Ruthenium Compounds As Anticancer Agents

Ruthenium compounds as anticancer agents New ruthenium-based compounds with fewer and less severe side effects, could replace longstanding platinum-based anticancer drugs Simon Page In short This observation led to cis- diamminedichloroplatinum(II), ● As clinical trials progress, ruthenium commonly known as cisplatin, being compounds may approved by the American Food and provide a less toxic and Drugs Administration (FDA) for more effective cancer therapy in 1978. It has since alternative to become the most widely used platinum therapies anticancer drug, with an estimated ● Many different 70% of patients receiving the ruthenium compounds compound as part of their treatment.1 have been tested for their anticancer Cisplatin properties, without Cisplatin was heralded as a completely enough investigation novel type of antitumour agent, and its into their mode(s) of discovery enticed a veritable army of action inorganic chemists to devise and test other precious metal-based therapies. Disappointingly however, fifty years and countless clinical candidates later, there have only been two more worldwide drug approvals for precious metal-containing anticancer drugs: carboplatin and oxaliplatin – both of which are direct analogues of cisplatin (fig 1) – approved in 1993 and 2002 respectively. The mode of action of these platinum complexes is known: the chloride or dicarboxylate ligands are hydrolysed within the cell to generate a bis-aqua species, which binds irreversibly to DNA – usually to two adjacent guanine bases – (fig 2) and the cell, unable to replicate, defaults to apoptosis (that SHUTTERSTOCK is, controlled cell death). Platinum therapies Rosenberg used a platinum electrode From platinum to ruthenium For half a century, the field of metal- to apply an electric field to a colony of Whilst the chemotherapeutic success based anticancer drugs has been E. coli, which was observed to inhibit of platinum is undeniable, it is by no dominated by the precious metal their growth. A diligent investigation means the perfect drug. It is not platinum. The discovery of platinum’s into the cause of this effect concluded effective against many common types anticancer properties was made by that the platinum electrode was of cancer, drug resistance is common chance during an experiment in 1965, breaking down to generate and it has a deplorable range of side conducted at Michigan State platinum(II) species in situ, which was effects, which can include nerve University by Barnett Rosenberg. stopping the cells from multiplying. damage, hair loss and nausea. 26 | EDUCATION IN CHEMISTRY | January 2012 www.rsc.org/eic O H concentration of molecular oxygen 1 N H2N Cl H2N O O O (due to their higher metabolic rate and Pt Pt Pt remoteness from the blood supply). H2N Cl H N O O O 2 N These two factors taken in parallel O H mean that compounds of ruthenium can be administered in the (relatively To overcome these limitations, Fig 1 Furthermore, ruthenium tends to inert) III oxidation state, causing some compounds based on ruthenium The chemical form octahedral complexes, which minimal damage to healthy cells, but have been developed and tested structures of gives the chemist two more ligands to being reduced to the (active) II against cancer cell lines. These cisplatin, exploit compared with platinum(II) oxidation state in cancer cells.3 compounds tend to cause fewer (and carboplatin and complexes, which adopt a square Recently, however, this theory has less severe) side effects compared to oxaliplatin planar geometry. Ruthenium can also come under considerable criticism platinum drugs. form strong chemical bonds with a and even the question of how Ruthenium’s properties are well range of different elements of varying ruthenium compounds enter cells has suited towards pharmacological chemical ‘hardness’ and been the subject of some literature debate. 2 Can ruthenium impersonate iron? Ruthenium is a transition metal in group 8 – the same chemical group as iron. Iron, in spite of its potential reactivity and biological toxicity, is a key element without which most cells cannot survive. In fact, nature has developed considerable machinery to sequester, transport and make use of iron. The fact that iron and ruthenium are in the same chemical group has led to some chemists postulating that it is capable of taking iron’s place in some proteins, most notably in the chaperone and uptake protein 4 AMERICAN CHEMICAL SOCIETY transferrin. However, others remain skeptical that the two metals are applications. It can access a range of Fig 2 electronegativities, meaning that similar enough to be interchangeable; oxidation states (II, III and IV) under A crystal structure ruthenium can bind to a range of specifically, ruthenium binds tighter physiologically relevant