shutterstock Simon Page longstanding platinum-based anticancer drugs New ruthenium-based compounds with fewer and less severe side effects, could replace anticancer agents Ruthenium compounds as 26 | University by Barnett Rosenberg. conducted at Michigan State chance during an experiment in 1965, anticancer properties was made by platinum. The discovery of platinum’s dominated by the precious metal based anticancer drugs has been For half a century, the field of metal- Platinum therapies Education in C h e mi s try | January 2012 January stopping the cells from multiplying. platinum(II) species breaking down to generate that the platinum electrode was into the cause of this effect concluded their growth. A diligent investigation E. coli, to apply an electric field to a colony of Rosenberg used a platinum electrode which was observed to inhibit in situ, which was platinum therapies alternative to more effective provide a less toxic and compounds may progress, ruthenium action into their mode(s) of enough investigation properties, without their anticancer have been tested for ruthenium compounds ● In short ● ● ● As As clinical trials Many different compound as part of their treatment. 70% of patients receiving the anticancer drug, with an estimated become the most widely used cancer therapy in 1978. It has since Drugs Administration (FDA) for approved by the American Food and commonly known as cisplatin, being diamminedichloroplatinum(II), and 2002 respectively. cisplatin ( both of which are direct analogues of drugs: carboplatin and oxaliplatin – precious metal-containing anticancer worldwide drug approvals for there have only been two more and countless clinical candidates later, damage, hair loss and nausea. effects, which can include nerve and it has a deplorable range of side of cancer, drug resistance is common effective against many common types means the perfect drug. It is not of platinum is undeniable, it is by no Whilst the chemotherapeutic success From platinum to ruthenium other precious metal-based therapies. inorganic chemists to devise and test discovery enticed a veritable army of novel type of antitumour agent, and its Cisplatin was heralded as a completely Cisplatin is, controlledis, cell death). replicate, defaults to apoptosis (that (fig 2) and the cell, unable to to two adjacent guanine bases – binds irreversibly to DNA – usually generate a which bis-aqua species, hydrolysed within the cell to chloride or dicarboxylate ligands are platinum complexes is known: the This observation led to cis- The mode of action of these Disappointingly however, fifty years fig 1 ) – approved in 1993 www.rsc.org/eic 1 Simon Page/J ReedJick american chemical society remainder of that cell’s lifetime. it is likely to remain bound for the ion does bind to something in the cell, (mitosis), meaning that if a ruthenium timescale of cellular reproduction water ( relatively slow ligand exchange rates in ruthenium complexes display of this flexibility in oxidation state, changes when inside the cell. In spite allowing for ready oxidation state oxidation states is relatively low, interconversion between these Also, the energy barriers to physiologically relevant conditions. oxidation states (II, III and IV) under applications. It can access a range of suited towards pharmacological platinum drugs. less severe) side effects compared to compounds tend to cause fewer (and against cancer cell lines. These have been developed and tested some compounds based on ruthenium www.rsc.org/eic 1 3 2 Ruthenium’s properties are well To overcome these limitations, fig 3 ) – its kinetics are on the H H 2 2 N N Pt Cl Cl H H 2 2 N N Pt Fig 3 (grey) and ‘kinking’ DNA (red) binding to showing cisplatin A structure crystal Fig 2 oxaliplatin carboplatin and cisplatin, structures of The chemical Fig 1 metals than those of other considerably slower group metals are rates of platinum The ligand exchange O O 2 O O biomolecules, not just DNA. ruthenium can bind to a range of electronegativities, meaning that chemical ‘hardness’ and range of different elements of varying form strong chemical bonds with a planar geometry. Ruthenium can also complexes, which adopt a square exploit compared with platinum(II) gives the chemist two more ligands to form octahedral complexes, which Furthermore, ruthenium tends to cells, owing to their lower reducing environment than healthy cells tend to have a more chemically nuclear charge (Z attributed to its higher effective ruthenium(II), which can partially be complexes are more inert than observation that ruthenium(III) Reduction’. This theory is based on the than platinum drugs is ‘Activation by compounds are less toxic in general One hypothesis as to why ruthenium Why is ruthenium less toxic? H N N H Pt eff O O ). Also, cancerous O O January 2012 January | KP1019 and NAMI-A fall into this bases with lone pairs. The compounds the metal is surrounded by Lewis debate. been the subject of some literature ruthenium compounds enter cells has and even the question of how come under considerable criticism