Challenges and Opportunities in the Development of Organometallic

Review pubs.acs.org/Organometallics

Challenges and Opportunities in the Development of Organometallic Anticancer Drugs Christian G. Hartinger,*,† Nils Metzler-Nolte,*,‡ and Paul J. Dyson*,§ †

School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand Inorganic Chemistry I-Bioinorganic Chemistry, Faculty of Chemistry and Biochemistry, Ruhr University Bochum, Universitaetsstrasse, 44801 Bochum, Germany § Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), EPFL−BCH, CH-1015 Lausanne, Switzerland ‡

ABSTRACT: This review provides an introduction into the fascinating area of organometallic anticancer compounds. Although the subject dates back many years, it has witnessed considerable growth only in the past decade. A brief overview of the subject together with recent pertinent examples is provided. The properties of organometallic compounds that lend themselves to medical applications, the main current approaches used, and possible avenues for future research are identified.

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important target.5 However, the limitation of DNA as a target is that DNA is ubiquitous and therefore present in healthy cells and the systemic toxicity of drugs that damage DNA is generally high unless ways to selectively deliver these compounds to cancer cells can be found. Targets that are overexpressed or even unique to cancer cells are now considered preferable.6 Nevertheless, the early and highly promising research on Ti(η 5 -C 5 H5 )2 Cl2 inspired other researchers to study the anticancer properties of organometallic compounds,7 who brought rational design and many new ideas to the field, ultimately playing a central role in the development of bioorganometallic chemistry more generally.8 In this focused review we have selected some of the main developments in the field and thereby identify worthwhile avenues for future research. The approach we have taken to convey these developments has been to classify organometallic compounds according to their ligand type, since the anticancer properties of compounds incorporating virtually all the classic ligand classes have been evaluated, at least in vitro. The specific roles of the ligands with respect to their bioloigcal effects are also discussed. For further details a number of more specialist or comprehensive reviews are available.8−14

INTRODUCTION The advent of modern medicinal chemistry is generally attributed to Paul Ehrlich’s discovery of salvarsan, an organometallic compound, following screening of a large number of compounds.1 Salvarsan is a potent antibiotic that was originally used to treat syphilis (in the original paper describing this application the 20 soldiers treated with the drug were even named). Over many years the structure of salvarsan was refined to improve its pharmacological properties, e.g. water solubility, and these latter organo-arsenic compounds were only phased out of clinical use after the discovery of penicillins. Attempts to explore the medicinal properties of organometallic compounds based on transition metals started after the discovery of the highly potent and versatile anticancer drug cisplatin2a compound that contains no carbon atoms! Köpf and Köpf-Maier started to explore the anticancer activity of transition-metal cyclopentadienyl complexes, including ferrocene, which itself is not a particularly toxic compound. Ferrocene can be injected, inhaled, or taken orally in rather high doses without causing major health problems, although we do not recommend trying this. However, titanocene dichloride, Ti(η5-C5H5)2Cl2, was identified as a lead anticancer compound.3 The biological anticancer properties of this organotitanium compound were extensively studied over many years, with several clinical trials conducted (trials on actual patients with various forms of cancer that have not responded to exisiting treatments, including surgery, chemotherapy, and radiotherapy), although finally the compound was not approved for use.4 The assumed target of this compound is DNA, and since cancer cells undergo uncontrolled replication, DNA is an © 2012 American Chemical Society

Special Issue: Organometallics in Biology and Medicine Received: May 3, 2012 Published: July 16, 2012 5677

dx.doi.org/10.1021/om300373t | Organometallics 2012, 31, 5677−5685

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CYCLOPENTADIENYL COMPLEXES As mentioned above, ferrocene, Fe(η5-C5H5)2, is not toxic; however, the ferrocenium cation, [Fe(η5-C5H5)2]+, exhibits an antiproliferative effect on a variety of cancer cell lines.15−17 The mechanism by which ferrocenium salts exert their antiproliferative effect is not fully understood, but since they have been shown to generate hydroxyl radicals in physiological solutions, it is plausible that they generate such radicals inside cancer cells, which leads to DNA damage or damage of the cell membrane.18 Irrespective of the precise mode of action, the notion to exploit the redox activity of ferrocene as an innovative metal-specific mechanism of action in the design of anticancer drugs is highly attractivei.e. deliver a nontoxic ferrocene moiety to a cancer cell that is subsequently oxidized to a toxic ferrocenium ion. Such an approach was applied to tamoxifen, a chemotherapeutic agent widely used to treat hormone-dependent breast cancers (its active metabolite is hydroxy-tamoxifen), by substituting one of the phenyl rings with a ferrocenyl group to afford the so-called “ferrocifen” derivatives (1; see Figure 1).19,20

cancer cells and exhibit antiproliferative activity against glioma in vivo models, when loaded on lipid nanocapsules as a drug carrier system.22,23 Ferrocifen (1, where n = 4) is also active against highly invasive ER(−) MDA-MB-231 breast cancer cells, which do not respond to tamoxifen. Interestingly, tamoxifen was modified with organometallic fragments with, for example, a ruthenocene analogue of 1, but they were found to be inactive when evaluated against MDA-MB-231 cells.19,24,25 In contrast, a rhodium analogue which is watersoluble shows promising anticancer properties.26,27 The behavior of ferrocifen suggests a dual mode of action combining tamoxifen-like binding to the estrogen receptor with a pathway involving redox activation,28 in which the active hydroxyferrocifen metabolite is oxidized to afford a reactive quinone methide intermediate. Reaction of this metabolite with biomolecules such as glutathione and nucleobases are presumably responsible for the enhanced activity. In a related study ferrocenyl diphenols, such as 2 (Figure 1), and unconjugated phenol derivatives were shown to be strongly antiproliferative and a related mechanism involving the formation of similar reactive intermediates may be invoked.29 Many critical redox processes are localized in the cell mitochondria, and redox-active drugs should exert their optimum effect inside this organelle. Certain peptides accumulate in specific cellular compartments, including the mitochondria or nuclei, and consequently attaching an intracellularly localizing peptide to ferrocene (and other organometallic compounds) allows an organometallic complex to be directed selectively to the respective compartment.30−37 Indeed, ferrocene−peptide conjugates (e.g., 3 in Figure 1) are considerably more cytotoxic than ferrocene itself, which could be due to better cellular uptake and in part also due to intracellular localization.38,39 As mentioned in the Introduction, Ti(η5-C5H5)2Cl2 was explored as an anticancer compound, and the structure of the molybdenum analogue bound to DNA was even determined and found to be reminiscent of that established for cisplatin;40 however, titanocene dichloride was abandoned following phase II clinical trials.41,42 Although the main reason that Ti(η5C5H5)2Cl2 was not approved for clinical use was due to no significant advantage over existing clinically approved drugs, the low water solubility and poor hydrolytic stability of Ti(η5C5H5)2Cl2 resulted in formulation problems that hampered its development. To increase both the aqueous solubility and the stability of titanocenes, ansa derivatives have been developed (4 and 5; see Figure 2).43 The two cyclopentadienyl rings are covalently linked, increasing stability by virtue of a chelate effect with the amino moieties enhancing water solubility.44 The pmethoxybenzyl-substituted titanocene complex 6 (see Figure 2)

Figure 1. The most active derivative of 1, in which n = 4 is referred to as ferrocifen, a ferrocenyl diphenol 2, and a ferrocene−enkephalin conjugate 3.

