Beautifully, its processes exhibit quantitative reaction yield, low E factor, excellent atom economy, absence of toxic metals and solvents, ultra-purity of products, excellent chemoselectivity and outstanding reaction reproducibility throughout billions of years — all accomplished at ambient temperature in water Figure 1 a. Conversely, synthetic processes prevail with breadth of substrate scope and reaction kinetics, but only due to availability of powerful organometallic catalysts, which, in combination with other discoveries in chemistry, materials and other disciplines, have enabled synthetic organic chemists to construct almost any desired molecule.
Astonishing catalytic transformations have been developed with modified enzymes 1 , nanomaterials 2 , photoredox chemistry 3 and organocatalysts 4. Asymmetric catalysis has led to independence from chiral auxiliaries and nonracemic starting materials 5. The 18th and 19th century progenitors of organometallic chemistry, Cadet 6 , Frankland 7 and Zeise 8 , could not have imagined this boom in organometallic catalysis, which continues into the 21st century with milestones including the birth of nanocatalysis 9 , the renaissance of photoredox catalysis 10 and the harnessing of micellar conditions to perform air-sensitive chemistry in water at room temperature While following Nature and enjoying the wealth of chemical properties of transition metals, one must marvel at how amazingly our processes differ.
Are they not responsible for huge chemical waste generation? This issue is somewhat truer with chemistry laboratories in academia where we put much focus on current trends while ignoring sustainability issues, deferring the topic to process chemists. Our preset perceptions sometimes blind us from important innovations, which may be particularly true for sustainability in chemical catalysis. If Nature can perform biochemical catalysis so ideally, why is it not generally possible to perform chemical catalysis in the same fashion?
Perhaps this goal presently seems unrealistic. Due to older beliefs, even gold was considered catalytically inactive 14 , leaving Sir Geoffrey C. Developments helping to save our reserves of threatened metals through the merger of photoredox chemistry with enzymatic, micellar and nanocatalysis are also noteworthy 1 — 4. Accordingly, endeavours to discover sustainable new catalysts, transformations and technologies that will preserve our beautiful blue planet should be undertaken with careful attention to all aspects of how Nature performs chemistry.
Such attention will yield solutions to many current and even untouched problems. Organometallic catalysis has a rich history. However, the traditional classification of metalloid complexes as organometallics would date the first synthesis of an organometallic compound to , when Cadet encountered the foul smell of cacodyl oxide and tetramethyldiarsine, generated from arsenic-containing cobalt salts while trying to develop new invisible inks 6. Further noteworthy metal alkyl complexes were reported between and , including diethyl zinc, tetraethyl tin, diethyl mercury and trimethylboron 18 , The first metal carbonyl complex, dichlorodicarbonyl platinum, was synthesised in , followed by syntheses of binary metal carbonyl complexes, including tetracarbonyl nickel in and pentacarbonyl iron in At the time, catalytic utility was unknown, and the bonding and structure of organometallic complexes was a mystery.
Early assumptions held that ligands were aligned in a chain with metal at the terminus. The coordination theory proposed by Werner in based on his experimental data was the first of many models to more correctly explain the nature of bonding in organometallic complexes Discovery of metal complexes important from catalysis perspective. The seminal application of organomagnesium compounds to organic synthesis by Barbier, Grignard and Sabatier occurred in 21 , 22 , and the birth of organometallic catalysis was soon to follow. This work initialised homogeneous catalysis and organometallic chemistry with its reports on the first alkyl metal and metal hydride catalysts Subsequently, Sabatier clearly distinguished homogeneous and heterogeneous catalysis through his method development for hydrogenation of organic compounds in the presence of finely divided metals 24 , an achievement that led to a Nobel Prize in Chemistry shared with Grignard in Important milestones during the next 50 years include the Fischer-Tropsch synthesis of linear hydrocarbons from syngas 25 — 27 , vanadium oxide catalysed oxidation of benzene 28 , silver-catalysed epoxidation of ethylene 29 , cobalt-catalysed hydroformylation of olefins, the oxo process 30 , the Pd-Cu-mediated Wacker process for acetaldehyde formation 31 and the Ziegler-Natta catalysts for olefin polymerisation, which earned their developers the Nobel Prize in Chemistry.
The Wacker process in particular was a bellwether of future directions, being the first useful transformation to employ homogeneous organopalladium catalysis. In Fischer isolated the first metal-carbene complex 33 , a tungsten-based complex that later provided a simple and fascinating means of olefin metathesis Another important achievement was the development of the first homogeneous hydrogenation in , independently reported by Wilkinson and Coffey 35 , This work marked the advent of asymmetric organometallic catalysis.