Recently, however, this theory has transferrin. chaperone and uptake protein some proteins, most notably in the it is capable of taking iron’s place in led to some chemists postulating that are in the same chemical group has iron. The fact that iron andruthenium sequester, transport and make use of developed considerable machinery to cannot survive. In fact, nature has key element without which most cells reactivity and biological toxicity, is a iron. Iron, in spite of its potential group 8 – the same chemical group as Ruthenium is a transition metal in iron? Can ruthenium impersonate oxidation state in cancer cells. being reduced to the (active) II minimal damage to healthy cells, but inert) III oxidation state, causing can be administered in the (relatively mean that compounds of ruthenium These two factors taken in parallel remoteness from the blood supply). (due to their higher metabolic rate and concentration of molecular oxygen I Coordination Compounds categorised as follows: remaining literature can be KP1019 ( as the author is aware): NAMI-A and evaluation as anticancer drugs (as far currently undergoing clinical Two ruthenium compounds are Key molecules iron is taken into the cell constant of 10 transferrin holds iron with a binding affinity iron binding sites (eg has also developed extremely high preference for ‘softer’ ligands. Nature and more slowly than iron and has a specifically,ruthenium binds tighter similar enough to be interchangeable; skeptical that the two metals are and ‘piggy-back’ into can bind to other sites on transferrin, Another suggestion is that ruthenium outcompete iron in these contexts. questioned whether ruthenium can n ‘classical’ coordination compounds, Education in fig 5 4 However, others remain ). A great deal of the 23 M -1 ), and it has been the cell when C h ( fig 4 e mi ) s 3 . 5 try | 27 Simon page/richard wheeler Ru(III) quite similar structurally (both are molecular structures shown ( are unlikely to be the same as the molecules which reach the cancer cell thought that the actual ‘active’ hydrolysed (eg chloride, DMSO), it is have some ligands that can feasibly be category. Given that these compounds bloodstream). Currently there are very different organ, eg via the the primary tumour have moved to a metastases which form after cells from against secondary tumour cells (ie the patient), whereas NAMI-A is active tumour mass which forms first in a against primary cancers (ie the main anticancer activity: KP1019 is active remarkably different types of counterion) yet they display heterocyclic ligands and a heterocyclic 28 | 4 KP1019 and NAMI-A appear to be 5 Education in + complexes with chloride and Cl Cl O Ru N SH NH Cl Cl C h e H N mi NH s try fig 5 | ). January 2012 January complexes are characterised by the ‘RAPTA’ complexes ( complexes have been the so-called ruthenium organometallic anticancer activity. interesting spectrum of anticancer water- and air-stability and an organometallics have displayed high therapeutic effects, someruthenium spontaneous combustion than compounds, better known for have a reputation as being unstable metal-carbon bond. Although they definedas a moleculewith a distinct An organometallic complex is often Organometallics this form of the disease is much worse. prognosis for patients who develop (metastatic) cancers, and the few treatment options for secondary Arguably the most successful Cl Cl HN Ru N N NH Cl Cl fig 6 HN ). RAPTA H N transferrin. uptake protein of surface the iron into cells on the ‘piggy-backing’ Ruthenium Fig 4 RAPTA complex An example of a Fig 6 enter clinical trials compounds to anticancer first ruthenium and KP1019, the to right) NAMI-A structures of (left Chemical Fig 5

released upon entry to the cancer cell contain a cytotoxic payload that is supramolecular ‘Trojan Horses’, which platinum mixed-metal compounds, strategies include ruthenium- only been explored recently. application to medicinal chemistry has known for some time, but their supramolecular architectures has been form multinuclear and The ability ofruthenium species to Multinuclear charge and geometry. differences in oxidation state, ligands, in spite NAMI-A, of their apparent to the coordination complex display a similar of spectrum activity soluble). Oddly, RAPTA complexes ligand (which is highly water (1,3,5-triaza-7-phosphaadamantane) hydrophobic) and a PTA aromatic ring (which is relatively presence of a facially-coordinated structure-based drug discovery (ie against a biological target) towards databases of molecules are screened discovery (ie those where vast throughput approaches to drug has been a trend away from high- A recent trend in medicinal chemistry drugs Biological target of ruthenium rational form of drug design. known, making this strategy a more biological target of the molecule is the above work is that here the differencebetween this strategy and of the drug (fig 8). The main could massively increase the potency binds directly to the cellular target, it to a target. specific If the metal then can ‘lead’ the metal into the cell and speculated that the organic molecule drug molecule. It has been has a known biological target – eg a directing molecule’ (ODM), which is chemically linked to an ‘organic compounds where a precious metal Recently, chemists have developed Directed therapies ruthenium cluster complexes, ruthenium DNA intercalators ( fig 7 Some particularly interesting 6 ). www.rsc.org/eic 7 8