Tamoxifen is active against hormone-dependent breast tumors, i.e. those containing the estrogen receptor, termed ER(+), corresponding to about two-thirds of all cases. These tumors are susceptible to selective estrogen receptor modulators such as tamoxifen, giving patients a significantly improved chance of successful treatment in comparison to patients with breast tumors that are not hormone dependent, viz. ER(−). The anticancer action of tamoxifen arises from the competitive binding to the ER-α subtype suppressing estradiol-mediated DNA transcription, thereby preventing replication.21 In some cases, however, expression of the estrogen receptor is downregulated following tamoxifen treatment, rendering the drug ineffectivei.e., acquired drug resistance. The activity of ferrocifens against ER(+) cancer cell lines can be rationalized by invoking a mechanism similar to that described for tamoxifen. In keeping with this mechanism, the ferrocifens are effective antiestrogens in ER(+) MCF-7 breast

Figure 2. ansa-Bridged titanocenes 4 and 5 and an example of a functionalized titanocene 6 and its oxalate derivative 7. 5678


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was found to be highly active against a panel of 36 human tumor cell lines.45 This compound also displays promising activity in vivo,46,47 but its hydrolytic stability remains problematic. Therefore, in an alternative approach to provide greater hydrolytic stability, the two chloride ligands are substituted by carboxylate groups, to afford equally active compounds, e.g. 7, with favorable pharmacokinetic properties.48,49 Indeed, much emphasis in modulating the efficacy of platinum drugs has been to replace the two chloride ligands in cisplatin with other ligands that are more resistant to hydrolysis, the classic example being the widely used drug carboplatin, with a bidentate dicarboxylate ligand.50 Going one step further, kinetically inert half-sandwich complexes based on Ru and Os have been developed as selective inhibitors of protein kinases.51−53 Kinases catalyze the transfer of phosphate groups from ATP to various substrates, thereby controlling a multitude of important cellular functions.51 As such, certain kinases are critical targets for anticancer chemotherapies. Inert organometallic inhibitors such as 8 and 9 (see Figure 3) are essentially analogues of the natural

Figure 4. Selected view of the X-ray structure of the organometallic enzyme inhibitor 9Ru bound to the ATP binding pocket of human protein kinase Pim-1 (modified from ref 55; pdb structure code 2BZH).

complexes with large, planar polypyridyl ligands that can intercalate into DNA.64−66

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METAL−ARENE COMPOUNDS The first transition-metal−arene compound evaluated for antiproliferative activity against cancer cells was Ru(η6-C6H6)(metronidazole)Cl2 (10; Figure 5) (metronidazole = 1-β-

Figure 3. Examples of half-sandwich complexes that selectively inhibit kinases.

product staurosporin, which inhibits kinases by competitively binding to the ATP binding site of the enzyme.54,55 While staurosporin has only limited selectivity for any one of the >500 different kinases that are encoded in the human genome,56 the three-dimensional bulk of the organometallic analogues enhances the affinity and selectivity for specific kinases due to the variations in the size and shape of the catalytic pocket. Several structures of kinases cocrystallized with these organometallic inhibitors,54,55,57−60 e.g. those shown in Figure 3, bound to the ATP-binding site have been reported. For example, the structure of 9Ru with the kinase Pim-1 (Figure 4) reveals the supramolecular binding between the H-bonding groups on the organometallic inhibitor and the enzyme active site and confirms the stability of the coligands which remain coordinated to the ruthenium center.55 Pim-1 is overexpressed in human prostate cancer cells and consequently represents an ideal target for chemotherapies for this type of cancer.61 Compound 9Ru is also an efficient inhibitor of kinase GSK-3 both in vitro and in vivo.57 The same antiproliferative activity is observed for both the Ru and Os complexes, substantiating the structural role of the metal centers as three-dimensional scaffolds.58 Various other half-sandwich cyclopentadienyl complexes have been evaluated for antiproliferative activity, including Ru(η 5 -C 5 R 5 )Cl(pta) 2 (R = H, Me; pta = triaza-7phosphatricyclo[3.3.1.1]decane),62 M(η5-C5Me5)(pta)Cl2, and [M(η5-C5Me5)(pta)2Cl]Cl (M = Rh, Ir)63 and a series of rhodium(III) and iridium(III) pentamethylcyclopentadienyl

Figure 5. Structures of ruthenium (and osmium) arene compounds with tumor-inhibiting properties (R1 = Cl, F, Me, H; R2 = isopropylidene, cyclohexylidene).

hydroxyethyl-2-methyl-5-nitroimidazole).67 The complex exhibits a greater, selective cyctotoxicity than metronidazole itself (metronidazole is a widely used antibiotic also prescribed to treat fungating tumors); however, further studies on the biological properties of this organometallic compound have not been disclosed. Another early derivative, purported to be Ru(η6-C6H6)(DMSO)Cl2 (11), was found to inhibit topoisomerase II (an enzyme that regulates the winding of DNA),68 an important target for antitumor drugs.69 More recently potent topoisomerase IIα inhibitors with flavonoid ligands 12 have been reported, with their antiproliferative activity correlating well with the enzyme inhibitory activity.70 5679


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analogues,86 and extensive studies regarding the mechanism of action of these compounds, mostly centered on DNA interactions, have been undertaken. Oligonucleotide binding studies show that [Ru(η6-pcymene)(en)Cl]+ preferentially binds to guanine bases forming monofunctional DNA adducts following activation of the complex via substitution of the chloride ligand by water.87 Moreover, characterization by NMR spectroscopy indicates that binding to guanine is enhanced by the formation of H bonds between the en ligand N−H groups and the exocyclic oxygen atom on guanine.88 Such behavior is somewhat reminiscent of that proposed for cisplatin, which is perhaps not that surprising given the relationship between the en ligand and two ammonia ligands in the platinum drug. With larger arene rings binding of the “[Ru(η6-arene)(en)]2+” fragment to nucleotide bases appears to be promoted by hydrophobic interactions and arene−purine base π−π stacking interactions. Many other ruthenium(II)−arene, and in some cases osmium(II)−arene, complexes have been reported that incorporate ligands based on natural products such as maltol derivatives,89−96 or bioactive compounds such as modified Paullone-type cyclin-dependent kinase inhibitors that are strongly cytotoxic may inhibit kinases via docking of the Paullone moiety in the enzyme active site combined with concomitant coordination of the metal ion.97,98 Moreover, the ruthenacycle 18 (Figure 7) has been reported to be antitumor active in vitro and in vivo, most likely through a pathway related to endoplasmic reticulum stress.99