At about the same time, Kagan reported an asymmetric rhodium-catalysed hydrogenation to obtain chiral amino acids using a C-2 symmetric chiral 2,3- O -isopropylidene-2,3-dihydroxy-1,4-bis diphenylphosphino butane DIOP ligand 38 , a discovery that soon led to the synthesis of enantiomerically pure L -3,4-dihydroxyphenylalanine L-DOPA by Knowles Scheme II b Thereafter, asymmetric epoxidation of allylic alcohols was reported by Sharpless These many discoveries in asymmetric catalysis by Knowles, Sharpless and Noyori earned them a Nobel Prize in Asymmetric catalysis at a very early stage.
The intense scientific interest in organometallic catalysis has not abated in the new millennium with Nobel Prizes being awarded for work in the area in and At present, however, it is shocking to observe that we seemingly have yet to fully realise the challenges that will be faced for decades into the foreseeable future. Awareness has begun to take root, thanks to the emergence of the green chemistry concept beginning in and its promotion of a more sustainable and environmentally responsible practice of chemistry Many advancements in organometallic catalysis and synthesis have been achieved and a few of them are summarised here.
When has Nature ever run a reaction in organic solvent? So if Nature can do chemistry in an aqueous environment, why then do chemists not do the same? Partly, we are not able to perfectly mimic Nature in every aspect, but conducting catalysis in water, even at room temperature, is certainly possible.
However, performing chemistry in water and then introducing that water into the waste stream would still adversely impact our environment and be a topic of criticism. The cost of such contaminated water treatment may even be greater than the disposal of organic solvents, and of course, the impact may be more detrimental. Is it possible to recycle the water if contaminated from catalytic reactions that are conducted in water? The hydrophobic interior of nanomicelles has been harnessed for chemical catalysis. In addition, asymmetric gold catalysis, aerobic oxidation, ring-closing metathesis RCM , Cu-H reductions, nitro reductions, trifluoromethylation and many more have been explored Figure 2 Interestingly, the authors are able to recycle the catalyst and reaction medium many times.
Amphiphile TPGS and its components are environmentally benign and do not yield any toxic fragments. Recycling has been performed without any energy intensive procedure. Products of resulting reactions have been extracted by a minimal amount of organic solvent and the aqueous layer is reused for the next catalytic reaction.
Reaction medium is an important parameter to the success of any catalytic process and the isolation of its resulting product. Large amounts of organic solvents are annually consumed in chemical transformations. Dissolution of all components of a reaction including the resulting product is traditionally considered as beneficial, especially for reaction yield and determining reaction kinetics and mechanism. With the emergence of green chemistry, this parameter has received fresh attention as chemists have begun to seek alternatives to conventional, oftentimes toxic, organic reaction media.
Financial concerns also prompt this renewed consideration, since with conventional reaction media we first pay upfront for toxic solvents and then pay again in the end for their disposal. While a temporary answer is to focus on the use of greener solvents, such as using 2-methyltetrahydrofuran in place of water-soluble THF, alternative reaction media are currently needed that are not only green but also do not lead to the same waste streams.
One class of alternative reaction medium, ionic liquids, has been put forward as a safer choice than organic solvents 45 , but despite the limited volatility, inert nature and relative stability of ionic liquids, risk of their post-reaction release into the environment is a significant concern. As Jordan and Gathergood noted: Supercritical carbon dioxide presents a nontoxic, nonflammable alternative, but high pressure and temperatures are required to maintain CO 2 in its liquefied state.
It has been explored as a reaction medium in many valued reactions such as Pd-catalysed Heck reactions and Rh-catalysed hydroformylation Traditionally, fluorinated solvents have also been considered to be safer and greener media This class includes perfluorinated hydrocarbons, fluorous amines and ethers. The characteristic supporting their greenness is their immiscibility with water, and thus, inability to contaminate water.
However, their miscibility with water is temperature-dependent. Heating the fluorous-bound catalyst in a non-fluorous solvent leads to homogeneity, resulting in catalysis. After reaction completion, cooling provides the separation of phases and ease of product separation from the organic solvent layer. New fluorous solvents, catalysts and reagents are now available that drop the costs associated with bond constructions Generally, switchable solvents reversibly change their physical properties in response to external stimulus such as a change in external temperature and addition or removal of gases.
For example, dimethyl sulfoxide DMSO is a high boiling solvent and this property makes product isolation very difficult. Piperylene sulfone 51 , a switchable solvent, has been used to replace DMSO for nucleophilic substitution reactions. Thus, it is more convenient to recover the solvent and reaction product.
An aqueous environment is also ideal for enzymatic processes, and many known transformations of synthetic utility can be effectively conducted Extension of the repertoire to other valued but unknown organic transformations catalysed by naturally occurring enzymes is the area of directed evolution Scheme IV With the aid of protein engineering, enzymatic properties can be fine-tuned through iterative mutagenesis, and then can be utilised as biocatalysts to perform target-oriented synthetic organic chemistry and enantioselective biocatalysis. Representative transformations using this approach include cyclopropanations 55 , aziridinations 56 and regio-divergent aminations Very recently, directed evolution of cytochrome c for carbon—silicon bond formation has been reported Enzymes had not previously been known to catalyse C—Si bond formation.