conditions. showing cisplatin biomolecules, not just DNA. and more slowly than iron and has a Also, the energy barriers to (red) binding to preference for ‘softer’ ligands. Nature interconversion between these and ‘kinking’ DNA Why is ruthenium less toxic? has also developed extremely high oxidation states is relatively low, (grey)2 One hypothesis as to why ruthenium affinity iron binding sites (eg allowing for ready oxidation state compounds are less toxic in general transferrin holds iron with a binding changes when inside the cell. In spite than platinum drugs is ‘Activation by constant of 1023 M-1), and it has been of this flexibility in oxidation state, Reduction’. This theory is based on the questioned whether ruthenium can ruthenium complexes display observation that ruthenium(III) outcompete iron in these contexts. relatively slow ligand exchange rates in Fig 3 complexes are more inert than Another suggestion is that ruthenium water (fig 3) – its kinetics are on the The ligand exchange ruthenium(II), which can partially be can bind to other sites on transferrin, timescale of cellular reproduction rates of platinum attributed to its higher effective and ‘piggy-back’ into the cell when group metals are 5 (mitosis), meaning that if a ruthenium nuclear charge (Zeff). Also, cancerous iron is taken into the cell (fig 4). ion does bind to something in the cell, considerably slower cells tend to have a more chemically it is likely to remain bound for the than those of other reducing environment than healthy Key molecules remainder of that cell’s lifetime. metals cells, owing to their lower Two ruthenium compounds are currently undergoing clinical 3 evaluation as anticancer drugs (as far as the author is aware): NAMI-A and KP1019 (fig 5). A great deal of the remaining literature can be categorised as follows: Coordination Compounds EEDJICK R In ‘classical’ coordination compounds, the metal is surrounded by Lewis bases with lone pairs. The compounds IMON PAGE/J S KP1019 and NAMI-A fall into this www.rsc.org/eic January 2012 | EDUCATION IN CHEMISTRY | 27 4 Fig 6 6 An example of a RAPTA complex presence of a facially-coordinated aromatic ring (which is relatively hydrophobic) and a PTA (1,3,5-triaza-7-phosphaadamantane) ligand (which is highly water soluble). Oddly, RAPTA complexes display a similar spectrum of activity to the coordination complex NAMI-A, in spite of their apparent differences in oxidation state, ligands, charge and geometry. Fig 4 Multinuclear Ruthenium The ability of ruthenium species to ‘piggy-backing’ form multinuclear and into cells on the supramolecular architectures has been surface of the iron AGE/RICHARDWHEELER known for some time, but their P uptake protein application to medicinal chemistry has IMON S transferrin. only been explored recently. Some particularly interesting category. Given that these compounds few treatment options for secondary strategies include ruthenium- have some ligands that can feasibly be (metastatic) cancers, and the platinum mixed-metal compounds,6 hydrolysed (eg chloride, DMSO), it is prognosis for patients who develop ruthenium cluster complexes,7 thought that the actual ‘active’ this form of the disease is much worse. ruthenium DNA intercalators8 and molecules which reach the cancer cell supramolecular ‘Trojan Horses’, which are unlikely to be the same as the Organometallics contain a cytotoxic payload that is molecular structures shown (fig 5). An organometallic complex is often released upon entry to the cancer cell9 KP1019 and NAMI-A appear to be defined as a molecule with a distinct (fig 7). quite similar structurally (both are metal-carbon bond. Although they + Ru(III) complexes with chloride and have a reputation as being unstable Directed therapies heterocyclic ligands and a heterocyclic compounds, better known for Recently, chemists have developed counterion) yet they display spontaneous combustion than compounds where a precious metal remarkably different types of therapeutic effects, some ruthenium is chemically linked to an ‘organic anticancer activity: KP1019 is active organometallics have displayed high directing molecule’ (ODM), which against primary cancers (ie the main water- and air-stability and an has a known biological target – eg a tumour mass which forms first in a interesting spectrum of anticancer drug molecule. It has been patient), whereas NAMI-A is active activity. speculated that the organic molecule against secondary tumour cells (ie the Arguably the most successful can ‘lead’ the metal into the cell and metastases which form after cells from ruthenium organometallic anticancer to a specific target. If the metal then the primary tumour have moved to a complexes have been the so-called binds directly to the cellular target,

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