Complexes incorporating the amphiphilic phosphine 1,3,5triaza-7-phosphatricyclo[3.3.1.1]decane (pta), i.e. Ru(η6arene)(pta)Cl2 (13), are generally not very cytotoxic. These compounds preferentially interact with protein targets as opposed to DNA71 and display selective activity on metastatic tumors in vivo.72 Part of the mode of action of these hydrophilic compounds involves extracellular interactions; indeed, one of the most interesting properties from a pharmacological perspective is the effect on invasion, a key step in metastatic progression.73 Substituting the pta ligand by phosphite−carbohydrate ligands affords the moderately cytotoxic compounds 14 (see Figure 5).74−76 Such carbohydratebased ligands could exploit the biochemical and metabolic functions of diverse sugars in living organisms, allowing the complex to be transported and taken up preferentially by cancer cells. Indeed, attaching a carbohydrate-based ligand to a metal complex invariably leads to improved solubility and reduced toxicity attributable to selective targeting.77 Cytotoxic derivatives are accessible by incorporating a bioactive functionality into the structure that can operate in a synergistic way with the ruthenium moiety.70,78−82 For example, derivatization of the arene ligand with ethacrynic acidan inhibitor of glutathione-S-transferases (GSTs)leads to a compound that overcomes acquired drug resistance.78 GSTs are detoxification enzymes that catalyze the covalent modification of intracellular xenobiotics, including drugs, with glutathione, leading to extrusion from the cell.83 Ru(η6phenylethacrynate)(pta)Cl2 (15) has been shown to inhibit the human enzyme GST P1-1 that is uniquely expressed in cancer cells. The crystal structure of the enzyme cocrystallized with the compound shows that the ruthenium(II) ion binds to the reactive cysteine (Cys101) residues via substitution of the chloride ligands (see Figure 6).79

Figure 7. Structures of the putative CDK inhibitor 17 and a compound that induced endoplasmic reticulum stress, 18.

Other classes of transition-metal−arene compounds have been evaluated against cancer cells in vitro, including Cr(CO)3−arene complexes,100 which appear to be reasonably stable in water, and cationic ruthenium(II) sandwich compounds containing C6 and C5 rings, e.g. ruthenium(II) pentamethylcylopentadienyl benzenesulfonamide complexes that inhibit carbonic anhydrases.101 However, in vivo data appear to be absent, and consequently it is not possible to assess the real pharmacological potential of these compounds.

Figure 6. Selected view showing binding of 15 to Cys residues at the dimer interface of GST P1-1. Glutathione is highlighted in form of a CPK model (modified from ref 79; pdb structure code 3DD3).

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Complexes of the type [Ru(η6-arene)(en)Cl]+ (16; en = ethylene-1,2-diamine) exhibit comparatively high cytotoxicities at levels similar to those of cisplatin.84 An early in vivo study showed that these complexes have pharmacological potential:85 treatment with [Ru(η6-biphenyl)(en)Cl][PF6] resulted in a reduction of tumor volume slightly superior to that of cisplatin in one of three in vivo ovarian cancer models studied. Antiproliferative activity depends on the arene ligand present, with larger systems such as biphenyl and tetrahydroanthracene increasing cytotoxicity. Many other structure−activity relationships have been explored, as have various osmium(II)−arene

METAL−CARBENES AND OTHER LIGAND TYPES Metal complexes with N-heterocyclic carbene (NHC) ligands were initially studied for their antimicrobial properties and subsequently as antiproliferative agents against cancer cells.102 Indeed, cytotoxic silver−NHC complexes, such as 19 (Figure 8), were shown to have promising antibacterial activity103,104 and in vivo anticancer activity on an ovarian cancer xenograft model.105 Various Au(I)−carbene complexes106,107 impair mitochondrial function leading to cell death, a mechanism that appears to be common to many gold complexes involving 5680


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applied to platinum drugs have been translated to organometallic systems, with ferrocene-containing polymers being perhaps the most extensively studied.128 Relatively small dendrimer systems decorated with ruthenium(II)−arene fragments have been reported and a correlation between size and cytotoxicity observed.129 Remarkably, recombinant human serum albumin (rHSA) derivatized with noncytotoxic Ru(η6-arene)(pta)Cl2 complexes (typically four per rHSA), via a pH-cleavable linker, dramatically increased accumulation of the metal within cancer cells, resulting in considerably greater antiproliferative activity in comparison to that of Ru(η6-arene)(pta)Cl2 complexes alone.130 Other methods to covalently modify proteins with organometallic agents have also been reported.131−133 Titanium−cyclopentadienyl units connected by oxo bridges, containing between two and eight “TiCp” fragments, linked as rings or in cage structures have been evaluated for in vitro antiproliferative activity.134 In a rather different approach the highly water-soluble hexaruthenium cage [Ru6(η6-p-cymene)6(tpt)2(dhbq)3]6+ (tpt = 2,4,6-tris(pyridin-4-yl)-1,3,5-triazine, dhbq = 2,5-dihydroxy-1,4-benzoquinonato) was used as a molecular host to a hydrophobic platinum guest.135 A synergy between the host and guest was observed in terms of cytotoxicity against ovarian cancer cells, including cells with acquired resistance to cisplatin. Subsequent studies involving [Ru6(p-cymene)6(tpt)2(dhbq)3]6+ encapsulating a fluorescent pyrene ring demonstrated that the guest molecule is released from a metallacage following cellular uptake. Moreover, cellular uptake is enhanced and apparently involves transporters that raise its potential as a drug delivery vehicle. The low oxidation states of many organometallic species lead to polynuclear clusters containing direct metal−metal bonds, and a number of these clusters have been evaluated for antiproliferative activity against cancer cells. The cytotoxicity of dicobalt hexacarbonyl alkyne compounds involving alkynes functionalized with peptides,136,137 proteins,138 therapeutic drugs,139,140 steroids,141 corticoids and androgens,142 and estrogens143 have been evaluated. In one such complex derivatized with aspirin, high cytotoxicities were obtained on a number of different cancer cell lines. Systematic studies of the anticancer activity of clusters with nuclearities of three and above have not been undertaken, although a series of triosmium carbonyl clusters with various coligands have been explored in some detail. These clusters were found to damage DNA,144,145 and some were found to inhibit telomerase,146 an enzyme that is responsible for the maintenance of the telomers, a guanine-rich part of DNA. High-nuclearity clusters such as the hexaosmium carbonyl cluster Os6(CO)18 are also cytotoxic, although there does not appear to be selectivity toward cancer cells,147 reducing their therapeutic potential.