This conjuncture between living systems and synthetic organic chemistry is a stepping stone to mimic Nature. Using a similar approach, the same group were able to achieve enhanced catalytic activity of cytochrome c by a fold increase in turnover rate relative to the state-of-the-art synthetic catalyst for C—Si bond forming reactions.
The reaction proceeded with excellent yields and enantioselectivities over a broad substrate range. Such discoveries and developments represent a significant step forward for mimicry of Nature in catalysis and a move away from scarce metal catalysed processes. Nature directed enzymatic catalysis. Notwithstanding, these milestones in exploring enzyme-mediated transformations in water are not the only simpler alternatives to traditional non-sustainable organometallic catalysis and organic solvents. Nonetheless, recent studies by Kobayashi and co-workers further demonstrate the synthetic potential of water in catalysis Interestingly, neither the reaction partners nor the copper catalyst is soluble in water.
The superior results with water may be due the formation of higher order aggregated states of the catalyst. Annually, about a billion tonnes of bulk and fine chemicals are produced through metal-catalysed processes. A catalyst is generally used in sub-stoichiometric quantity as it is regenerated after completion of each catalytic cycle. From a pharmaceuticals industry perspective, it is equally important that the resulting product must be free from trace metal impurities which usually come from organometallic catalysts used in the process.
Thus, process chemists prefer to use such metal catalysts at early steps of the synthesis. However, sometimes it becomes more challenging to remove trace metal impurities, especially if the product is either an active pharmaceutical ingredient or its intermediate.
Thus, catalyst loading is also a very crucial parameter for product purity, especially for pharmaceutical and material chemists. There are many precedents for chemical transformations achieved with a very low catalyst loading 63 , However, many of them involve elevated temperature, microwave assistance, toxic organic solvents, dry reaction conditions, no opportunity to recycle the catalyst, limited substrate scope or excessive amounts of reactant. Despite these pitfalls, such contributions are steps toward sustainable catalysis.
Doucet and co-workers reported a low catalyst loading for ligand-free palladium-catalysed direct arylation of furans Scheme V a Key features of this work include high reaction yield, better atom economy than traditional Suzuki-Miyaura couplings, very low catalyst loading, high turnover number TON , high reaction yield and greater functional group tolerance with broad substrate scope.
Transition-metal catalysis at ppm levels of catalyst loading.
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A discovery of an artful RCM reaction by Dider Villemin and its further development through Grubbs and Schrock catalysts provided a new route to synthesise cyclic hydrocarbons With low catalyst loading, it has been explored on many substrates Scheme V b. However, all the dogs recovered afterward. The ferrocene-induced hepatic Fe overload could be reduced after the removal of large quantities of Fe by repeated venesection. Ferrocene can undergo a one-electron oxidation, yielding the ferrocenium cation see Scheme 1 , bottom.
This cation is rather stable and the redox reaction is reversible for most ferrocene derivatives. Simple ferrocenium salts were the first iron compounds for which an antiproliferative effect on certain types of cancer cells was demonstrated. Nuclear DNA, cell membrane, and the enzyme topoisomerase II 20 , 21 were proposed as possible targets. More precisely, Osella et al. Direct evidence for hydroxyl and superoxide radicals stems from ESR and spin-trapping experiments.
A more detailed review on the physiological chemistry of ferrocene and the antiproliferative properties of ferrocene or ferrocenium alone has recently been given elsewhere. They bound ferrocene to polymeric supports such as poly aspartamide. This assumption is confirmed by the fact that the cytotoxicity of ferricenium salts depends greatly on the nature of the counterion.
Indeed, the poorly soluble heptamolybdate is inactive while ferricenium salts with good aqueous solubility such as the picrate and trichloroacetate display high antitumor activity. Numerous ferrocene derivatives have been tested for antiproliferative purposes. The acridine moiety served to bring the ferrocene close to DNA by intercalation.
Schmalz and co-workers synthesized several nucleoside analogues of ferrocene 39 e. In more general terms, redox activity is a property that is not unique to metal compounds but frequently encountered with them. It is thus interesting to correlate the redox properties of metal compounds with electron transfer, oxidative stress, the formation of reactive oxygen species, and generally the redox status of cells.
However, a mechanism whereby redox activation induces anticancer activity in ferrocene derivatives has recently been suggested by Jaouen and co-workers. Increasing the length of the dimethylaminoalkyl chain has an adverse effect on receptor binding. In addition, it also changes the bioavailability and determines whether estrogenic or antiestrogenic activity is observed in animal experiments.
