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Ferrocene (Fc) is a widely used metallocene, with well‐characterized redox behaviour that is vastly used in a variety of applications. Ferrocene‐coupling to peptides renders the resulting bioorganometallic peptide conjugate redox active and sensitive to changes in the chemical environment. The disulfide‐linked ferrocene peptide conjugate (FcCO‐Phe‐Cys‐OH)2 was synthesized and characterized by NMR, MS, and FT‐IR spectroscopies and then exploited for the detection of ascorbic acid. Here we demonstrate that the Cu(II) complex of this peptide conjugate allows the detection of ascorbic acid with a limit of detection of 0.02 μM with a linear range of 0.1–25 μM. This is the first report of the use of a peptide metal complex for direct modification of a glass carbon electrode and its application for ascorbic acid detection and quantification, including in commercial beverages. The modified GCE exhibited excellent selectivity, stability, and sensitivity. [ABSTRACT FROM AUTHOR]

Abstract Ferrocene (Fc) is a widely used metallocene, with well‐characterized redox behaviour that is vastly used in a variety of applications. Ferrocene‐coupling to peptides renders the resulting bioorganometallic peptide conjugate redox active and sensitive to changes in the chemical environment. The disulfide‐linked ferrocene peptide conjugate (FcCO‐Phe‐Cys‐OH)2 was synthesized and characterized by NMR, MS, and FT‐IR spectroscopies and then exploited for the detection of ascorbic acid. Here we demonstrate that the Cu(II) complex of this peptide conjugate allows the detection of ascorbic acid with a limit of detection of 0.02 μM with a linear range of 0.1–25 μM. This is the first report of the use of a peptide metal complex for direct modification of a glass carbon electrode and its application for ascorbic acid detection and quantification, including in commercial beverages. The modified GCE exhibited excellent selectivity, stability, and sensitivity.

Studies of organometallic reactions in living cells commonly rely on ensemble‐averaged measurements, which can obscure the detection of reaction dynamics or location‐specific behavior. This information is necessary to guide the design of bioorthogonal catalysts with improved biocompatibility, activity, and selectivity. By leveraging the high spatial and temporal resolution of single‐molecule fluorescence microscopy, we have successfully captured single‐molecule events promoted by Ru complexes inside live A549 human lung cells. By observing individual allylcarbamate cleavage reactions in real‐time, our results revealed that they occur with greater frequency inside the mitochondria than in the non‐mitochondria regions. The estimated turnover frequency of the Ru complexes was at least 3‐fold higher in the former than the latter. These results suggest that organelle specificity is a critical factor to consider in intracellular catalyst design, such as in developing metallodrugs for therapeutic applications. [ABSTRACT FROM AUTHOR]

Although reactive aldehyde species (RASP) are associated with the pathogenesis of many major diseases, there are currently no clinically approved treatments for RASP overload. Conventional aldehyde detox agents are stoichiometric reactants that get consumed upon reacting with their biological targets, which limits their therapeutic efficiency. To achieve longer‐lasting detoxification effects, small‐molecule intracellular metal catalysts (SIMCats) were used to protect cells by converting RASP into non‐toxic alcohols. It was shown that SIMCats were significantly more effective in lowering cell death from the treatment with 4‐hydroxynon‐2‐enal than aldehyde scavengers over a 72 h period. Studies revealed that SIMCats reduced the aldehyde accumulation in cells exposed to the known RASP inducer arsenic trioxide. This work demonstrates that SIMCats offer unique benefits over stochiometric agents, potentially providing new ways to combat diseases with greater selectivity and efficiency than existing approaches. [ABSTRACT FROM AUTHOR]

Eight novel carbohydrate-tethered trithiolato dinuclear ruthenium(II)-arene complexes were synthesized using CuAAC 'click' (Cu(I)-catalyzed azide-alkyne cycloaddition) reactions, and there in vitro activity against transgenic T. gondii tachyzoites constitutively expressing β-galactosidase (T. gondii β-gal) and in non-infected human foreskin fibroblasts, HFF, was determined at 0.1 and 1 µM. When evaluated at 1 µM, seven diruthenium-carbohydrate conjugates strongly impaired parasite proliferation by >90%, while HFF viability was retained at 50% or more, and they were further subjected to the half-maximal inhibitory concentration (IC50) measurement on T. gondii β-gal. Results revealed that the biological activity of the hybrids was influenced both by the nature of the carbohydrate (glucose vs. galactose) appended on ruthenium complex and the type/length of the linker between the two units. 23 and 26, two galactose-based diruthenium conjugates, exhibited low IC50 values and reduced effect on HFF viability when applied at 2.5 µM (23: IC50 = 0.032 µM/HFF viability 92% and 26: IC50 = 0.153 µM/HFF viability 97%). Remarkably, compounds 23 and 26 performed significantly better than the corresponding carbohydrate non-modified diruthenium complexes, showing that this type of conjugates are a promising approach for obtaining new antiparasitic compounds with reduced toxicity. [ABSTRACT FROM AUTHOR]

The formation of carbon–carbon bonds from prebiotic precursors such as carbon dioxide represents the foundation of all primordial life processes. In extant organisms, this reaction is carried out by the carbon monoxide dehydrogenase (CODH)/acetyl coenzyme A synthase (ACS) enzyme, which performs the cornerstone reaction in the ancient Wood–Ljungdahl metabolic pathway to synthesize the key biological metabolite, acetylCoA. Despite its significance, a fundamental understanding of this transformation is lacking, hampering efforts to harness analogous chemistry. To address these knowledge gaps, we have designed an artificial metalloenzyme within the azurin protein scaffold as a structural, functional, and mechanistic model of ACS. We demonstrate the intermediacy of the NiI species and requirement for ordered substrate binding in the bioorganometallic carbon–carbon bond-forming reaction from the one-carbon ACS substrates. The electronic and geometric structures of the nickel-acetyl intermediate have been characterized using time-resolved optical, electron paramagnetic resonance, and X-ray absorption spectroscopy in conjunction with quantum chemical calculations. Moreover, we demonstrate that the nickel-acetyl species is chemically competent for selective acyl transfer upon thiol addition to biosynthesize an activated thioester. Drawing an analogy to the native enzyme, a mechanism for thioester generation by this ACS model has been proposed. The fundamental insight into the enzymatic process provided by this rudimentary ACS model has implications for the evolution of primitive ACS-like proteins. Ultimately, these findings offer strategies for development of highly active catalysts for sustainable generation of liquid fuels from one-carbon substrates, with potential for broad applications across diverse fields ranging from energy storage to environmental remediation. [ABSTRACT FROM AUTHOR]