Figure 8. Examples of metal−NHC complexes that are cytotoxic.

inhibition of the enzyme thioredoxin reductase (TrxR).108,109 The advantage of the NHC complexes is that the Au−NHC bond is relatively stable, giving superior pharmacological properties relative to other ligand types. [Au(NHC) 2]+ complexes such as 20 (Figure 8) accumulate in mitochondria and inhibit TrxR, inducing apoptosis,110,111 whereas others cause S-phase arrest of cancer cells and induce apoptosis through a p53-bak pathway.112 NHC complexes have been functionalized with peptides,113 which could further improve their function, as certain peptides are known to accumulate in the mitochondria, as shown for other Au−peptide conjugates.114 The antiproliferative activity of NHC complexes based on other metals has also been reported.115−117 Other Au(I) complexes bearing alkynyl and phosphine coligands are highly cytotoxic toward the cisplatin-sensitive A2780 cell line and also in its resistant variant.118 Luminescence studies on their intracellular distribution reveal accumulation in lysosomes rather than in mitochondria, which are suggested as relevant for the mode of action of other gold-based anticancer agents. Au(I) complexes with substituted alkyne ligands exhibit high in vitro anticancer activity, which might be driven mainly by the triphenylphosphine−gold(I) propargyl moiety.119 Complexes with π-bonded alkynes have also been evaluated for their in vitro anticancer activity, including the dicobalt systems described in the section below. The intriguing compound Ir(η5-C5Me5)(η4-p-C6H4Se2), containing a diselenobenzoquinone ligand, was also shown to have cytotoxicity equivalent to that of cisplatin in human ovarian A2780 cancer cells, whereas the S-containing analogue was about 2 orders of magnitude less active.120 A mode of action involving redox processes might be of relevance in keeping with other quinonoids.121

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POLYNUCLEAR COMPLEXES, CLUSTERS, AND MACROMOLECULES Multinuclear platinum complexes have been shown to have interesting anticancer properties, especially against cisplatinresistant cancers,122 with a trinuclear complex having undergone clinical evaluation.123 Related di- and polynuclear organometallic species have also been studied, and some appear promising, although their biological properties have not been studied to the same extent as polynuclear platinum systems.124 Interestingly, dimeric ruthenium(II)−arene trithiolato complexes have been shown to exert their antiproliferative behavior through catalytic processesan area of much potential interest to organometallic chemists.125 In addition, numerous macroscopic polynuclear platinumcontaining systems, based on polymers, dendrimers, nanotubes, proteins, etc., have been developed in order to target cisplatin to tumors, spare healthy tissue, and reduce side effects.126 Passive targeting of macromolecules to the tumor environment is possible due to their enhanced vascular permeability that is not present in the healthy endothelial layer surrounding the blood vessels feeding healthy tissue.127 Many of the strategies

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CONCLUSIONS The same skills that organometallic chemists apply to designing new reagents and new catalysts can be applied to the design of anticancer organometallic-based anticancer drugs. While screening of compound libraries may reveal hits, rational design requires an understanding of the mechanism by which the compound reaches and enters a cancer cell and subsequently how it induces apoptosis. From this short review it is clear that a greater understanding of the mechanism of action of organometallic drugs is required and such studies represent a formidable challenge. However, a number of 5681


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Biographies

distinct strategies can be gleaned from this review that provide worthwhile opportunities for organometallic chemists, including (1) Organometallic scaffolds can be used to provide threedimensional structures that accurately fill enzyme active sites and hence inhibit enzyme function. The innovative kinase inhibitors mentioned herein, in which the metal is only present to provide a scaffold, illustrates the value of this approach, which can easily be adapted to other enzymes relevant to cancer progression. (2) Tethering redox active (ferrocene) groups to certain bioactive molecules can enhance or alter their function to obtain compounds with a different activity spectrum in

Christian Hartinger studied chemistry at the University of Vienna and received his Ph.D. there in 2001 under B. K. Keppler. He was an Erwin Schrödinger Fellow with P. J. Dyson at the École Polytechnique Fédérale de Lausanne (EPFL) from 2006 to 2008, did his habilitation at the University of Vienna in 2009, and accepted an Associate Professorship at the University of Auckland in 2011. His research focuses on the development of metal-based anticancer agents and of analytical methods to characterize their behavior in presence of biomolecules. His work earned him the 2011 Carl Duisberg Memorial Prize.

comparison to that of the bioactive molecules alone. (3) Combining a reactive metal moiety that can coordinate to a biomolecular target with an organic molecule of complementary function can improve anticancer properties. (4) Supramolecular organometallic cages can be used to deliver hydrophobic cytotoxins to cancer cells. The development of benign supramolecular platforms would be interesting from a drug delivery perspective. (5) Targeting tumors via well-defined macromolecules loaded with organometallic agents represents an excellent way to deliver nonspecific organometallics to tumors so that their damage to healthy tissue is minimized. Such approaches are widely used for organic drugs, and the approach could prove highly profitable with organometallics that do not discriminate between healthy and cancerous cells. One of the limitations in the field is the lack of in vivo data,

Paul J. Dyson is the director of the Institute of Chemical Sciences and Engineering at the Swiss Federal Institute of Technology Lausanne. He received his Ph.D. in 1993 at the University of Edinburgh and moved to Imperial College as a fixed-term lecturer. In 1995 he obtained a Royal Society University Research Fellowship, later moving to the University of York, and in 2002 he joined the EPFL, where he heads the Laboratory of Organometallic and Medicinal Chemistry.

which is essential to ascertain whether a compound has any genuine pharmacological potential. Many in vivo studies have been performed that are not published, either due to commercial interests or because the data show that the compounds are inactive or highly toxic in animals, and consequently only encouraging in vitro data are reported. However, in recent years many innovative compounds have been reported by bioorganometallic chemists which deserve further investigations at more advanced preclinical stages.

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AUTHOR INFORMATION

Corresponding Author

*E-mail [email protected] (C.G.H.); [email protected] (N.M.-N.); paul.dyson@epfl.ch (P.J.D.). Notes