This indicates a new and different mode of action for 5. In an elegant study, redox activation has been proposed as the second mode of action. This intermediate is activated for nucleophilic attack by nucleophiles. Quinone methides of the metal-free 4-hydroxytamoxifen are known to be stable for hours under physiological conditions.
Adducts of such tamoxifen metabolites with glutathione and nucleobases are thought to be responsible for its general toxicity and mutagenic potential. It is now proposed that related chemistry applies to the activated ferrocifens. Moreover, production of reactive oxygen species has been demonstrated in cell lines treated with ferrocifen and derivatives.
It is particularly noteworthy that redox activity of the metallocene is the key for additional biological activity that exceeds that of a purely organic analogue. Once this redox-activation mode of action was established, it is clearly not dependent on the tamoxifen-related substructure. Recently, the same group has presented work on ferrocenyl diphenols and unconjugated phenol derivatives that also have good antiproliferative activity, presumably via a related mechanism of activation and formation of similar intermediates.
Following oxidation and proton abstraction a quinone methide is formed, which is readily attacked by nucleophiles at the positions indicated by arrows. In order to advance the use of ferrocifens toward clinical studies, several formulation studies were performed using nanoparticles, 60 lipid nanocapsules, 61 , 62 and cyclodextrins. For the bent metallocene dihalides, SARs were established for the halides, and substitution of the Cp rings 11 , 14 , 15 , 69 and model studies of such compounds with amino acids, nucleic acids, proteins, and blood plasma were performed.
Furthermore, because of its decomposition and low solubility in water, there were also problems with the formulation of the drug. Earlier work investigated DNA interaction, induction of apoptosis, and topoisomerase inhibition as possible modes of action. Despite the resemblance of titanocene dichloride with cisplatin, there has never been clear evidence of a similar mode of action, i. No protein targets were so far considered for the bent metallocenes. Titanocene Y 6 and the ansa-bridged derivatives titanocenes X 7 and Z 8.
The two main problems of the titanocene dihalides, i. To increase aqueous solubility, amino-substituted bent metallocenes were successfully prepared. The group of Tacke has developed a versatile synthetic access to Cp-substituted bent metallocenes via the fulvene route. This approach yields unbridged via hydrido lithiation as well as ansa -bridged metallocenes via carbo lithiation. Even more interesting, this compound showed very good activity against renal cell cancer and pleura mesothelioma cell lines, for which no effective chemotherapeutic agents are currently available.
In an obvious extension of their work and inspired by second-generation platinum drugs, the Tacke group has recently replaced the two chloride ligands on titanocene Y with carboxylate groups to yield equally active compounds with possibly even more favorable pharmacokinetics. Again with relation to cisplatin, DNA was envisaged as the target, and in early work, several X-ray structures with the Cp 2 Mo fragment coordinated to nucleobases were obtained.
Furthermore, extensive spectroscopic studies, mainly by 1 H and 31 P NMR, were carried out in solution to assess the binding mode of molybdocene dichloride with DNA. Together, these findings agree well with the notion that all metallocenes have a different biological profile. The idea of using ruthenium-containing organometallics as anticancer agents was first developed by Tochter et al.
It was initially anticipated that the binding of all ruthenium compounds to DNA was the main reason for their anticancer effect, similar to the platinum derivatives; i. However, the exact mechanism by which these metallodrugs exert their effects has not yet been fully understood. Nonetheless, in this section, we will highlight recent developments on the elucidation of the mechanism of action of anticancer ruthenium half-sandwich organometallic compounds, as well as the exact role of the metal center.
A nonexhaustive catalogue of ruthenium organometallic antitumor agents can be found in recent reviews or book chapters. However, to the best of our current knowledge, they appear to be much different. Indeed, the Ru arene compounds can only form monofunctional adducts compared to cisplatin which is known to form bifunctional adducts and DNA cross-links. As for Ru II arene ethylenediamine compounds, RAPTA derivatives containing two chloride ligands were also found to be susceptible to hydrolysis and it was first anticipated that DNA was a primary target.
In analogy to the Pt compounds, it was assumed that the carboxylato ligands would hydrolyze more slowly and in a more controllable way than the chloride ligands in the original RAPTA-C compound. All evidence taken together, RAPTA compounds seem to operate by a different mode of action compared to cisplatin, Ru II arene ethylenediamine compounds, and most of the known anticancer compounds in general. In vitro cytotoxicity studies showed that these compounds were much less cytotoxic than cisplatin.
Indeed, many of the RAPTA compounds could not even be classified as cytotoxic and were also nontoxic to healthy cells. The extent of this nontoxicity was proven in an in vivo study when healthy mice were treated at quite high doses with RAPTA compounds without triggering toxic side effects. Nonetheless, these very exciting findings engendered naturally a new and obvious question: The final answer has not yet been determined, but at this stage of the research, enzyme binding is the most probable explanation. Computer docking experiments validated this finding.