Eight novel carbohydrate-tethered trithiolato dinuclear ruthenium(II)-arene complexes were synthesized using CuAAC ‘click’ (Cu(I)-catalyzed azide-alkyne cycloaddition) reactions, and there in vitro activity against transgenic T. gondii tachyzoites constitutively expressing β-galactosidase (T. gondii β-gal) and in non-infected human foreskin fibroblasts, HFF, was determined at 0.1 and 1 µM. When evaluated at 1 µM, seven diruthenium-carbohydrate conjugates strongly impaired parasite proliferation by >90%, while HFF viability was retained at 50% or more, and they were further subjected to the half-maximal inhibitory concentration (IC50) measurement on T. gondii β-gal. Results revealed that the biological activity of the hybrids was influenced both by the nature of the carbohydrate (glucose vs. galactose) appended on ruthenium complex and the type/length of the linker between the two units. 23 and 26, two galactose-based diruthenium conjugates, exhibited low IC50 values and reduced effect on HFF viability when applied at 2.5 µM (23: IC50 = 0.032 µM/HFF viability 92% and 26: IC50 = 0.153 µM/HFF viability 97%). Remarkably, compounds 23 and 26 performed significantly better than the corresponding carbohydrate non-modified diruthenium complexes, showing that this type of conjugates are a promising approach for obtaining new antiparasitic compounds with reduced toxicity.

Tethering known drugs to a metalorganic moiety is an efficient approach for modulating the anticancer, antibacterial, and antiparasitic activity of organometallic complexes. This study focused on the synthesis and evaluation of new dinuclear ruthenium(II)–arene compounds linked to several antimicrobial compounds such as dapsone, sulfamethoxazole, sulfadiazine, sulfadoxine, triclosan, metronidazole, ciprofloxacin, as well as menadione (a 1,4-naphtoquinone derivative). In a primary screen, 30 compounds (17 hybrid molecules, diruthenium intermediates, and antimicrobials) were assessed for in vitro activity against transgenic T. gondii tachyzoites constitutively expressing β-galactosidase (T. gondii β-gal) at 0.1 and 1 µM. In parallel, the cytotoxicity in noninfected host cells (human foreskin fibroblasts, HFF) was determined by an alamarBlue assay. When assessed at 1 µM, five compounds strongly impaired parasite proliferation by >90%, and HFF viability was retained at 50% or more, and they were further subjected to T. gondii β-gal dose-response studies. Two compounds, notably 11 and 13, amide and ester conjugates with sulfadoxine and metronidazole, exhibited low IC50 (half-maximal inhibitory concentration) values 0.063 and 0.152 µM, and low or intermediate impairment of HFF viability at 2.5 µM (83 and 64%). The nature of the anchored drug as well as that of the linking unit impacted the biological activity.

A tailored series of coumarin-based ferrocenyl 1,3-oxazine hybrid compounds was synthesized and investigated for potential antiparasitic activity, drawing inspiration from the established biological efficacy of the constituent chemical motifs. The structural identity of the synthesized compounds was confirmed by common spectroscopic techniques: NMR, HRMS and IR. Biological evaluation studies reveal that the compounds exhibit higher in vitro antiparasitic potency against the chemosensitive malarial strain (3D7 P. falciparum) over the investigated trypanosomiasis causal agent (T. b. brucei 427) with mostly single digit micromolar IC50 values. When read in tandem with the biological performance of previously reported structurally similar non-coumarin, phenyl derivatives (i.e., ferrocenyl 1,3-benzoxazines and α-aminocresols), structure-activity relationship analyses suggest that the presence of the coumarin nucleus is tolerated for biological activity though this may lead to reduced efficacy. Preliminary mechanistic studies with the most promising compound (11b) support hemozoin inhibition and DNA interaction as likely mechanistic modalities by which this class of compounds may act to produce plasmocidal and antitrypanosomal effects.

Abstract The electrochemical behavior of osmociphenol (3 , Oc-OH), an organometallic osmium-based anticancer drug candidate, has been investigated by cyclic voltammetry in the absence and presence of lutidine used as a base model. Osmociphenol exhibited spontaneous deprotonation of the phenol function upon oxidation of the osmocene moiety due to its high acidity. In the presence of lutidine, a base-dependent and different electrochemical behavior was observed at low scan rates indicating a second oxidation step leading to the corresponding cationic quinone methide precursor (3b + ). However, compared to ruthenocene derivatives, the stability of 3b + prevented its conversion into quinone methide as the final and stable complex. Despite differences in their oxidative processes, osmociphenol and ruthenociphenol derivatives exhibit similar biological activities. Highlights • Electrochemical behavior of an organometallic osmium-based anticancer drug candidate. • Mechanistic investigations by cyclic voltammetry. • Evidence of a stable quinone methide carbocation intermediate. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Exploited a metallocene to gain access to a biplanar pharmacophoric arrangement. • Leveraged this organometallic architecture in the design of potent anti-HCV agents. • These efforts informed the design of the clinical candidate odalasvir (ACH-3102). Abstract An unprecedented series of organometallic HCV (hepatitis C virus) NS5A (nonstructural 5A protein) replication complex inhibitors that incorporates a 1,1′-ferrocenediyl scaffold was explored. This scaffold introduces the elements of linear flexibility and non-planar topology that are unconventional for this class of inhibitors. Data from 2-D NMR spectroscopic analyses of these complexes in solution support an anti (unstacked) arrangement of the pharmacophoric groups. Several complexes demonstrate single-digit picomolar in vitro activity in an HCV genotype-1b replicon system. One complex to arise from this investigation (10a) exhibits exceptional picomolar activity against HCV genotype 1a and 1b replicons, low hepatocellular cytotoxicity, and good pharmacokinetic properties in rat. [ABSTRACT FROM AUTHOR]