The authors declare no competing financial interest. 5682


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(23) Huynh, N. T.; Morille, M.; Bejaud, J.; Legras, P.; Vessieres, A.; Jaouen, G.; Benoit, J.-P.; Passirani, C. Pharm. Res. 2011, 28, 3189− 3198. (24) Top, S.; Kaloun, E. B.; Vessières, A.; Laïos, I.; Leclercq, G.; Jaouen, G. J. Organomet. Chem. 2002, 643−644, 350−356. (25) Pigeon, P.; Top, S.; Vessieres, A.; Huche, M.; Hillard, E. A.; Salomon, E.; Jaouen, G. J. Med. Chem. 2005, 48, 2814−2821. (26) Top, S.; Vessieres, A.; Jaouen, G.; Fish, R. H. Organometallics 2006, 25, 3293−3296. (27) Top, S.; Efremenko, I.; Rager, M. N.; Vessieres, A.; Yaswen, P.; Jaouen, G.; Fish, R. H. Inorg. Chem. 2011, 50, 271−284. (28) Hillard, E.; Vessieres, A.; Thouin, L.; Jaouen, G.; Amatore, C. Angew. Chem., Int. Ed. 2006, 45, 285−290. (29) Vessieres, A.; Top, S.; Pigeon, P.; Hillard, E.; Boubeker, L.; Spera, D.; Jaouen, G. J. Med. Chem. 2005, 48, 3937−3940. (30) van Staveren, D. R.; Metzler-Nolte, N. Chem. Rev. 2004, 104, 5931−5985. (31) Noor, F.; Wustholz, A.; Kinscherf, R.; Metzler-Nolte, N. Angew. Chem., Int. Ed. 2005, 44, 2429−2432. (32) Metzler-Nolte, N. Conjugates of peptides and PNA with organometallic complexes: syntheses and applications. In Bioorganometallics; Jaouen, G., Ed.; Wiley-VCH: Weinheim, Germany, 2006; pp 125−179. (33) Kirin, S. I.; Kraatz, H.-B.; Metzler-Nolte, N. Chem. Soc. Rev. 2006, 35, 348−354. (34) Kirin, S. I.; Noor, F.; Metzler-Nolte, N.; Mier, W. J. Chem. Educ. 2007, 84, 108−111. (35) Metzler-Nolte, N. Chimia 2007, 61, 736−741. (36) Noor, F.; Kinscherf, R.; Bonaterra, G. A.; Walczak, S.; Wolfl, S.; Metzler-Nolte, N. ChemBioChem 2009, 10, 493−502. (37) Metzler-Nolte, N., Biomedical applications of organometalpeptide conjugates. In Topics in Organometallic Chemistry; Jaouen, G., Metzler-Nolte, N., Eds.; Springer: Heidelberg, Germany, 2010; Vol. 32, pp 195−217. (38) Kirin, S. I.; Ott, I.; Gust, R.; Mier, W.; Weyhermuller, T.; Metzler-Nolte, N. Angew. Chem., Int. Ed. Engl. 2008, 47, 955−959. (39) Köster, S. D.; Dittrich, J.; Gasser, G.; Hüsken, N.; Henao Castañeda, I. C.; Jios, J. L.; Della Védova, C. O.; Metzler-Nolte, N. Organometallics 2008, 27, 6326−6332. (40) Kuo, L. Y.; Kanatzidis, M. G.; Sabat, M.; Tipton, A. L.; Marks, T. J. J. Am. Chem. Soc. 1991, 113, 9027−9045. (41) Harding, M. M.; Mokdsi, G. Curr. Med. Chem. 2000, 7, 1289− 1303. (42) Mross, K.; Robben-Bathe, P.; Edler, L.; Baumgart, J.; Berdel, W. E.; Fiebig, H.; Unger, C. Onkologie 2000, 23, 576−579. (43) Sweeney, N. J.; Claffey, J.; Muller-Bunz, H.; Pampillon, C.; Strohfeldt, K.; Tacke, M. Appl. Organomet. Chem. 2007, 21, 57−65. (44) Strohfeldt, K.; Tacke, M. Chem. Soc. Rev. 2008, 37, 1174−1187. (45) Kelter, G.; Sweeney, N. J.; Strohfeldt, K.; Fiebig, H.-H.; Tacke, M. Anti-Cancer Drugs 2005, 16, 1091−1098. (46) Beckhove, P.; Oberschmidt, O.; Hanauske, A. R.; Pampillon, C.; Schirrmacher, V.; Sweeney, N. J.; Strohfeldt, K.; Tacke, M. Anti-Cancer Drugs 2007, 18, 311−315. (47) Oberschmidt, O.; Hanauske, A. R.; Pampillon, C.; Sweeney, N. J.; Strohfeldt, K.; Tacke, M. Anti-Cancer Drugs 2007, 18, 317−321. (48) Claffey, J.; Hogan, M.; Müller-Bunz, H.; Pampillón, C.; Tacke, M. ChemMedChem 2008, 3, 729−731. (49) Fichtner, I.; Behrens, D.; Claffey, J.; Gleeson, B.; Hogan, M.; Wallis, D.; Weber, H.; Tacke, M. Lett. Drug Des. Discovery 2008, 5, 489−493. (50) Pasini, A.; Zunino, F. Angew. Chem., Int. Ed. Engl. 1987, 26, 615−624. (51) Meggers, E. Chem. Commun. 2009, 1001−1010. (52) Mulcahy, S. P.; Meggers, E. Organometallics as Structural Scaffolds for Enzyme Inhibitor Design. In Medicinal Organometallic Chemistry; Jaouen, G., Metzler-Nolte, N., Eds.; Springer-Verlag: Heidelberg, Germany, 2010; pp 141−153.

Nils Metzler-Nolte studied chemistry at the Universities of Hamburg, Freiburg, and Munich. After a Ph.D. in main-group chemistry in 1994 and a postdoctoral period with Prof. M. L. H. Green in Oxford, he started his independent research on Bioorganometallic Chemistry at the Max-Planck-Institut in Mülheim in 1996. He was appointed professor for pharmaceutical and bioinorganic chemistry at the University of Heidelberg in 2000 and full professor of Inorganic Chemistry at the Ruhr-University Bochum in 2006. He was elected Dean of the University-wide graduate school in 2009 and currently serves as Vice President for early career researchers and international affairs for the University. Nils has received several fellowships and awards for his work.

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ACKNOWLEDGMENTS C.G.H. is grateful for financial support from the University of Auckland, the University of Vienna, the Austrian Science Fund, and the Johanna Mahlke geb. Obermann Foundation. N.M.-N. thanks the Deutsche Forschungsgemeinschaft (DFG) for funding through the research unit “Biological Function of Organometallic Compounds” (FOR 630, www.rub.de/for630) and Ruhr-University Bochum. P.J.D. thanks the Swiss National Science Foundation, COST (Switzerland), EPFL, and EU for financial support. We gratefully acknowledge support from the COST action D39 “Metallodrug Design and Action”.

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REFERENCES

(1) Sepkowitz, K. A. N. Engl. J. Med. 2011, 365, 291−293. (2) Barnes, K. R.; Lippard, S. J. Metal Complexes in Tumor Diagnosis and as Anticancer Agents; Marcel Dekker: New York/Basel, 2004; Vol. 42, pp 179−208. (3) Köpf, H.; Köpf-Maier, P. Angew. Chem. 1979, 91, 509. (4) Kröger, N.; Kleeberg, U. R.; Mross, K.; Edler, L.; Hossfeld, D. K. Onkologie 2000, 23, 60−62. (5) Jung, Y.; Lippard, S. J. Chem. Rev. 2007, 107, 1387−1407. (6) Sava, G.; Bergamo, A.; Dyson, P. J. Dalton Trans. 2011, 40, 9069−9075. (7) Jaouen, G.; Vessieres, A.; Butler, I. S. Acc. Chem. Res. 1993, 26, 361−369. (8) Jaouen, G., Bioorganometallics; Wiley-VCH: Weinheim, Germany, 2006; p 444. (9) Peacock, A. F. A.; Sadler, P. J. Chem. Asian J. 2008, 3, 1890−1899. (10) Hartinger, C. G.; Dyson, P. J. Chem. Soc. Rev. 2009, 38, 391− 401. (11) Cuesta, L.; Sessler, J. L. Chem. Soc. Rev. 2009, 38, 2716−2729. (12) Suss-Fink, G. Dalton Trans. 2010, 39, 1673−1688. (13) Gasser, G.; Ott, I.; Metzler-Nolte, N. J. Med. Chem. 2011, 54, 3− 25. (14) Gasser, G.; Metzler-Nolte, N. Curr. Opin. Chem. Biol. 2012, 16, 84−91. (15) Köpf-Maier, P.; Köpf, H.; Neuse, E. W.; Köpf, H. Angew. Chem. 1984, 96, 446−447. (16) Koepf-Maier, P.; Koepf, H. Chem. Rev. 1987, 87, 1137−1152. (17) Köpf-Maier, P.; Köpf, H. Struct. Bonding (Berlin) 1988, 70, 103− 185. (18) Salmain, M.; Metzler-Nolte, N. Bioorganometallic Chemistry of Ferrocene. In Ferrocenes; Stepnicka, P., Ed.; Wiley: Chichester, U.K., 2008; pp 499−639. (19) Jaouen, G.; Top, S.; Vessieres, A.; Leclercq, G.; McGlinchey, M. J. Curr. Med. Chem. 2004, 11, 2505−2517. (20) Nguyen, A.; Vessieres, A.; Hillard, E. A.; Top, S.; Pigeon, P.; Jaouen, G. Chimia 2007, 61, 716−724. (21) Shiau, A. K.; Barstad, D.; Loria, P. M.; Cheng, L.; Kushner, P. J.; Agard, D. A.; Greene, G. L. Cell 1998, 95, 927−937. (22) Allard, E.; Jarnet, D.; Vessieres, A.; Vinchon-Petit, S.; Jaouen, G.; Benoit, J.-P.; Passirani, C. Pharm. Res. 2010, 27, 56−64. 5683