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Assuming that one of the two chloride ligands of the RAPTA derivatives was first replaced by a water molecule, it was then found that the Ru II center coordinates to the active site cysteine residue. Other proteins have been proposed as the target for Ru organometallics. P-Glycoprotein Pgp is a plasma membrane protein that is responsible for drug efflux from cells and is involved in multidrug resistance MDR. These newly formed complexes were found to be, in general, more cytotoxic and inhibited to a lesser extent the Pgp protein than the original Pgp inhibitor derivatives used as ligands.
Furthermore, because of the presence of the fluorescent anthracene group, it was observed that 13 was accumulating in cell nuclei, suggesting a DNA synthesis inhibition as the mechanism of cytotoxic action. Nonetheless, because of the strong increase in cytotoxicity upon ruthenium coordination, Dyson et al. EA is known to bind competitively to the hydrophobic cosubstrate H-site of GST, while the RAPTA compounds are recognized to react with soft nucleophilic centers such as thiol groups see above. As assumed, these two new compounds were found to bind the catalytic H-site in a similar fashion as EA.
The authors therefore concluded that the ruthenium centers were also involved in the inhibition of GST P Interestingly, it was demonstrated by X-ray crystallography and by ESI-MS that 16 decomposed, over a period of time, into a ruthenium derivative and EA. It is anticipated that the cleavage occurs, by virtue of a possible allosteric effect or simply over time, when the EA moiety of 16 is bound to the H-site. The compounds had a consistently higher potency against CQ-resistant parasites than the standard drug chloroquine diphosphate CQDP.
This is of clinical interest, as this type of tumor does not respond to currently employed chemotherapies. Ru arene chloroquinone antimalarial and antitumor agents. Other proteins have been shown to be the target of cytotoxic ruthenium organometallics. For example, Sheldrick et al. Although these complexes are remarkably inert toward ligand substitution. Surprisingly, these Ru complexes act as catalysts for the oxidation of the tripeptide glutathione GSH , which is a strong reducing agent present in millimolar concentrations in cells.
Indeed, millimolar amounts of GSH were oxidized to glutathione disulfide in the presence of micromolar ruthenium concentrations! It must be pointed out that Sadler et al. Interestingly, the o -bqdi complexes can be reduced by GSH but readily undergo reoxidation in air. The activity of these organometallics was found to be strongly influenced by the presence of the substituents.
IC 50 values of the fluoro compounds were in general much lower than those of the nonfluorinated analogues. Probably because of its reputation of being highly toxic see OsO 4 and relatively inert toward substitution, osmium organometallics have been neglected as therapeutic agents in comparison to its lighter congener ruthenium. Their results indicate that Os II organometallics might be promising candidates as antitumor drugs.
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The kinetic and thermodynamic properties found for the first Os complexes were unsatisfactory despite the fact that they were isostructural to the active Ru complexes. SARs were then established and then used to improve their activity. In order to restore activity, a new series of Os complexes were prepared in which the neutral N,N-chelate ethylenediamine was replaced by O,O and N,O anionic chelating ligands with a stronger trans effect.
They showed that complexes such as 25 had respectable antiproliferative activity in submicromolar to very low micromolar concentrations in three cell lines, with no significant differences between the Os and Ru complexes. This indicates that they exert their anticancer activity either by binding to crucial proteins or by noncovalent DNA interactions.
It is therefore a crucial enzyme for cancer progression. However, they were ineffective in vitro on Taq, a different DNA polymerase. Furthermore, none of the osmium clusters decreased the telomerase activity in the MCF-7 breast cancer cell line, as observed by the telomeric repeat amplification protocol TRAP assay. This may well be due to the low aptitude of these organometallics to cross the cell membrane.
However, all compounds were acutely cytotoxic, probably because of their accumulation on cell membranes, as shown for compound 29a by inductively coupled plasma mass spectrometry ICP-MS. It was hypothesized that 29a interfered with the normal trafficking and functions of the membrane. Gobetto, Rosenberg, and co-workers also investigated the interaction of other positively and negatively charged triosmium carbonyl clusters with albumin, using the transverse and longitudinal relaxation times of the hydride resonances as 1 H NMR probes of binding to the protein.
However, they exhibit distinctly different rotational correlation times. Triosmium clusters as potential inhibitors of telomerase enzyme. It is worth mentioning that Os 3 CO 9 type clusters and dicobalt carbonyl fragments were also reacted with derivatives of tamoxifen, a widely used drug in the treatment of hormone-dependent breast cancer see also the section Metallocenes above. Nevertheless, even though it was shown that these compounds were indeed targeting the desired biomolecules, their exact mode of cytotoxic action is still unknown.
