel multifunctional bioreducible compounds. II. A metronidazole adduct of a ruthenium-arene compound. AntiCancer Drug Des 7 3-14... 

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