Organometallics

Review

(81) Turel, I.; Kljun, J. Curr. Top. Med. Chem. 2011, 11, 2661−2687. (82) Kljun, J.; Bytzek, A. K.; Kandioller, W.; Bartel, C.; Jakupec, M. A.; Hartinger, C. G.; Keppler, B. K.; Turel, I. Organometallics 2011, 30, 2506−2512. (83) Hayes, J. D.; Flanagan, J. U.; Jowsey, I. R. Annu. Rev. Pharmacol. Toxicol. 2005, 45, 51−88. (84) Bruijnincx, P. C. A.; Sadler, P. J., Controlling platinum, ruthenium, and osmium reactivity for anticancer drug design. In Advances in Inorganic Chemistry, van Eldik, R. E., Colin, D. H., Eds.; Academic Press: London, 2009; Vol. 61, pp 1−62. (85) Aird, R. E.; Cummings, J.; Ritchie, A. A.; Muir, M.; Morris, R. E.; Chen, H.; Sadler, P. J.; Jodrell, D. I. Br. J. Cancer 2002, 86, 1652−1657. (86) Fu, Y.; Habtemariam, A.; Basri, A. M. B. H.; Braddick, D.; Clarkson, G. J.; Sadler, P. J. Dalton Trans. 2011, 40, 10553−10562. (87) Novakova, O.; Chen, H.; Vrana, O.; Rodger, A.; Sadler, P. J.; Brabec, V. Biochemistry 2003, 42, 11544−11554. (88) Melchart, M.; Habtemariam, A.; Parsons, S.; Sadler, P. J. J. Inorg. Biochem. 2007, 101, 1903−1912. (89) Mendoza-Ferri, M. G.; Hartinger, C. G.; Eichinger, R. E.; Stolyarova, N.; Jakupec, M. A.; Nazarov, A. A.; Severin, K.; Keppler, B. K. Organometallics 2008, 27, 2405−2407. (90) Kandioller, W.; Hartinger, C. G.; Nazarov, A. A.; Bartel, C.; Skocic, M.; Jakupec, M. A.; Arion, V. B.; Keppler, B. K. Chem. Eur. J. 2009, 15, 12283−12291. (91) Kandioller, W.; Hartinger, C. G.; Nazarov, A. A.; Kuznetsov, M. L.; John, R. O.; Bartel, C.; Jakupec, M. A.; Arion, V. B.; Keppler, B. K. Organometallics 2009, 28, 4249−4251. (92) Mendoza-Ferri, M. G.; Hartinger, C. G.; Mendoza, M. A.; Groessl, M.; Egger, A. E.; Eichinger, R. E.; Mangrum, J. B.; Farrell, N. P.; Maruszak, M.; Bednarski, P. J.; Klein, F.; Jakupec, M. A.; Nazarov, A. A.; Severin, K.; Keppler, B. K. J. Med. Chem. 2009, 52, 916−925. (93) Mendoza-Ferri, M. G.; Hartinger, C. G.; Nazarov, A. A.; Eichinger, R. E.; Jakupec, M. A.; Severin, K.; Keppler, B. K. Organometallics 2009, 28, 6260−6265. (94) Novakova, O.; Nazarov, A. A.; Hartinger, C. G.; Keppler, B. K.; Brabec, V. Biochem. Pharmacol. 2009, 77, 364−374. (95) Hanif, M.; Henke, H.; Meier, S. M.; Martic, S.; Labib, M.; Kandioller, W.; Jakupec, M. A.; Arion, V. B.; Kraatz, H. B.; Keppler, B. K.; Hartinger, C. G. Inorg. Chem. 2010, 49, 7953−7963. (96) Kandioller, W.; Kurzwernhart, A.; Hanif, M.; Meier, S. M.; Henke, H.; Keppler, B. K.; Hartinger, C. G. J. Organomet. Chem. 2011, 696, 999−1010. (97) Schmid, W. F.; John, R. O.; Arion, V. B.; Jakupec, M. A.; Keppler, B. K. Organometallics 2007, 26, 6643−6652. (98) Schmid, W. F.; John, R. O.; Muehlgassner, G.; Heffeter, P.; Jakupec, M. A.; Galanski, M.; Berger, W.; Arion, V. B.; Keppler, B. K. J. Med. Chem. 2007, 50, 6343−6355. (99) Meng, X.; Leyva, M. L.; Jenny, M.; Gross, I.; Benosman, S.; Fricker, B.; Harlepp, S.; Hebraud, P.; Boos, A.; Wlosik, P.; Bischoff, P.; Sirlin, C.; Pfeffer, M.; Loeffler, J.-P.; Gaiddon, C. Cancer Res. 2009, 69, 5458−5466. (100) Jones, G. B.; Mathews, J. E. Bioorg. Med. Chem. Lett. 1995, 5, 93−96. (101) Loughrey, B. T.; Williams, M. L.; Healy, P. C.; Innocenti, A.; Vullo, D.; Supuran, C. T.; Parsons, P. G.; Poulsen, S.-A. J. Biol. Inorg. Chem. 2009, 14, 935−945. (102) Kascatan-Nebioglu, A.; Panzner, M. J.; Tessier, C. A.; Cannon, C. L.; Youngs, W. J. Coord. Chem. Rev. 2007, 251, 884−895. (103) Hindi, K. M.; Siciliano, T. J.; Durmus, S.; Panzner, M. J.; Medvetz, D. A.; Reddy, D. V.; Hogue, L. A.; Hovis, C. E.; Hilliard, J. K.; Mallet, R. J.; Tessier, C. A.; Cannon, C. L.; Youngs, W. J. J. Med. Chem. 2008, 51, 1577−1583. (104) Patil, S.; Deally, A.; Gleeson, B.; Muller-Bunz, H.; Paradisi, F.; Tacke, M. Metallomics 2011, 3, 74−88. (105) Medvetz, D. A.; Hindi, K. M.; Panzner, M. J.; Ditto, A. J.; Yun, Y. H.; Youngs, W. J. Met. Based Drugs 2008, 2008, 384010. (106) Barnard, P. J.; Baker, M. V.; Berners-Price, S. J.; Day, D. A. J. Inorg. Biochem. 2004, 98, 1642−1647.