Three compounds have been prepared in which a 4-aminochloroquinoline moiety is covalently linked to a cyclopentadienyl manganese tricarbonyl moiety. One of these (“cymanquine”, 4 ) is the analogue of the potent antimalarial drug ferroquine in which an FeCp group has been replaced by a Mn(CO) 3 group. The anodic electrochemistry of the new compounds was investigated in dichloromethane, using [NBu 4 ][B(C 6 F 5 ) 4 ] as the supporting electrolyte. Compared to ferroquine, oxidations of the new compounds occur at considerably more positive potentials and are highly irreversible, being located at their amine groups rather than at the organometallic center. [ABSTRACT FROM AUTHOR]

Three dipeptides bearing alkynes on their side chains ( 9 (derived from dilysine), 14 (derived from dicysteine) and 17 (derived from diglycine)) were prepared and reacted with W(CO) 3 (dmtc) 2 [dmtc = dimethyldithiocarbamate] to afford, respectively, three metallacyclicpeptides, 18 , 19 and 20 . The metallacyclicpeptides were characterized by HPLC, ES-MS, and 1 H NMR. The conformational behavior of the alkynes about the tungsten center was assessed using 1 H NMR. It was found that all three metallacyclicpeptides adopt multiple conformations of the alkynes relative to the tungsten. Both 18 and 19 appear to adopt all 8 possible conformations, while 20 adopts a limited number of conformations. The ability of the alkynes to equilibrate between the syn and anti conformations was assessed by examining the alkyne hydrogen resonances using variable temperature 1 H NMR. It was found that the alkyne ligands in 18 and 19 will equilibrate between the syn and anti conformations. The alkyne hydrogen resonances in 18 coalesce to one signal around 343 K, while the alkyne hydrogen resonances in 19 do not completely coalesce even by 360 K. Complex 18 has a larger ring than complex 19 , and the higher temperature of coalescence for 19 is attributed to its smaller ring size. In contrast, complex 20 , which has the smallest ring size, cannot equilibrate between the syn and anti conformations, even at elevated temperatures. The results show that cyclic tungsten–bis(alkyne) complexes will form ring systems with ring sizes of approximately 10 atoms, that ring sizes of approximately 10 atoms are rigid, and that rigidity is lost as the ring size is increased. [ABSTRACT FROM AUTHOR]

[Display omitted] • Study of organometallic complexes as antiplasmodials. • Iridium (III), rhodium (III), and ruthenium(II) pyridyl-benzimidazole complexes. • Transfer hydrogenation of NAD+ to NADH. Six half-sandwich complexes of iridium (III), rhodium (III), and ruthenium (II) (C1 - C6) bearing the N,N' -chelated ligand 2-(2-pyridyl)benzimidazole (L) were synthesized and characterized, three of which, bearing the iodido ligand are new. The complexes were isolated as yellow or orange solids in moderate to good yields. The complexes were tested for their ability to catalyse the hydrogenation of NAD+ to NADH at pH 7 at 37 °C. The iridium complexes (C1 and C 2) were found to perform the best with NADH yields of up to 74% after one hour. All of the complexes and the ligand were screened for their ability to inhibit growth of the drug-sensitive strain of malaria-causing parasite Plasmodium falciparum, NF54. The complexes containing the rhodium (III) metal centre had the highest activity with the IC 50 values for the chlorido (C3) and iodido (C4) complexes determined to be 11.4 µM and 9.65 µM respectively. Both complexes performed better than the ligand (IC 50 = 55.9 µM). Complexes bearing the iodido ligand were found to be favourable in both the catalysis as well as the antimalarial assays. [ABSTRACT FROM AUTHOR]

Binuclear diphenyltin(IV) dithiocabamate macrocyclic complexes [(Ph2SnIV)2-μ2-bis{(κ2 S, S-S2CN(R)CH2CONHC6H4)2O}] (R = iPr ( 1), sBu ( 2), nBu ( 3), Cy ( 4), 2-furfuryl ( 5) or benzyl ( 6)) were synthesized through a self-assembly process involving novel diamino precursors 4,4′-bis(2-(alkylamino)acetamido)diphenyl ethers ( L1, L2, L3, L4, L5, L6), CS2 and Ph2SnCl2. These were characterized using microanalysis and relevant spectroscopic methods. The geometry of all compounds was optimized using the density functional theory method. In vitro cytotoxic activity was evaluated against HEP 3B (hepatoma) and IMR 32 (neuroblastoma) using the MTT assay. Notably, complexes 1, 2, 3, 4, 5, 6 were found to be extremely active against both cell lines and cytotoxicity data confirmed their 16-fold better potency compared to cisplatin, a well-known antineoplastic drug. Flow cytometric analysis of annexin V-propidium iodide-stained cells demonstrated the ability of L5, 4 and 6 to induce apoptosis in HEP 3B and IMR 32 cells, required for major therapeutic implication in . The extraordinary potency of binuclear complex 4 can be correlated with higher LUMO energy together with the greatest value of residual charge on the Sn(IV) centre among the compounds under investigation. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Two pentamethylcyclopentadienyl (Cp*) rhodium(III) and iridium(III) metalla-prisms of the general formula [(Cp*M) 6 (tpt) 2 (dhnq) 3 ] 6+ (tpt = 2,4,6-tri-(pyridin-4-yl)-1,3,5-triazine, dhnq = 5,8-dihydroxy-1,4-naphthoquinonato; M = Rh, [ 1 ] 6+ ; M = Ir, [ 2 ] 6+ ) have been synthesized by mixing in methanol the neutral dinuclear complexes (Cp*M) 2 (dhnq)Cl 2 (M = Rh, Ir), AgCF 3 SO 3 and tpt. In a similar fashion, the addition of porphin during the formation of [ 1 ] 6+ and [ 2 ] 6+ leads to the carceplex systems [porphin⊂ 1 ] 6+ and [porphin⊂ 2 ] 6+ . All complexes were isolated as their triflate salts and characterized by different analytical techniques including for the carceplex [porphin⊂ 1 ][CF 3 SO 3 ] 6 by a single-crystal X-ray structure analysis. The hosts were evaluated as drug delivery vectors on the HT-29 cancer cell line, and after internalization, porphin was photo-activated to generate phototoxicity. Interestingly, the IC 50 values of the empty and filled metalla-cages are around 1 μM, while upon irradiation (20 J/cm 2 ) only lower nanomolar concentrations of the [porphin⊂ cage ][CF 3 SO 3 ] 6 systems are necessary to inhibit cell growth by 50%, showing an excellent ratio between cytotoxicity and phototoxicity. [ABSTRACT FROM AUTHOR]