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Simon page www.rsc.org/eic of different compounds to screen but instead generating large numbers biological target for their compounds, current approach, without a clear ruthenium drug design. to three possible strategies for future unknown mode of action. This leads ruthenium drug discovery is their trials. However, a major limitation in are being evaluated in phase II clinical and humans. To date, two compounds anticancer activity in cells, animals have shown highly promising In conclusion, ruthenium compounds Future ruthenium drugs discovering a drug. 50% of the cost associated with research estimates can save around biological target) which recent specific structural information about a those where drug design is based on of action of these complexes. work aimed at elucidating the modes with relatively little rational design or generating novel complexes for testing, deal of research has been directed at unknown) proteins. To date, a great compounds target DNA or (as yet two main theories are that ruthenium agreed biological target. Currently, the limitation in the field is the lack of an Chemists could continue the 7 Ruthenium DNA intercalator Ruthenium cluster complex 10 However, a major target protein Fig 8 complexes anticancer ruthenium multinuclear Selected Fig 7 active active Acid (B) near the a Lewis Basic Amino directs a metal (M) to An organic molecule 8 site of a Supramolecular ‘Trojan Horse’ it gets into cells etc – chemists can media – what it prefers to bind to, how ruthenium behaves in biological detailed information about how compounds. Then, armed with action of existing ruthenium be directed at eliciting the mode of regulatory approval. complexes could complicate physiological target of the resultant and a lack of information about the simplicity, but it would be inefficient This strategy has the advantage of molecule affect its anticancer activity. different functional groups on the in order to determine how altering structure-activity relationships (SARs) This approach could include against different targets and cell lines. Ruthenium-platinum mixed Alternatively, more research could metal complex begin to design ruthenium drugs which have a January 2012 January | powerful and effective drugs. of the periodic table to generate potential of the less explored regions oxygen, and begin to consider the carbon, hydrogen, nitrogen and classical ‘biological’ elements of medicinal chemists look beyond the literature point towards a future where containing drug candidates in the exciting reports of new ruthenium- clinical trials, and the frequent and progress of ruthenium compounds in anticancer drugs. The continued newly emerging field of ruthenium as more and more chemists enter the followed to a greater or lesser degree, all three of these approaches will be crystallography. enzyme inhibition studies and protein studies can be performed – such as target against which enzymological known (or, at least, desired) biological approach is that the compound has a medicines. The advantage to this available to ‘traditional’ organic energy mode of bonding which isn’t offers medicinal chemists a high- between the metal and the target The high-energy interaction set up nearby residue of the same protein. attached ruthenium ion binds to a active site of an enzyme and the an organic molecule binds to the ruthenium-ODM complexes, in which the generation of further to ruthenium drug design would be if a target can be identified. strategy could be highly advantageous far less severe side effects. This high affinity for cancer targets, with 1. at Chemistry the University of Cambridge Research UK PhD Programme in Medicinal Simon Page is a PhD student in the Cancer 2. 5. 4. 3. 6. References 7. 9. 8. 10. A Dorcier P Takahara (DOI: 10.1021/om060394o) S Page DOI: 10.1016/j.bbagen.2011.07.003 J Vincent and S Love, (DOI: 10.1039/B511792E) P Schluga DOI: 10.1021/ja9625079) (DOI: 10.1021/ic062419h) A Herman (DOI: 10.4155/fmc.09.25) B Therrien B Therrien (DOI: 10.1002/ejic.200500110) A Hotze (DOI: 10.1007/s10876-007-0140-y) (DOI: 10.1002/anie.200800186) Of course, in reality, it is likely that The final and most recent approach R Stevens, (DOI: 10.1038/nsmb0404-293) Education in et al, et al, Eur. J. Inorg. Chem., et al, Organometallics, 2006, et al, Dalton Trans., et al, et al, et al, J. Cluster Sci., et al, Future Med. Chem., 2009, Nat. Struct. Mol. Biol., 2004, Inorg. Chem., 2008, . Angew J. Am. Chem. , Soc 1996, Biochim. Biophys. Acta, 2011, Chem. Int. Ed., 2008, 2007, 2006, 1796 C 2005, 2648 h 18, 741 47, 274 e 1, 541 mi 25, 4090 11, 293 118, 12309 s try 47, 3773 | 29