(53) Gasser, G.; Metzler-Nolte, N. Metal Compounds as Enzyme Inhibitors. In Bioinorganic Medicinal Chemistry; Alessio, E., Ed.; WileyVCH: Weinheim, Germany, 2011; pp 351−382. (54) Atilla-Gokcumen, G. E.; Williams, D. S.; Bregman, H.; Pagano, N.; Meggers, E. ChemBioChem 2006, 7, 1443−1450. (55) Debreczeni, J. É.; Bullock, A. N.; Atilla, G. E.; Williams, D. S.; Bregman, H.; Knapp, S.; Meggers, E. Angew. Chem. 2006, 45, 1580− 1585. (56) Meggers, E. Curr. Opin. Chem. Biol. 2007, 11, 287−292. (57) Williams, D. S.; Atilla, G. E.; Bregman, H.; Arzoumanian, A.; Klein, P. S.; Meggers, E. Angew. Chem., Int. Ed. Engl. 2005, 44, 1984− 1987. (58) Maksimoska, J.; Williams, D. S.; Atilla-Gokcumen, G. E.; Smalley, K. S. M.; Carroll, P. J.; Webster, R. D.; Filippakopoulos, P.; Knapp, S.; Herlyn, M.; Meggers, E. Chem. Eur. J. 2008, 14, 4816− 4822. (59) Xie, P.; Streu, C.; Qin, J.; Bregman, H.; Pagano, N.; Meggers, E.; Marmorstein, R. Biochemistry 2009, 48, 5187−5198. (60) Atilla-Gokcumen, G. E.; Di, C. L.; Meggers, E. J. Biol. Inorg. Chem. 2011, 16, 45−50. (61) Valdman, A.; Fang, X.; Pang, S.-T.; Ekman, P.; Egevad, L. The Prostate 2004, 60, 367−371. (62) Akbayeva, D. N.; Gonsalvi, L.; Oberhauser, W.; Peruzzini, M.; Vizza, F.; Bruggeller, P.; Romerosa, A.; Sava, G.; Bergamo, A. Chem. Commun. 2003, 264−265. (63) Casini, A.; Edafe, F.; Erlandsson, M.; Gonsalvi, L.; Ciancetta, A.; Re, N.; Ienco, A.; Messori, L.; Peruzzini, M.; Dyson, P. J. Dalton Trans. 2010, 39, 5556−5563. (64) Ali, N. M.; Bangert, J.-A.; Ott, I.; Gust, R.; Stoll, R.; Sheldrick, W. S. J. Inorg. Biochem. 2009, 103, 1405−1414. (65) Kokoschka, M.; Bangert, J.-A.; Stoll, R.; Sheldrick, W. S. Eur. J. Inorg. Chem. 2010, 1507−1515. (66) Geldmacher, Y.; Rubbiani, R.; Wefelmeier, P.; Prokop, A.; Ott, I.; Sheldrick, W. S. J. Organomet. Chem. 2011, 696, 1023−1031. (67) Dale, L. D.; Tocher, J. H.; Dyson, T. M.; Edwards, D. I.; Tocher, D. A. Anti-Cancer Drug Des. 1992, 7, 3−14. (68) Gopal, Y. N. V.; Jayaraju, D.; Kondapi, A. K. Biochemistry 1999, 38, 4382−4388. (69) Pommier, Y.; Leo, E.; Zhang, H.; Marchand, C. Chem. Biol. 2010, 17, 421−433. (70) Kurzwernhart, A.; Kandioller, W.; Bartel, C.; Baechler, S.; Trondl, R.; Muehlgassner, G.; Jakupec, M. A.; Arion, V. B.; Marko, D.; Keppler, B. K.; Hartinger, C. G. Chem. Commun. 2012, 48, 4839− 4841. (71) Wu, B.; Ong, M. S.; Groessl, M.; Adhireksan, Z.; Hartinger, C. G.; Dyson, P. J.; Davey, C. A. Chem. Eur. J. 2011, 17, 3562−3566. (72) Scolaro, C.; Bergamo, A.; Brescacin, L.; Delfino, R.; Cocchietto, M.; Laurenczy, G.; Geldbach, T. J.; Sava, G.; Dyson, P. J. J. Med. Chem. 2005, 48, 4161−4171. (73) Bergamo, A.; Masi, A.; Dyson, P. J.; Sava, G. Int. J. Oncol. 2008, 33, 1281−1289. (74) Berger, I.; Hanif, M.; Nazarov, A. A.; Hartinger, C. G.; John, R. O.; Kuznetsov, M. L.; Groessl, M.; Schmitt, F.; Zava, O.; Biba, F.; Arion, V. B.; Galanski, M.; Jakupec, M. A.; Juillerat-Jeanneret, L.; Dyson, P. J.; Keppler, B. K. Chem. Eur. J. 2008, 14, 9046−9057. (75) Hanif, M.; Nazarov, A. A.; Hartinger, C. G.; Kandioller, W.; Jakupec, M. A.; Arion, V. B.; Dyson, P. J.; Keppler, B. K. Dalton Trans. 2010, 39, 7345−7352. (76) Hanif, M.; Nazarov, A. A.; Hartinger, C. G. Inorg. Chim. Acta 2012, 380, 211−215. (77) Hartinger, C. G.; Nazarov, A. A.; Ashraf, S. M.; Dyson, P. J.; Keppler, B. K. Curr. Med. Chem. 2008, 15, 2574−2591. (78) Dyson, P. J. Chimia 2007, 61, 698−703. (79) Ang, W. H.; Parker, L. J.; De Luca, A.; Juillerat-Jeanneret, L.; Morton, C. J.; Lo Bello, M.; Parker, M. W.; Dyson, P. J. Angew. Chem., Int. Ed. 2009, 48, 3854−3857. (80) Turel, I.; Kljun, J.; Perdih, F.; Morozova, E.; Bakulev, V.; Kasyanenko, N.; Byl, J. A. W.; Osheroff, N. Inorg. Chem. 2010, 49, 10750−10752. 5684


Organometallics

Review

(137) Savignac, M.; Sasaki, A.; Potier, P.; Jaouen, G. J. Chem. Soc., Chem. Commun. 1991, 615−617. (138) Varenne, A.; Salmain, M.; Brisson, C.; Jaouen, G. Bioconjugate Chem. 1992, 3, 471−476. (139) Salmain, M.; Jaouen, G. J. Organomet. Chem. 1993, 445, 237− 243. (140) Vessieres, A.; Salmain, M.; Brossier, P.; Jaouen, G. J. Pharm. Biomed. Anal. 1999, 21, 625−633. (141) Vessieres, A.; Tondu, S.; Jaouen, G.; Top, S.; Ismail, A. A.; Teutsch, G.; Moguilewsky, M. Inorg. Chem. 1988, 27, 1850−1852. (142) Philomin, V.; Vessieres, A.; Gruselle, M.; Jaouen, G. Bioconjugate Chem. 1993, 4, 419−424. (143) Vessieres, A.; Top, S.; Vaillant, C.; Osella, D.; Mornon, J.; Jaouen, G. Angew. Chem. 1992, 104, 790−792. (144) Nervi, C.; Gobetto, R.; Milone, L.; Viale, A.; Rosenberg, E.; Spada, F.; Rokhsana, D.; Fiedler, J. J. Organomet. Chem. 2004, 689, 1796−1805. (145) Rosenberg, E.; Spada, F.; Sugden, K.; Martin, B.; Gobetto, R.; Milone, L.; Viale, A. J. Organomet. Chem. 2004, 689, 4729−4738. (146) Colangelo, D.; Ghiglia, A.; Ghezzi, A.; Ravera, M.; Rosenberg, E.; Spada, F.; Osella, D. J. Inorg. Biochem. 2005, 99, 505−512. (147) Kong, K. V.; Leong, W. K.; Lim, L. H. K. J. Organomet. Chem. 2009, 694, 834−839.