Five new organometallic Ru(II) compounds (VI−X) with the general formula [Ru(η 6 -arene)( N , N )Cl]PF 6 , where arene- N , N correspond to methylisoeugenol-bipyridine (VI); anethole-bipyridine (VII); methylisoeugenol-ethylenediamine (VIII); anethole-ethylenediamine (IX) and methylisoeugenol-1,2-diaminobenzene (X), have been synthesized, fully characterized and biologically evaluated in vitro . The reaction conditions based on the reduction of [Ru(1,5-COD)Cl 2 ] n in situ with methyleugenol and estragole, which are natural ligands, induced an alkene isomerization on the allylic substituent of coordinated arenes. The Ru(II)-arene bond formation and isomerization of the C C bond on the allyl substituent was confirmed using 1 H NMR spectroscopy; this result was validated for compound VIII by X-ray diffraction. An XRD analysis revealed the presence of both enantiomers of the complex in the single-crystal. Compounds IX and X exhibited a better cytotoxic activity in vitro than carboplatin, which is a commercial drug, against three human tumor cell lines (MCF-7, PC-3 and HT-29). [ABSTRACT FROM AUTHOR]

Peptide derivatives ( 8 and 9 ) of 2-amino-2′-carboxydiphenylacetylene ( 1 ) were prepared using the Sonogashira reaction and standard peptide chemistry. As reported earlier by Kemp and Li (Ref. [1]), 8 and 9 adopt anti-parallel β-sheet conformations in solution. Reaction of 8 and 9 with W(CO) 3 (dmtc) 2 produced the tungsten mono-alkyne complexes 10 and 11 as a mixture of two inseparable diastereomers ( 10a and 10b , and 11a and 11b ) resulting from two different spatial arrangements of the dmtc ligands. The respective mixtures of the two diastereomers were characterized by ES-MS and 1 H NMR spectroscopy. The solution conformations of the diastereomers were probed using NOESY and DMSO titration experiments. The data from these experiments show that the peptide portions of 10 and 11 maintain their anti-parallel β-sheet conformations following coordination to tungsten. [ABSTRACT FROM AUTHOR]

Water soluble arene-functionalised trithiolato-bridged ruthenium complexes of general formula [(η 6 -C 6 H 5 OCH 2 CH 2 OH) 2 Ru 2 (μ-SR) 3 ] + , where R = C 6 H 5 ( 1 ), C 6 H 4 - p -Me ( 2 ), C 6 H 4 - p -OMe ( 3 ), C 6 H 4 - p -Pr i ( 4 ), C 6 H 4 - p -Bu t ( 5 ), CH 2 C 6 H 5 ( 6 ), CH 2 CH 2 C 6 H 5 ( 7 ) and CH 2 C 6 H 4 - p -Bu t ( 8 ), were prepared from the reaction of [(η 6 -C 6 H 5 OCH 2 CH 2 OH) 2 Ru 2 (μ-Cl) 2 Cl 2 ] with the corresponding thiol, RSH. Complexes [ 1 ]Cl–[ 8 ]Cl were isolated in good yields as their chloride salts and they were fully characterised using spectroscopic and analytical techniques and the structures of [ 1 ]Cl, [ 3 ]Cl and [ 4 ]Cl were determined in the solid-state by single-crystal X-ray diffraction. The antiproliferative activity of [ 1 ]Cl–[ 8 ]Cl was evaluated against human ovarian cancer (A2780, A2780cisR) and non-cancerous (HEK293) cells with [ 4 ]Cl and [ 5 ]Cl being more active than cisplatin on the cancer cells and also more selective. [ABSTRACT FROM AUTHOR]

Trithiolato-bridged arene osmium complexes of the general formula [( p -cymene) 2 Os 2 (μ-SR) 3 ] + (R = C 6 H 5 , [ 1 ] + ; C 6 H 4 - p -Me, [ 2 ] + ; C 6 H 4 - p -OMe, [ 3 ] + ; C 6 H 4 - p -Pr i , [ 4 ] + ; C 6 H 4 - p -Bu t , [ 5 ] + ; CH 2 C 6 H 5 , [ 6 ] + ; CH 2 CH 2 C 6 H 5 , [ 7 ] + ; CH 2 C 6 H 4 - p -Bu t , [ 8 ] + ) were synthesized in ethanol by reacting the p- cymene osmium dimer [( p -cymene) 2 Os 2 (μ-Cl) 2 Cl 2 ] with the corresponding thiol (RSH). The complexes were isolated as their chloride salts, and fully characterized by spectroscopic methods. The single-crystal X-ray structure analysis of the salt [ 6 ]Cl is also presented. These osmium complexes were found to be highly cytotoxic towards several cancerous cell lines (A2780, A549, B16F10, HeLa) with IC 50 values comparable or even better to those found for doxorubicin. [ABSTRACT FROM AUTHOR]

Abstract: Escherichia coli O157:H7 can cause life-threatening gastrointestinal diseases and has been a severe public health problem worldwide in recent years. A novel biosensor for the detection of E. coli O157:H7 is described here using a film composed of ferrocene–peptide conjugates, in which the antimicrobial peptide magainin I has been incorporated as the biorecognition element. Electrochemical impedance spectroscopy was employed to investigate the surface characteristics of the newly developed biosensor and to monitor the interactions between the peptide film and the pathogenic bacteria. X-ray photoelectron spectroscopy and time-of-flight secondary ion mass spectrometry (ToF-SIMS) were employed to confirm the immobilization of ferrocene-conjugate onto the gold surface. Non-pathogenic E. coli K12, Staphylococcus epidermidis and Bacillus subtilis were used in this study to evaluate the selectivity of the proposed biosensor. The results have shown the order of the preferential selectivity of the method is E. coli O157:H7>non-pathogenic E. coli>gram positive species. The detection of E. coli O157:H7 with a sensitivity of 103 cfu/mL is enabled by the biosensor. The experimental conditions have been optimized and the plot of changes of charge transfer resistance (ΔR CT ) and the logarithm of the cell concentration of E. coli O157:H7 shows a linear correlation in the range of 103–107 cfu/mL with a correlation coefficient of 0.983. [Copyright &y& Elsevier]