Hence, Sheldrick et al. Whereas an interaction with the DNA might significantly contribute to the cytotoxic activity of the agents, the presence of additional cellular targets or alternative modes of action is very likely to contribute to this activity and is therefore the subject of ongoing research projects. In order to design new biological probes for bovine serum albumin BSA , Lo et al. Indeed, tumors are notoriously hypoxic and radioresistant. Both factors limit the success of radiotherapy. Modulation of the radiosensitivity by drugs such as cisplatin is in routine clinical application.
Re organometallics are another very new class of promising antiproliferative compounds. Until recently, only few examples of cytotoxic Re complexes were described in the literature. It is still premature to draw any definite conclusions on a molecular basis for the activity of the Re organometallics presented in this figure. However, a few targets are now envisaged. As expected, 43 was internalized by a folate receptor-mediated endocytotic pathway in this cell line.
The toxicity of 43 was attributed to intercalation into DNA. Aggregation of 45 in the cytosol and in the nucleus was observed. The positively charged rhenium chelate component is envisaged to interact with the negatively charged DNA backbone, thus playing a role in the observed cytotoxicity.
In contrast, Meggers et al. Their chosen targets were protein kinases that are known to regulate many aspects of cellular physiology and pathophysiology. They successfully designed nanomolar and even picomolar ATP-competitive ruthenium-based inhibitors. This concept has been confirmed by, so far, six different cocrystal structures of Ru complexes with protein kinases. However, the organic ligands can be optimized to occupy the available space in the active site, as well as providing additional hydrogen bonding interactions, thus making the individual inhibitors highly specific.
Moreover, physiological functions as a consequence of kinase inhibition were demonstrated within mammalian cells, Xenopus embryos, and zebrafish embryos. The green area indicates a patch of high hydrophobicity. Adapted from refs and Schematic view of how the metal complex mimics the overall shape of staurosporine. Ru complexes seem like ideal candidates for this purpose, as they are chemically stable in air, water, and buffer containing millimolar concentrations of thiols, as well as being configurationally stable against ligand exchange or scrambling around the metal center. N-Heterocyclic carbenes NHCs are generally derived from the so-called persistent carbenes, which are stable compounds of divalent carbon.
Metal NHC complexes are well-known for their catalytic properties. Additionally, their high stability and ease of derivatization make them suitable candidates for drug development. Initial reports on the biological application of NHC complexes dealt with the discovery of new antimicrobal compounds and have also stimulated the evaluation of these compounds as antiproliferative agents.
Silver complexes have a long tradition as anti-infectives; however, their mode of action is not yet completely understood. Interactions with the bacterial cell walls and the related biochemistry seem to be of relevance. In most cases, structures described as antiproliferative are closely related to the above-mentioned antibacterial agents, thereby highlighting the broad applicability of the class of transition metal species.
In , Barnard et al. Moreover, evidence that the impairment of mitochondrial functions is a major route of gold metallodrug activity keeps steadily increasing. TrxR is involved in various physiological processes including proliferation and is overexpressed in several cancerous tissues.
The active site of mammalian TrxR contains a selenocysteine residue, which is considered to be the target of gold metallodrugs. A complex 53 with intermediate lipophilicity was selected for further studies confirming the significant antimitochondrial properties. It was found that 53 induced apoptosis via caspase 9 and caspase 3 activation. Recently, Lemke et al. This therefore strongly suggests that the development of structurally diverse bioactive gold NHC species is possible and that activity as well as pharmacokinetic properties can be optimized by appropriate choice of the oxidation state of the metal and more sophisticated ligands.
In this context, NHC complexes can be functionalized with peptide ligands, which opens the possibility of developing metal NHC derivatives for targeted drug delivery. Besides the mentioned gold and silver derivatives, NHC complexes with palladium, nickel, copper, or platinum have also been recently reported to exhibit antiproliferative properties. Thus, the copper NHC complex 55 was more cytotoxic than cisplatin. Complex 55 induced apoptosis and, unlike cisplatin, arrested the cell cycle progression in the G1 phase.
Concerning a plausible mode of action for this compound, its nuclease-like activity and O 2 -activating properties, which led to DNA strand breaks, appear to be of high relevance. Overall, metal NHC complexes display promising pharmacological properties as novel antibacterial and antitumor drugs. Regarding their mode of action, the choice of the coordinated metal most probably determines the respective main biological target, e. Metal CO complexes or metal carbonyls are organometallic complexes containing one or more carbon monoxide ligands.
So far, a large variety of different metal carbonyl complexes with promising antiproliferative properties have been reported including the above-mentioned rhenium and osmium derivatives but also various cobalt, iron, 40 chromium half-sandwich , , ruthenium, or manganese , bioorganometallic species. For example, an increasing number of reports deal with the biological properties of alkyne hexacarbonyldicobalt Co 2 CO 6 species, a class of bioorganometallic complexes whose cytotoxic properties had been mentioned first in and then studied in more detail again since Clinical studies on aspirin and other nonsteroidal anti-inflammatory drugs NSAIDs have indicated a correlation between the long-term intake of NSAIDs and positive effects for cancer patients mainly concerning a substantial decrease in recidive risks , thereby making NSAIDs interesting candidates for chemoprevention and combination chemotherapy.
