Elsevier

Journal of Organometallic Chemistry

Volume 751, 1 February 2014, Pages 251-260
Journal of Organometallic Chemistry

Review
Opening the lid on piano-stool complexes: An account of ruthenium(II)–arene complexes with medicinal applications

https://doi.org/10.1016/j.jorganchem.2013.09.016Get rights and content

Highlights

  • The origins of bioorganometallic (medicinal) chemistry.

  • Properties of Ru(II)–arene complexes lend themselves pharmacological applications.

  • Rational target specific drug design.

  • Drug targeting strategies.

  • Beyond the ruthenium(II)–arene unit: Os, Rh and Ir and cyclopentadienyl systems.

Abstract

Interest in the medicinal properties of ruthenium(II)–arene compounds has grown rapidly over the last decade. In this account we describe the origins of the field and subsequently highlight developments in the field, including the design of compounds that inhibit enzymes, the application of multinuclear systems to act as drug delivery vehicles, and the development of bioanalytical and biophysical methods to help elucidate the mechanisms by which these compounds function. The conducive properties and reasons for the rapid growth in interest in these and related compounds for their medicinal applications, especially in the treatment of solid tumours, are identified.

Graphical abstract

  1. Download : Download full-size image
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.

References (163)

  • T.W. Hambley

    Coord. Chem. Rev.

    (1997)
  • S.M. Cohen et al.

    Prog. Nucleic Acid Res. Mol. Biol.

    (2001)
  • C.G. Hartinger et al.

    J. Inorg. Biochem.

    (2006)
  • B. Therrien

    Coord. Chem. Rev.

    (2009)
  • N. Yan et al.

    Coord. Chem. Rev.

    (2010)
  • J. Bravo et al.

    Coord. Chem. Rev.

    (2010)
  • M. Melchart et al.

    J. Inorg. Biochem.

    (2007)
  • M. Groessl et al.

    J. Inorg. Biochem.

    (2008)
  • A.D. Phillips et al.

    Coord. Chem. Rev.

    (2004)
  • M. Hanif et al.

    J. Inorg. Biochem.

    (2011)
  • W. Kandioller et al.

    J. Organomet. Chem.

    (2011)
  • E.A. Enyedy et al.

    J. Organomet. Chem.

    (2013)
  • O. Novakova et al.

    Biochem. Pharmacol.

    (2009)
  • M.H. Garcia et al.

    Inorg. Chim. Acta

    (2010)
  • B. Rosenberg et al.

    Nature

    (1965)
  • P.J. Dyson et al.

    Dalton Trans.

    (2006)
  • Z. Guo et al.

    Angew. Chem., Int. Ed. Engl.

    (1999)
  • M.A. Jakupec et al.

    Rev. Physiol. Biochem. Pharmacol.

    (2003)
  • M.A. Jakupec et al.

    Dalton Trans.

    (2008)
  • C.M. Moore et al.

    Laser Surg. Med.

    (2011)
  • C.G. Hartinger et al.

    Chem. Biodivers.

    (2008)
  • S. Pacor et al.

    J. Pharmacol. Exp. Ther.

    (2004)
  • J.M. Rademaker-Lakhai et al.

    Clin. Cancer Res.

    (2004)
  • H. Köpf et al.

    Angew. Chem.

    (1979)
  • N. Kroger et al.

    Onkologie

    (2000)
  • K. Strohfeldt et al.

    Chem. Soc. Rev.

    (2008)
  • P. Köpf-Maier et al.

    Angew. Chem., Int. Ed. Engl.

    (1984)
  • P. Köpf-Maier et al.

    Chem. Rev.

    (1987)
  • P. Köpf-Maier et al.

    Struct. Bonding

    (1988)
  • G. Jaouen et al.

    Curr. Med. Chem.

    (2004)
  • A. Nguyen et al.

    Chimia

    (2007)
  • P. Pigeon et al.

    J. Med. Chem.

    (2005)
  • S. Top et al.

    Inorg. Chem.

    (2010)
  • L.Y. Kuo et al.

    J. Am. Chem. Soc.

    (1991)
  • D.P. Smith et al.

    J. Am. Chem. Soc.

    (1992)
  • D.P. Smith et al.

    Inorg. Chem.

    (1993)
  • D.P. Smith et al.

    Inorg. Chem.

    (1993)
  • D.P. Smith et al.

    Organometallics

    (1993)
  • M.S. Eisen et al.

    Organometallics

    (1995)
  • L.D. Dale et al.

    Anti-Cancer Drug Des.

    (1992)
  • L. Quebatte et al.

    Angew. Chem., Int. Ed.

    (2005)
  • J. Wolf et al.

    Organometallics

    (2008)
  • Y.N.V. Gopal et al.

    Biochemistry

    (1999)
  • Y.N.V. Gopal et al.

    Arch. Biochem. Biophys.

    (2002)
  • C.S. Allardyce et al.

    Chem. Commun.

    (2001)
  • P.J. Dyson

    Chimia

    (2007)
  • N.J. Farrer et al.

    Medicinal Inorganic Chemistry: State of the Art, New Trends, and a Vision of the Future

  • R.O. Gould et al.

    Cryst. Struct. Commun.

    (1978)
  • M.V. Babak et al.

    Chem.—Eur. J.

    (2013)
  • H. Chen et al.

    J. Am. Chem. Soc.

    (2002)
  • Cited by (238)

    • “Editorial” for volume 1000

      2023, Journal of Organometallic Chemistry
    View all citing articles on Scopus
    View full text