Abstract: Bioorganometallic chemistry is a rapidly growing subfield of organometallic chemistry. One important facet is the study of organometallic•protein complexes that contain a covalent bond between the protein and an organometallic prosthetic group. Structural elucidation of these complexes is being used with increasing frequency to determine exactly where metal binding takes place and to obtain accurate structural information. This review summarizes the structures in this field, highlighting how this information has driven the frontier of this research. [Copyright &y& Elsevier]

Ruthenium-based compounds are an attractive alternative to clinically used platinum drugs due to several features including a wide range of accessible oxidation states, varied synthetic chemistry and typically lower general toxicities. One series of ruthenium(II)-arene-pta, RAPTA (pta = 1,3,5-triaza-7-phosphatricyclo[3.3.1.1] decane) compounds has been found to show particularly high selectivity towards cancer cells in both in vitro and in vivo studies.

Organometallic ruthenium compounds that are effective anticancer and antimetastasis agents are currently under intensive investigation (see also the article by Peter Sadler in this issue). This article provides a personal account of the way in which we have exploited the different properties of the organoruthenium (and osmium and rhodium) compounds to rival traditional DNA-binding platinum drugs, culminating in the discovery of a non-classical molecule that is in an advanced stage of pre-clinical evaluation.

Abstract: A new family of nitrogenous derivatives is synthesized, characterized and evaluated for the investigation of the impact of some structural motifs such as functionalization and conjugation on the antiproliferative activity of ferrocenic complexes against cancer cells. These compounds are 4,4′-([3]ferrocenophan-1-ylidenemethylene)dianilides and tetramethylated dianilines derived from Michler's ketone. An alternative McMurry direct heterocoupling method for 4,4′-([3]ferrocenophan-1-ylidenemethylene)dianiline synthesis is described and electrochemical studies are also discussed. [Copyright &y& Elsevier]

Abstract: Sawhorse-type diruthenium tetracarbonyl complexes incorporating carboxyphenyl porphyrin bridges and pyridine axial ligands have been prepared, characterized and evaluated as potential photosensitizing and chemotherapeutic agents in several human cancer cells (A2780, A549, Me300, HeLa). The mono carboxyphenyl porphyrin derivatives, 5-(4-carboxyphenyl)-10,15,20-triphenyl-21,23H-porphyrin (HOOCR1-H2) and 5-(4-carboxyphenyl)-10,15,20-triphenylporphyrin-Zn (HOOCR1-Zn), after reaction with Ru3(CO)12 and pyridine, give the dinuclear complexes [Ru2(CO)4(OOCR1-H2)2(NC5H5)2] (1) and [Ru2(CO)4(OOCR1-Zn)2(NC5H5)2] (2), respectively. Under the same reaction conditions, the di-carboxyphenyl porphyrin derivatives, 5,10-di(4-carboxyphenyl)-15,20-diphenyl-21,23H-porphyrin (HOOCR2-H2COOH) and 5,10-di(4-carboxyphenyl)-15,20-diphenylporphyrin-Zn (HOOCR2-ZnCOOH), give rise to the tetranuclear complexes, [{Ru2(CO)4(NC5H5)2}2(OOCR2-H2COO)2] (3) and [{Ru2(CO)4(NC5H5)2}2(OOCR2-ZnCOO)2] (4), in which two sawhorse diruthenium tetracarbonyl units are linked by the di-carboxyphenyl porphyrin ligands. When tested in human cancer cell lines, both Zn(II) metallo-porphyrin derivatives 2 and 4 and the tetranuclear derivative 3 show some degree of cytotoxicity in the dark, but seem to present no phototoxicity upon irradiation at 652nm. These results demonstrate the effect of the Zn(II) ion insertion into the porphyrin core, resulting in increased cytotoxicity and decreased phototoxicity. On the other hand, complex 1, the less cytotoxic derivative with IC50 >170μM in HeLa cervix and A2780 ovarian cancer cell lines, shows an excellent phototoxicity toward these cancer cell lines with LD50 comprised between 4.5 and 7.5J/cm2 (irradiance 30mW/cm2) at 5μM concentration (incubation time: 24h). Overall, an excellent ratio between photo- and cytotoxicity has been found for the metal-free porphyrin derivative [Ru2(CO)4(OOCR1-H2)2(NC5H5)2] (1). [Copyright &y& Elsevier]

Abstract: A series of N-protected amino acid alkynylesters were prepared by reaction of the amino acid carboxylate group with either propargyl alcohol (to yield the asymmetric esters 2a–c) or with 1, 4-but-2-yne diol (to yield the symmetric esters 3a–d). The alkynylesters were reacted with W(CO)3(dmtc)2 to yield monoalkyne complexes having the general formula W(CO)(dmtc)2(alkynyl ester). The monoalkyne complexes 6a–f were unstable in the presence of oxygen and had to be kept under an inert atmosphere. Analysis of the NMR spectra of the monoalkyne complexes showed that two diastereomers were formed in the synthesis, and that there was rapid rotation of the alkyne about the tungsten center at 23 °C and above with both diastereomers. At lower temperatures alkyne rotation is significantly slowed. Symmetric alkynylesters of a dipeptide (4) and tripeptide (5) were also prepared and reacted with W(CO)3(dmtc)2 to yield monoalkyne complexes. The resulting complexes (6g and 6h) also formed two diastereomers and displayed rapid rotation of the alkyne about the tungsten center at 23 °C and above, and slow rotation at lower temperatures. The amide NH protons in 6g and 6h were probed by DMSO titration to see if they were involved in intramolecular hydrogen bonds; they were not, which indicates that the peptide portions of 6g and 6h adopt an extended conformation in solution. [Copyright &y& Elsevier]

Abstract: To integrate the respective advantages exhibited by half-sandwich arene-Ru(II) fragments and 5-FU derivatives, a multifunctional ligand that links isonicotinic acid and 5-Fu (5-fluorouracil) through an ester bond for achieving the enhanced effect and an organoruthenium(II) complex containing this ligand were prepared and characterized by standard analytical techniques. The cytotoxicity of these organoruthenium(II) compounds containing 5-fluorouracil-1-methyl isonicotinate against BEL-7402 human cancer cells was moderately improved, which implies synergistic action of 5-Fu and the half-sandwich-structured arene-Ru(II). In addition, the organoruthenium(II) compounds containing isonicotinic acid and methyl isonicotinate are also discussed, and the crystal structure of [(η6-p-cymene)RuCl2(methyl isonicotinate)] (4) was determined; its piano-stool structure is analyzed in this paper. [Copyright &y& Elsevier]