Recently, it was confirmed that Co-ASS exhibited several biochemical properties related to the reported antitumoral effects of NSAIDs including induction of apoptosis, inhibition of PGE 2 formation, and triggering of antiangiogenic effects. A variety of hexacarbonyldicobalt species with interesting biological properties have been reported including nucleosides e. Thus, for complexes with hormone derived ligands, it was demonstrated that the hormonal activity and the receptor binding were retained.
For nucleoside ligand-containing derivatives, preliminary studies indicated that the uptake of the compounds into the tumor cells might correlate with their cytotoxic activity. Because a similar dependence was also observed for the uptake into the nuclei, it can be concluded that for the nucleoside derivatives, a possible mode of action might involve an interaction with the DNA or the DNA related enzyme machinery. Hormonal activity has also been described for metal CO complexes other than hexacarbonyldicobalt alkynes, mainly by the group of Jaouen. In the case of iron-containing metal carbonyl complexes, nucleoside containing derivatives have been the subject of major attention.
Additionally, further unspecific effects of the iron diene unit of 61 could be ruled out, as close analogues of the lead compound and the non-iron-containing free ligand were not active. It was suggested that the Nmediated ROS production could be due to its capacity as an iron donor with the nucleoside ligand functioning as a carrier. In the above-mentioned examples, the structural influence of the CO ligands on the bioactivity and molecular receptor interaction is not yet clear but increasing evidence exists that the presence of these ligands is crucial for the efficacy of the compounds.
From this crystal structure it is obvious that the CO ligand together with a cyclopentadienyl ring occupies a binding pocket in the active site of the enzyme, which is usually filled by the carbohydrate moiety of staurosporin. Besides their potential role in the molecular interaction with biological targets, another relevant feature of CO complexes is their high lipophilicity, which led to increased cellular uptake levels in a number of studies. Another interesting concept for the biomedical use of metal carbonyl species is the fact that the CO ligands can be released under appropriate conditions, enabling the released carbon monoxide to trigger pharmacological effects.
For a more detailed description of the group of CORMs the reader is referred to recent reviews on this topic. Metal carbonyl species have also shown potential for application as diagnostics. While this topic is also beyond the scope of this Perspective, the concept shall be mentioned briefly here: The fact that intensive IR vibrations of the CO ligands are suitable for detection purposes found use in the so-called carbonylmetallo immunoassay CMIA.
Other strategies and ideas for the treatment of cancer involving the use of organometallics were recently employed by Therrien et al. They investigated the possibility of combining the chemotherapeutic activity of organometallics with photosensitizing agents for photodynamic therapy PDT. All complexes had similar moderate cytotoxicity toward cancer cells with the exception of the Rh complex, which was found to be nontoxic. Importantly, the Ru II complexes exhibit excellent phototoxicity toward melanoma cells when exposed to laser light at nm. In a similar perspective, very recently, the same group described the use of sawhorse-type diruthenium tetracarbonyl complexes containing porphyrin-derived ligands as highly selective photosensitizers for female reproductive cancer cells.
Remarkably, these compounds were equally potent against cisplatin-resistant and -nonresistant cell lines, which is indicative of a mode of action different from that of cisplatin. Diarene ruthenium compound bridged by a ferrocene. Interestingly, once inside the cells, [Pd acac 2 ] or [Pt acac 2 ] is released and exerts a cytotoxic effect. The use of such metallaboxes is currently being investigated by this group. Reproduced, with modification, with permission from Angewandte Chemie, International Edition.
Sadler, Brabec, and co-workers also investigated the photoactivation of dinuclear ruthenium II arene complexes to trigger DNA binding and fluorescence. Interestingly, the fluorescence of the unbound arene is roughly 40 times greater than when it is complexed to the Ru center, therefore enabling visualization of the intracellular localization of the arene moiety. Furthermore, irradiation also had a significant effect on DNA binding in that the formed ruthenium adducts strongly block RNA polymerase. These complexes therefore have the potential to combine photoinduced cell death and fluorescence imaging of the location and efficiency of the photoactivation process.
In this Perspective, we summarized recent developments toward the use of organometallic compounds as anticancer drug candidates. The general notion that organometallic compounds would be sensitive to air and water and therefore unstable under physiological conditions and unsuitable for medicinal purposes has been disproved. Rather, our above analysis demonstrates a broad range of classes of compounds that are stable and well characterized for biological applications.
