Ruthenium Arene Anticancer Complexes

The recent clinical success of platinum anticancer drugs has illustrated that metal complexes can be designed to have a specificity of biological activity. For example, not all platinum complexes are active anticancer agents. Some platinum complexes are inert and relatively non-toxic, some attack DNA, some do not. In general, the nature of the metal ion itself, its oxidation state, and the types and number of bound ligands can all play critical roles in the biological activity [4, 5]. 

Current interest in the use of metal complexes for the treatment of cancer was triggered by the discovery of the anticancer activity of Pt(ll) amine complexes in 1969 by Rosenberg [10]. Now at least four platinum complexes have been approved for clinical use (complexes 1-4, Fig. 2.1) and platinum complexes are the most widely-used anticancer drugs. Stimulation for the discovery of anticancer complexes of metals other than platinum arises from the cellular resistance to platinum which is sometimes encountered in the clinic, the toxic side-effects of dsplatin (1), which can be severe, and the limited spectrum of activity against different types of cancer [11]. 

Other metallocenes are active in vitro, e.g. CP2VCI2 and Cp2NbCl2 [7], but have not reached clinical trials. Attempts to modify the aqueous solubility and stability of titanocenes are underway in several laboratories [15, 16]. Another Ti(IV) complex, budotitane (6, Fig. 2.2), was the first non-platinum complex to be approved for clinical trials, but poor solubility and hydrolysis made formulation difficult even in micelles, and the trials were abandoned [17]. 

Biological interest in ruthenium has centered on the use of ruthenium red to inhibit Ca uptake, on ruthenium complexes as nitric oxide scavengers, as 

Clarke has proposed that the activity of Ru(III) complexes, which are usually relatively inert towards ligand substitution, is dependent on in vivo reduction to more labile Ru(II) complexes [19, 24]. With this in mind we have explored the activity of Ru(II) complexes. We discovered that Ru(II) aminophosphine complexes were cytotoxic to cancer cells [25], but they had poor aqueous solubility and were difficult to isolate and purify in large quantities. Since arenes are known to stabilize ruthenium in its +2 oxidation state, we have investigated the potential of Ru(II) arene complexes as anticancer agents and their associated aqueous chemistry. We have found that half-sandwich Ru(II) mono-arene complexes often possess good aqueous solubility (an advantage for clinical use) and that the Ru(II)-arene bonds are very stable. 

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Melchart M, Sadler PJ (2006) Ruthenium arene anticancer complexes. In Jaouen G (ed) Bioorganometallics. Wiley-VCH, Weinheim, pp 39-64... 

Yan YK, Melchart M, Habtemariam A, Sadler PJ (2005) Organometallic chemistry, biology and medicine ruthenium arene anticancer complexes. Chem Commun 4764-4776... 

Wang F, Bella J, Parkinson JA, Sadler PJ (2005) Competitive reactions of a ruthenium arene anticancer complex with histidine, cytochrome c and an oligonucleotide. J Biol Inorg Chem 10 147-155... 

Wang F, Weidt S, Xu J, Mackay CL, Langridge-Smith PRR, Sadler PJ (2008) Identification of clusters from reactions of ruthenium arene anticancer complex with glutathione using nanoscale liquid chromatography fourier transform ion cyclotron mass spectrometry combined with 180-labeling. J Am Soc Mass Spectrom 19 544-549... 

Melchart, M. Sadler, P. J. Ruthenium Arene Anticancer Complexes. In Bioorganometallics-, Jaouen, G., Ed. Wiley-VCH Weinheim, 2006 pp 39-64. 

Wang F, Xu J, Habtemariam A, Bella J, Sadler PJ (2005) Competition between glutathione and guanine for a ruthenium(II) arene anticancer complex detection of a sulfenato intermediate. J Am Chem Soc 127 17734—17743... 

Sriskandakumar T, Petzold H, Bruijnincx PCA, Habtemariam A, Sadler PJ, Kennepohl P (2009) Influence of oxygenation on the reactivity of ruthenium-thiolato bonds in arene anticancer complexes insights from XAS and DFT. J Am Chem Soc 131 13355-13361... 

Zobi F, Mood BB, Wood PA, Fabbiani FPA, Parsons S, Sadler PJ (2007) Tagging (arene) ruthenium(II) anticancer complexes with fluorescent labels. Eur J Inorg Chem 2783-2796... 

Fig.6 Ruthenium(II)-arene anticancer complexes a from [186] b from [187,188] c from [189,190] d from [191] e from [192] f from [193]...

Two ruthenium containing anticancer complexes NAMI-A and KP1019 (Fig 13.8) are currently undergoing clinical evaluation which has stimulated significant interest in the development of new Ru-based anticancer complexes [8]. In recent years, ruthenium(II)-arene complexes have been extensively evaluated as anticancer agents, with the ruthenium stabilised in the oxidation state (+2) by the ty coordinated arene [29]. 

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).

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... 

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). 

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