Abstract: An electrochemical biosensor was developed for the determination of sarcoma (Src)-related protein kinase-catalyzed phosphorylation reactions in the presence of adenosine 5′-γ-ferrocenoyl triphosphate (Fc-ATP). The sensing platform is based on a highly specific amino acid sequence Glu-Gly-Ile-Tyr-Asp-Val-Pro (EGIYDVP), to which a Fc-PO2 moiety can be transferred from Fc-ATP by the action of the Src kinase. The enzyme kinetics and kinase inhibition were investigated by square wave voltammetry (SWV). The kinetic parameters K m and V max were determined for Src protein kinase with respect to Fc-ATP co-substrate and were found to be 200μM and 115μAcm−2 min, for phosphorylation of the EGIYDVP peptide substrate. Furthermore, the Src-catalyzed phosphorylation of Tyr was investigated in the presence of the small molecule inhibitors PP1, PP2, SU6656, and roscovitine. PP3 does not inhibit Src activity and was used as a control. The percent inhibition at half concentration, IC50, values were determined for all inhibitors under the study and were estimated to be in the 5–30nM range. The electrochemical study suggests that the increase in inhibition efficiency was in the order PP3

Abstract: Some ferrocene compounds, such as tamoxifen derivatives hydroxyferrocifen 1 and ferrociphenol 2, show strong antiproliferative activity on hormone-dependent and hormone-independent breast cancer cells. In order to evaluate their antimicrobial activity, they were tested, together with their purely organic analogs, on the bacteria Pseudomonas aeruginosa and Staphylococcus aureus and the fungus Candida albicans. It has been found that the compounds bearing alkylamino chains are active, and in these cases the antimicrobial activity increases for compounds bearing two amino chains. These dialkyamino compounds are equally as active as doxycycline on P. aeruginosa and S. aureus but superior to it on C. albicans. The results show that there are no general correlation between the antitumoral activity and the bactericidal and fungicidal activities of these compounds. The ferrocene derivatives and their organic analogs have similar activity on bacteria and fungus. This bactericidal and fungicidal behaviour is a novel area of activity for these entities. [Copyright &y& Elsevier]

The syntheses of dendrimers based on aspartic acid (Asp) from generation 1 to generation 4 ( G1 → G4) are reported. The ferrocene (Fc) conjugates of Asp dendrimers are synthesized. The solution structure of the monosubstituted Fc conjugates ( FcG n) and the disubstituted Fc conjugates ( Fc[G n ]), n = 1–3, is studied using spectroscopic techniques. The structural analyses display the Fc core “wired” to the dendrimer shells via a net of H-bonds. Consequently, the conjugates exhibit higher heterogeneous electron transfer rate compared to the Fc glutamate analogues. FcG2 exhibits an unusual β-reverse turn structure in solution. [ABSTRACT FROM AUTHOR]

Abstract: The dinuclear dichloro complexes [(η6-arene)2Ru2(μ-Cl)2Cl2] and [(η5-C5Me5)2M2(μ-Cl)2Cl2] react with 2-(pyridine-2-yl)thiazole (pyTz) to afford the cationic complexes [(η6-arene)Ru(pyTz)Cl]+ (arene=C6H6 1, p- i PrC6H4Me 2 or C6Me6 3) and [(η5-C5Me5)M(pyTz)Cl]+ (M=Rh 4 or Ir 5), isolated as the chloride salts. The reaction of 2 and 3 with SnCl2 leads to the dinuclear heterometallic trichlorostannyl derivatives [(η6-p- i PrC6H4Me)Ru(pyTz)(SnCl3)]+ (6) and [(η6-C6Me6)Ru(pyTz)(SnCl3)]+ (7), respectively, also isolated as the chloride salts. The molecular structures of 4, 5 and 7 have been established by single-crystal X-ray structure analyses of the corresponding hexafluorophosphate salts. The in vitro anticancer activities of the metal complexes on human ovarian cancer cell lines A2780 and A2780cisR (cisplatin-resistant), as well as their interactions with plasmid DNA and the model protein ubiquitin, have been investigated. [Copyright &y& Elsevier]

Abstract: A series of water soluble compounds of general formula [{(η6-arene)Ru(HMP)Cl}], [η6-arene=η6-cymene (1), η6-HMB (2), η6-C6H6 (3); HMP=5-hydroxy-2-(hydroxymethyl)-4-pyrone] have been prepared by the reaction of [{(η6-arene) RuCl2}2] with HMP. The complexes 1 and 2 react with NaN3 to give in excellent yield tetra-azido complexes [{(η6-arene)Ru(μN3)N3}2] (arene=cymene 4, HMB= 5) but similar reaction of complex 3 with NaN3 yielded di-azdo complex [{(η6-C6H6)Ru(μN3)Cl}2] (6). Reaction of [{(η6-arene)Ru(μN3)Cl}2] with HMP in the presence of NaOMe resulted in the formation of azido complex [{(η6-arene)Ru(HMP)N3}]. Mono and dinuclear complexes [{(η6-arene)Ru(HMP)(L1)}]+ and [{(η6-arene)Ru(HMP)}2(μL2)]2+ were also prepared by the reaction of complexes 1 and 2 with the appropriate ligand, L1 or L2 in the presence of AgBF4 (L1 =PyCN, DMAP; L2 =4,4′-bipy, pyrazine). The complexes are characterized on the basis of spectroscopic data and molecular structures of three representative compounds have been determined by single crystal X-ray diffraction study. [Copyright &y& Elsevier]

