ReviewOpening the lid on piano-stool complexes: An account of ruthenium(II)–arene complexes with medicinal applications
Graphical abstract
The medicinal properties of ruthenium(II)–arene compounds are attracting growing interest but how long will it be for one of these compounds to enter clinical trials?
Introduction
The discovery of the anticancer properties of cisplatin, cis-Pt(NH3)2Cl2, in 1965 is arguably the most significant and life-changing breakthrough in bioinorganic chemistry [1]. Cisplatin rapidly became, and today remains, one of the most widely used anticancer drugs and it is estimated that today 50–70% of all cancer patients are treated with cisplatin [2]. The landmark discovery of cisplatin initiated the search for other coordination complexes with anticancer properties, since cisplatin is not without problems [3], [4], [5], [6], [7], and two other platinum compounds, namely oxaliplatin and carboplatin, are in worldwide clinical use (Fig. 1) [7]. A vast number of complexes centred on metals other than platinum have also been evaluated as anticancer chemotherapeutics and the most advanced compounds include two palladium(II) porphyrin compounds, TOOKAD® and TOOKAD® Soluble, that are in phase III clinical trials as sensitizers in photodynamic therapy [8], and two ruthenium(III) complexes, indazolium [trans-tetrachloridobis(1H-indazole)ruthenate(III)], KP1019 [9], [10], and imidazolium trans-[tetrachlorido(dimethylsulfoxide-κS)(1H-imidazole)ruthenate(III)], NAMI-A [11], [12], that are currently undergoing phase II clinical trials (Fig. 1).
The discovery of cisplatin and the exciting developments in the field of metal-based drugs for the treatment of cancer and other diseases were not ignored by the organometallic community. Indeed, shortly after the initial clinical success of cisplatin a series of metallocene complexes were evaluated for anticancer activity [13]. From the series of metallocenes studied titanocene dichloride, Ti(η5-C5H5)2Cl2 (Fig. 2), was identified as a lead compound, and following extensive biological studies it entered clinical trials, although it was eventually abandoned following a phase III clinical trial [14]. Many titanocene derivatives have since been prepared and evaluated for their cytotoxicity against cancer cells and in animal models including more stable complexes that potentially overcome the problems associated with the limited aqueous stability of titanocene dichloride [15].
Increasing interest in organometallic pharmaceuticals has centred on the evaluation and application of Group 8 compounds. Notably, the quintessential organometallic sandwich compound ferrocene, Fe(η5-C5H5)2, is not particularly toxic whereas the ferrocenium cation, [Fe(η5-C5H5)2]+, exhibits an anti-proliferative effect on various cancer cell lines [16], [17], [18]. Consequently, the delivery of a non-toxic ferrocene moiety to a cancer cell that is subsequently oxidized to a toxic ferrocinium ion is an attractive strategy assuming that the oxidation takes place selectively in tumours, which is not inconceivable given the different pharmacological features that distinguish rapidly growing cancer cells and healthy cells. Based on this hypothesis tamoxifen, a key chemotherapeutic agent used to treat hormone-dependent breast cancers (its active metabolite is hydroxy-tamoxifen), was modified with a ferrocenyl group in place of a phenyl ring affording ferrocifen (Fig. 2) [19], [20].
In addition to ferrocene derivatives of tamoxifen both ruthenocene- and osmacene-based compounds have been prepared and evaluated in vitro for cytotoxicity, however, the iron-based compounds have the most relevant pharmacological properties [19], [21]. A rhodium pentamethylcyclopentadienyl derivative of hydroxytamoxifen has also been reported [22]. Previously, rhodium(III)–pentamethylcyclopentadienyl aqua complexes had been shown to readily react with DNA model compounds indicating that under physiological conditions such compounds could be of therapeutic use [23], [24], [25], [26], [27], [28].
Section snippets
Promising nascent studies
The first paper to describe a medicinal application of a ruthenium(II)–arene compound, to the best of our knowledge, was published in 1992 [29]. The known anticancer agent 1-β-hydroxyethyl-2-methyl-5-nitroimidazole (metronidazole) was coordinated to the ruthenium(II)–benzene fragment via a nitrogen donor atom (Fig. 3) giving a compound with superior, selective cytotoxicity compared to metronidazole. This paper went largely unnoticed at the time and further papers describing its biological
Method development
During the relatively nascent studies on the anticancer properties of ruthenium(II)–arene complexes it was necessary to develop and apply bioanalytical techniques to facilitate the study of these compounds with biomolecules and ultimately to study the behaviour of these compounds in extremely complex environments such as human cancer cells [55]. Consequently, in parallel to the research on the development of new drug candidates much effort was oriented towards rationalizing drug delivery and
Variations on a theme
The versatility of the ruthenium(II)–arene unit as a useful synthon has led to a vast number of compounds that have been evaluated for cytotoxicity in cancer cells. A wide range of complexes with three monodentate co-ligands have been prepared and evaluated in vitro. Various pta derivatives have been studied but to date there does not appear to be any clear advantages over pta itself [63]. It would appear that pta forms specific hydrogen bonding interactions with potential targets that are
Target-focused compounds
Various proteins and enzymes are overexpressed or uniquely expressed in cancers and they consequently represent excellent drug targets as opposed to DNA – the usual (albeit often assumed) target of metal-based drugs. Progress in the development of selective organometallic inhibitors of enzyme targets has occurred in parallel with that of the medicinal chemistry of ruthenium(II)–arene complexes [97]. Kinases are one of the critical targets for anticancer chemotherapies. Their function is to
Polynuclear complexes
The use of polynuclear complexes as anticancer agents provides compounds that may bind to biomolecular targets via more than one metal. In this respect, a trinuclear platinum anticancer complex that is active on cisplatin resistant cancers was undergoing clinical trials [114]. This principle has been extended to ruthenium(II)–arene systems providing some highly cytotoxic compounds (see above) [85], [97]. Interestingly, trithiolato-bridge ruthenium(II)–arene dimers are highly cytotoxic and
Concluding remarks
When Bennett and co-workers published the facile synthesis of some ruthenium(II)–arene dimers bridged by chlorido ligands in 1974 [143], it is unlikely that they would have anticipated the profound impact their work would have in many different domains. A plethora of compounds have been derived from these truly versatile starting materials that have found extensive, important applications in catalysis (for example see Refs. [144], [145], [146], [147], [148], [149], [150], [151], [152], [153],
Acknowledgements
We thank the EPFL, the University of Auckland, Moscow State University, COST CM1105, the Royal Society of New Zealand (C.G.H.), Genesis Oncology Trust (C.G.H.) and the Russian Foundation for Basic Research (A.A.N., grant 13-03-00513) for financial support.
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