(107) Baker, M. V.; Barnard, P. J.; Berners-Price, S. J.; Brayshaw, S. K.; Hickey, J. L.; Skelton, B. W.; White, A. H. Dalton Trans. 2006, 3708−3715. (108) Rush, G. F.; Smith, P. F.; Hoke, G. D.; Alberts, D. W.; Snyder, R. M.; Mirabelli, C. K. Toxicol. Appl. Pharmacol. 1987, 90, 391−400. (109) Rush, G. F.; Smith, P. F.; Alberts, D. W.; Mirabelli, C. K.; Snyder, R. M.; Crooke, S. T.; Sowinski, J.; Jones, H. B.; Bugelski, P. J. Toxicol. Appl. Pharmacol. 1987, 90, 377−390. (110) Hickey, J. L.; Ruhayel, R. A.; Barnard, P. J.; Baker, M. V.; Berners-Price, S. J.; Filipovska, A. J. Am. Chem. Soc. 2008, 130, 12570− 12571. (111) Jellicoe, M. M.; Nichols, S. J.; Callus, B. A.; Baker, M. V.; Barnard, P. J.; Berners-Price, S. J.; Whelan, J.; Yeoh, G. C.; Filipovska, A. Carcinogenesis 2008, 29, 1124−1133. (112) Wang, C.-H.; Shih, W.-C.; Chang, H. C.; Kuo, Y.-Y.; Hung, W.C.; Ong, T.-G.; Li, W.-S. J. Med. Chem. 2011, 54, 5245−5249. (113) Lemke, J.; Metzler-Nolte, N. Eur. J. Inorg. Chem. 2008, 3359− 3366. (114) Koster, S. D.; Alborzinia, H.; Can, S.; Kitanovic, I.; Wolfl, S.; Rubbiani, R.; Ott, I.; Riesterer, P.; Prokop, A.; Merz, K.; MetzlerNolte, N. Chem. Sci. 2012, in press. (115) Ray, S.; Mohan, R.; Singh, J. K.; Samantaray, M. K.; Shaikh, M. M.; Panda, D.; Ghosh, P. J. Am. Chem. Soc. 2007, 129, 15042−15053. (116) Ray, S.; Asthana, J.; Tanski, J. M.; Shaikh, M. M.; Panda, D.; Ghosh, P. J. Organomet. Chem. 2009, 694, 2328−2335. (117) Teyssot, M.-L.; Jarrousse, A.-S.; Chevry, A.; De Haze, A.; Beaudoin, C.; Manin, M.; Nolan, S. P.; Díez-González, S.; Morel, L.; Gautier, A. Chem. Eur. J. 2009, 15, 314−318. (118) Vergara, E.; Cerrada, E.; Casini, A.; Zava, O.; Laguna, M.; Dyson, P. J. Organometallics 2010, 29, 2596−2603. (119) Schuh, E.; Valiahdi, S. M.; Jakupec, M. A.; Keppler, B. K.; Chiba, P.; Mohr, F. Dalton Trans. 2009, 10841−10845. (120) Amouri, H.; Moussa, J.; Renfrew, A. K.; Dyson, P. J.; Rager, M. N.; Chamoreau, L. M. Angew. Chem., Int. Ed. 2010, 49, 7530−7533. (121) Hartinger, C. G. Angew. Chem., Int. Ed. 2010, 49, 8304−8305. (122) Manzotti, C.; Pratesi, G.; Menta, E.; Domenico, R. D.; Cavalletti, E.; Fiebig, H. H.; Kelland, L. R.; Farrell, N.; Polizzi, D.; Supino, R.; Pezzoni, G.; Zunino, F. Clin. Cancer Res. 2000, 6, 2626− 2634. (123) Jodrell, D. I.; Evans, T. R.; Steward, W.; Cameron, D.; Prendiville, J.; Aschele, C.; Noberasco, C.; Lind, M.; Carmichael, J.; Dobbs, N.; Camboni, G.; Gatti, B.; De Braud, F. Eur. J. Cancer 2004, 40, 1872−1877. (124) Hartinger, C. G.; Phillips, A. D.; Nazarov, A. A. Curr. Top. Med. Chem. 2011, 11, 2688−2702. (125) Giannini, F.; Suss-Fink, G.; Furrer, J. Inorg. Chem. 2011, 50, 10552−10554. (126) Zutphen, S. v.; Reedijk, J. Coord. Chem. Rev. 2005, 249, 2845− 2853. (127) Matsumura, Y.; Maeda, H. Cancer Res. 1986, 46, 6387−6392. (128) Mufula, A. I.; Neuse, E. W. J. Inorg. Organomet. Polym. Mater. 2012, 22, 134−148. (129) Govender, P.; Renfrew, A. K.; Clavel, C. M.; Dyson, P. J.; Therrien, B.; Smith, G. S. Dalton Trans. 2011, 40, 1158−1167. (130) Ang, W. H.; Daldini, E.; Juillerat-Jeanneret, L.; Dyson, P. J. Inorg. Chem. 2007, 46, 9048−9050. (131) Haquette, P.; Salmain, M.; Svedlung, K.; Martel, A.; Rudolf, B.; Zakrzewski, J.; Cordier, S.; Roisnel, T.; Fosse, C.; Jaouen, G. ChemBioChem 2007, 8, 224−231. (132) Tan, Y. Q.; Dyson, P. J.; Ang, W. H. Organometallics 2011, 30, 5965−5971. (133) Hanif, M.; Nazarov, A. A.; Legin, A.; Groessl, M.; Arion, V. B.; Jakupec, M. A.; Tsybin, Y. O.; Dyson, P. J.; Keppler, B. K.; Hartinger, C. G. Chem. Commun. 2012, 48, 1475−1477. (134) Caruso, F.; Rossi, M. Mini-Rev. Med. Chem. 2004, 4, 49−60. (135) Therrien, B.; Suess-Fink, G.; Govindaswamy, P.; Renfrew, A. K.; Dyson, P. J. Angew. Chem., Int. Ed. 2008, 47, 3773−3776. (136) Sasaki, N. A.; Potier, P.; Savignac, M.; Jaouen, G. Tetrahedron Lett. 1988, 29, 5759−5762. 5685


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