Diruthenium tetracarbonyl complexes of the type [Ru2(CO)4(μ2-η2-O2CR)2L2] containing a Ru–Ru backbone with four equatorial carbonyl ligands, two carboxylato bridges, and two axial two-electron ligands in a sawhorse-like geometry have been synthesized with porphyrin-derived substituents in the axial ligands [ 1: R is CH3, L is 5-(4-pyridyl)-10,15,20-triphenyl-21,23 H-porphyrin], in the bridging carboxylato ligands [ 2: RCO2H is 5-(4-carboxyphenyl)-10,15,20-triphenyl-21,23 H-porphyrin, L is PPh3; 3: RCO2H is 5-(4-carboxyphenyl)-10,15,20-triphenyl-21,23 H-porphyrin, L is 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane], or in both positions [ 4: RCO2H is 5-(4-carboxyphenyl)-10,15,20-triphenyl-21,23 H-porphyrin, L is 5-(4-pyridyl)-10,15,20-triphenyl-21,23 H-porphyrin]. Compounds 1– 3 were assessed on different types of human cancer cells and normal cells. Their uptake by cells was quantified by fluorescence and checked by fluorescence microscopy. These compounds were taken up by human HeLa cervix and A2780 and Ovcar ovarian carcinoma cells but not by normal cells and other cancer cell lines (A549 pulmonary, Me300 melanoma, PC3 and LnCap prostate, KB head and neck, MDAMB231 and MCF7 breast, or HT29 colon cancer cells). The compounds demonstrated no cytotoxicity in the absence of laser irradiation but exhibited good phototoxicities in HeLa and A2780 cells when exposed to laser light at 652 nm, displaying an LD50 between 1.5 and 6.5 J/cm2 in these two cell lines and more than 15 J/cm2 for the others. Thus, these types of porphyric compound present specificity for cancer cell lines of the female reproductive system and not for normal cells; thus being promising new organometallic photosensitizers. [ABSTRACT FROM AUTHOR]

Abstract: Organometallic half-sandwich complexes based on ruthenium with aminomethyl-substituted 3-hydroxy-2-pyridone ligands exist in aqueous solution as monomeric O,O′-chelate complexes or trimeric metallamacrocycles depending upon the pH. We hypothesized that administration of the compounds as stable trimers, which subsequently convert to active monomers at the reduced pH of the cancer environment, could facilitate their delivery to cancer cells without undergoing deactivation. Thus, the compounds were evaluated against cancer and fibroblast cell lines in vitro. A series of rhodium complexes, which exist mainly as monomers at neutral pH, were also studied for comparative purposes. [Copyright &y& Elsevier]

Abstract: Prior work has shown that covalently linking the side chains of amino acids in the i and i+3 and i and i+4 positions in a peptide will enforce a helical conformation. In this work the ability of an organometallic entity to enforce a helical conformation in a peptide was explored. The tetrapeptide Boc-Lys-Ala-Val-Lys-NHCH3 was prepared, then reacted with 1,1′-ferrocenedicarboxylic acid chloride. Reaction of the lysine side chain amines with the diacid chloride resulted in a metallacyclicpeptide (1) in which the two lysines are crosslinked via the ferrocene. The solution conformation of the metallacyclicpeptide (1) was studied using CD and NMR spectroscopy. The NMR methods employed were Karplus analysis of coupling constants, chemical shift changes of NH protons and ROESY data. The results show that the metallacyclicpeptide (1) adopts a single turn of the 310-helix conformation. [Copyright &y& Elsevier]

Abstract: To establish the role of the ferrocenyl moiety in the antiplasmodial activity of ferroquine, compounds in which this moiety is replaced by the corresponding ruthenium-based moieties were synthesized and evaluated. In both the sensitive (D10) and resistant (K1) strains of Plasmodium falciparum, ruthenoquine analogues showed comparable potency to ferroquine. This suggests that a probable role of the ferrocenyl fragment is to serve simply as a hydrophobic spacer group. In addition, ferroquine analogues with different aromatic substituents were synthesized and evaluated. Unexpectedly high activity for quinoline compounds lacking the 7-chloro substituent suggests the ferrocenyl moiety may have an additive and/or synergistic effect. [Copyright &y& Elsevier]

Abstract: We have synthesised (Et4N)[ReBr2(NCCH3)2(CO)2] 1 in two steps from [ReBr3(CO)3]2−. Complex 1 is water and air stable and the two Br− ligands are easily exchanged for coordinating solvent molecules such as water. The reactivity of 1 with several ligands such as imidazole (imz) and 2-picolinic acid (2-pic) are easily possible with substitution exclusively occurring in trans-position to the carbonyl groups. The resulting complexes [Re(imz)2(NCCH3)2(CO)2]+ and [Re(2-pic)(NCCH3)2(CO)2] have been isolated and structurally characterised. The two acetonitrile ligands are strongly bound and are not substituted under any conditions. Complex 1 represents therefore the new moiety “trans,cis-[Re(NCCH3)2(CO)2]+” which can be considered as a further building block in organometallic chemistry. [Copyright &y& Elsevier]

Abstract: This article will emphasize the particular role of organometallic radiopharmaceutical chemistry, namely the need for syntheses from water and the emerging implications for other (bio)organometallic fields. After some basic insights into the different directions of bioorganometallic chemistry, some facets of the [M(CO)3]+ (M=Tc, Re) moiety are reviewed and discussed in the respective context. The mechanism for the synthesis of [M(OH2)3(CO)3]+ which is still little understood, will be touched. The formation of additional M–C bonds is exemplified with cyclopentadienyl chemistry, the potential impact on targeted molecular imaging with the labelling of amino acids and the reactivity towards essential biomolecules such as guanine is shown. Future perspectives and implications for organometallic radiopharmaceutical chemistry will close this article. [Copyright &y& Elsevier]

Abstract: Accumulation of radiopharmaceuticals in the liver is frequently observed and represents in general a limiting factor when developing novel labeled compounds for any purpose in nuclear medicine. Aiming at the treatment of liver cancer with radiopharmaceuticals, such accumulation is desired but the compounds have to remain in the liver over an extended time period rather than being washed out or redistributed over time in the whole body. Lipiodol is known to remain in the liver and we present here a study for the preparation of 186Re and 99mTc labeled Lipiodol surrogates expected to behave similarly. We have synthesized two bidentate and two tridentate ligands conjugated to a pendant C18 chain as well as their corresponding fac-[Re(CO)3]+ and fac-[Tc(CO)3]+ complexes. Three of the rhenium complexes have been structurally characterized. Labelling with [186Re(OH2)3(CO)3]+ and [99mTc(OH2)3(CO)3]+, respectively, gave yields in the range of 90%. The complexes could be extracted into Lipiodol due to their high lipophilicity and close structural relationship with the major components of Lipiodol. The complexes are stable in water and in Lipiodol for more than 24h. These Lipiodol surrogates present new low-valent technetium and rhenium complexes for applications in liver cancer imaging and therapy. [Copyright &y& Elsevier]