Organometallic compounds are frequently kinetically inert and amenable to multiple derivatization reactions. They are thus suitable for conventional structure-based drug design, including computer docking experiments similar to those for the more traditional organic drug candidates. The successful development of ruthenium kinase inhibitors by Meggers and co-workers impressively demonstrates this capacity. A recent multistep synthesis of chromium-based antibiotics modeled after the natural lead structure platensimycin further demonstrates that even complicated lead structures can be realized with organometallic cores.
Organometallic chemists frequently collaborate with medicinal chemists, biochemists, and molecular or cell biologists. Arriving at the forefront of medicinal chemistry research, they employ the whole toolbox of modern biomedical research, including structural biology, computer-aided design, and biochemical and cell-based assays to gain a deep insight into possible cellular targets and the molecular details of target interactions.
For a number of compounds, even in vivo testing is in progress. We have pointed to prior work and mentioned in vivo results in the respective sections. More studies are currently underway but not yet publicly available. However, we would certainly expect that this is the next frontier for medicinal organometallic chemistry, on the way to bringing at least some of the most promising organometallic drug candidates described herein as drugs to the market.
In this Perspective, we have tried to emphasize such biochemical studies where available to elucidate molecular targets and modes of action. While it is clear that for many organometallic complexes interesting bioactivities were observed, the molecular modes of target interaction or the targets themselves are not perfectly clear for each class of compounds at this stage.
It is clear, however, that DNA is not the target for most bioorganometallics and protein interactions e. Moreover, some metal complexes may even exhibit completely novel, metal-specific modes of action, such as the ferrocifen derivatives in which the metallocene acts as a redox antenna for intramolecular redox activtion.
Clearly, exploitation of the distinct properties of metal complexes for biologically active compounds deserves more attention. It is hoped that the advent of organometallic complexes in clinical trials will improve acceptance of such compounds in the pharmaceutical industry and support further research into the fascinating field of organometallic drugs and their biological targets.
The authors thank the Alexander von Humboldt Foundation fellowship to G. Roger Alberto for generous access to all the facilities of the Institute of Inorganic Chemistry of the University of Zurich. Gilles Gasser received his B. Since , Gilles has started his independent research group at the University of Zurich Switzerland. Afterwards he focused on several projects in bioinorganic and bioorganometallic medicinal chemistry at the same institution and performed postdoctoral studies in the group of Prof.
His current research interests involve the development of novel anticancer therapeutics with a focus on bioinorganic and bioorganometallic compounds as well as the study of the biological functions of transition metal complexes in general. Nils Metzler-Nolte obtained his Ph.
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Green at Oxford U. He is a member of the international advisory boards of several journals. With research interests in medicinal organometallic chemistry and functional metal bioconjugates, the group is running a full program from inorganic synthesis to cell biology. National Center for Biotechnology Information , U. Journal of Medicinal Chemistry. Published online Nov Received Jan 8. Any use of this article, must conform to the terms of that license which are available at http: This article has been cited by other articles in PMC. Open in a separate window.
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Organometallic Ruthenium Half-Sandwich Complexes The idea of using ruthenium-containing organometallics as anticancer agents was first developed by Tochter et al. Structures of catalytically active organometallic anticancer complexes. Organometallic Osmium Half-Sandwich Complexes Probably because of its reputation of being highly toxic see OsO 4 and relatively inert toward substitution, osmium organometallics have been neglected as therapeutic agents in comparison to its lighter congener ruthenium.
Rhenium Organometallics Re organometallics are another very new class of promising antiproliferative compounds. Metal Carbonyl Complexes Metal CO complexes or metal carbonyls are organometallic complexes containing one or more carbon monoxide ligands. Miscellaneous Other strategies and ideas for the treatment of cancer involving the use of organometallics were recently employed by Therrien et al.
Conclusion and Perspective In this Perspective, we summarized recent developments toward the use of organometallic compounds as anticancer drug candidates. Metal-based antitumour drugs in the post genomic area. Cellular processing of platinum anticancer drugs. Drug Discovery , 4 , — Bioorganometallic chemistry—from teaching paradigms to medicinal applications. From Fundamentals to Applications ; Crabtree R.
A categorization of metal anticancer compounds based on their mode of action. Biomolecules, Labeling, Medinice ; Jaouen G. Titanocene dichloride—the first metallocene with cancerostatic activity. Tumor inhibition by metallocenes: Drugs Future , 11 , — Ferrocenium salts—the first antineoplastic iron compounds. Non-platinum-group metal antitumor agents: Transition and main-group metal cyclopentadienyl complexes: Bonding Berlin , 70 , — Enzymic hydroxylation of ferrocene. Ferrocene conjugates of chloroquine and other antimalarials: ChemMedChem , 3 , — Insights into the mechanism of action of ferroquine.
Relationship between physicochemical properties and antiplasmodial activity. Pharmaceutics , 2 , — Chronic toxicity of dicyclopentadienyliron ferrocene in dogs.