Organometallic compounds offer broad scope for the design of therapeutic agents, but this avenue has yet to be widely explored. A key concept in the design of anticancer complexes is optimization of chemical reactivity to allow facile attack on the target site (e.g., DNA) yet avoid attack on other sites associated with unwanted side effects. Here, we consider how this result can be achieved for monofunctional "piano-stool" ruthenium(II) arene complexes of the type [(η6-arene)Ru(ethylenediamine)(X)]n+. A potentially important activation mechanism for reactions with biomolecules is hydrolysis. Density functional calculations suggested that aquation (substitution of X by H2O) occurs by means of a concerted ligand interchange mechanism. We studied the kinetics and equilibria for hydrolysis of 21 complexes, containing, as X, halides and pseudohalides, pyridine (py) derivatives, and a thiolate, together with benzene (bz) or a substituted bz as arene, using UV-visible spectroscopy, HPLC, and electrospray MS. The x-ray structures of six complexes are reported. In general, complexes that hydrolyze either rapidly (e.g., X = halide [arene = hexamethylbenzene (hmb)]} or moderately slowly [e.g., X = azide, dichloropyridine (arene = hmb)] are active toward A2780 human ovarian cancer cells, whereas complexes that do not aquate (e.g., X = py) are inactive. An intriguing exception is the X = thiophenolate complex, which undergoes little hydrolysis and appears to be activated by a different mechanism. The ability to tune the chemical reactivity of this class of organometallic ruthenium arene compounds should be useful in optimizing their design as anticancer agents. [ABSTRACT FROM AUTHOR]

Bifunctional chelating molecules linking the fac-[99mTc(CO)3]+ core with targeting biomolecules are required for the development of specific diagnostic radiopharmaceuticals. Diethylenetriamine (1) and N-(pyridin-2-ylmethyl)ethane-1,2-diamine (2) both react readily with [99mTc(H2O)3]+ in 0.9% saline at micromolar concentrations to form the cationic complexes [99mTc(1)(CO)3]+ (5) and [99mTc(2)(CO)3]+ (6) in quantitative yields. The crystal structures of the corresponding Re or 99Tc complexes were determined and exhibit in particular the small size of 5. Challenging both 99Tc complexes 5 and 6 with a 104 excess of histidine or cysteine showed no decomposition or ligand exchange after 24 hours and both compounds were also stable against reoxidation to [99mTcO4]-. In normal mice, complex 5 revealed a good and fast clearance from the blood, and most organs. Only limited accumulation in the large intestine was visible after 4 hours. Complex 6 was also excreted relatively quicklv from the blood but retention was observed in some tissues after 4h. In order to illustrate the potential of both ligands to be further functionalized, two derivatives containing potentially DNA binding functionalities, N-(quinolin-2-ylmethyl)ethane-1,2-diamine (4) were synthesized. The respective Re or 99Tc complexes were fully characterized. Based on these results, it appears that functionalization of biomolecules with acyclic triamine ligands is biologically relevant. Complex 5 in particular could he used to mimic a terminal amino group in, e.g., a peptide due to its small size and positive charge. [ABSTRACT FROM AUTHOR]

The water soluble ruthenium-p-cymene complexes [Ru(η6-p-cymene)X2]2 (X=Cl, Br, I or NCS), [Ru(η6-p-cymene)X2(pta)] (X=Cl, Br, I, or NCS; pta=1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane) and the tetraruthenium cluster [H4Ru4(η6-p-benzene)4]2+ have been prepared and their antimicrobial properties evaluated. They have been screened for antibacterial activity against Eschericia coli, Bascillus subtilis, Pseudomonas aeruginos, for antifungal activity against Candida albicans, Cladosporium resinae and Trichrophyton mentagrophytes and for antiviral activity against Herpes simplex and Polio viruses. The antimicrobial activity of these compounds does not appear to be correlated to DNA binding, but it could be due to specific interactions with proteins. The solid-state structure of the dimer complex [Ru(η6-p-cymene)Cl2]2, an important precursor complex in organometallic chemistry, is also reported. [Copyright &y& Elsevier]

The synthesis of 4′, a titanocene derivative of the anticancer drug tamoxifen is presented together with its biochemical properties. Compound 4′ is prepared by a McMurry coupling followed by a ligand exchange. Compound 4′ reveals an unexpected proliferative effect on the hormone-dependent cell line MCF7. Surprisingly this effect is also observed with Cp2TiCl2 alone. [Copyright &y& Elsevier]

Tethering known drugs to a metalorganic moiety is an efficient approach for modulating the anticancer, antibacterial, and antiparasitic activity of organometallic complexes. This study focused on the synthesis and evaluation of new dinuclear ruthenium(II)–arene compounds linked to several antimicrobial compounds such as dapsone, sulfamethoxazole, sulfadiazine, sulfadoxine, triclosan, metronidazole, ciprofloxacin, as well as menadione (a 1,4-naphtoquinone derivative). In a primary screen, 30 compounds (17 hybrid molecules, diruthenium intermediates, and antimicrobials) were assessed for in vitro activity against transgenic T. gondii tachyzoites constitutively expressing β-galactosidase (T. gondii β-gal) at 0.1 and 1 µM. In parallel, the cytotoxicity in noninfected host cells (human foreskin fibroblasts, HFF) was determined by an alamarBlue assay. When assessed at 1 µM, five compounds strongly impaired parasite proliferation by >90%, and HFF viability was retained at 50% or more, and they were further subjected to T. gondii β-gal dose-response studies. Two compounds, notably 11 and 13, amide and ester conjugates with sulfadoxine and metronidazole, exhibited low IC50 (half-maximal inhibitory concentration) values 0.063 and 0.152 µM, and low or intermediate impairment of HFF viability at 2.5 µM (83 and 64%). The nature of the anchored drug as well as that of the linking unit impacted the biological activity. [ABSTRACT FROM AUTHOR]