Search

Heterobimetallic cages built from Pd and either octahedral Ru or square-planar Pt moieties and bridged by ligands with H bonding-accepting or -donating properties are reported. They showed stimulus-responsive dis- and reassembly, while guest binding was found to be dependent on the complementary properties of the guest to the host in terms of charge, size and H bonding properties.

Metallosupramolecular architectures formed from metal ions and bridging ligands are increasing in popularity due to their range of applications and ease of self-assembly. Many are able to readily change their shape and/or function in response to an external stimulus and have the ability to encapsulate guest molecules within their internal cavities. Ferrocenyl groups (Fc) have been incorporated previously within the bridging ligands of metallosupramolecular structures due to their ideal attributes brought about by the structural and rotational flexiblity of the two cyclopentadienyl (Cp) rings coordinated to the Fe(II) centre. However, the majority of these Fc-based structures contain symmetrically substituted Cp rings. We report the synthesis and characterisation of non-symmetrically functionalised Fc-based ligands incorporating both N , N ' and NHC-donor groups chosen for their differing coordination properties. Both substituents were designed to coordinate to a single metal centre with the dissimilar coordination properties of each donor group facilitating stimulus-induced dissociation/association of one of the substituents as an opening/closing mechanism. Preliminary investigations into the coordination of these Fc-based ligands to a [Ru(η 6 - p -cymene)] 2+ moiety indicated complexation through a mixture of either a bi- or tridentate fashion, as alluded by 1 H NMR spectroscopy and mass spectrometry. Density functional theory (DFT) calculations revealed the Fc-based ligands adopt a syn conformation driven by H-bonding and π-interactions between the two Cp substituents, which facilitate coordination of both donor groups towards the metal centre.

A dynamic covalent approach was exploited to generate a family of homometallic [Pt n L 2 n ] 2 n + cage (predominantly [Pt 2 L 4 ] 4+ systems) architectures. The family of platinum(II) architectures were characterized using 1 H nuclear magnetic resonance (NMR) and diffusion ordered spectroscopy (DOSY), electrospray ionization mass spectrometry (ESI-MS) and the molecular structures of two cages were determined by X-ray crystallography.

A new sequential metalation strategy that enables the assembly of a new more robust reduced symmetry heterobimetallic [PdPtL 4 ] 4+ cage C is reported. By exploiting a low-symmetry ditopic ligand (L) that features imidazole and pyridine donor units we were able to selectively form a [Pt(L) 4 ] 2+ "open-cage" complex. When this was treated with Pd(ii) ions the cage C assembled. 1 H and DOSY nuclear magnetic resonance (NMR) spectroscopy and electrospray ionisation mass spectrometry (ESIMS) data were consistent with the quantitative formation of the cage and the heterobimetallic structure was confirmed by single crystal X-ray crystallography. The cage C was shown to bind anionic guest molecules. NMR studies suggested that these guests interacted with the cavity of the cage in a specific orientation and this was confirmed for the mesylate ion (MsO - ) : C host-guest adduct using X-ray crystallography. In addition, the system was shown to be stimulus-responsive and could be opened and closed on demand when treated with appropriate stimuli. If a guest molecule was bound within the cage, the opening and closing was accompanied by the release and re-uptake of the guest molecule., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Pt(terpyridine) complexes are well-known DNA intercalators. The introduction of an NHC co-ligand rendered such a complex highly antiproliferative in cancer cells compared to its chlorido derivative. Despite the high potency, zebrafish embryos tolerated the compound well, especially compared to cisplatin. DNA interaction studies support a mode of action related to intercalation.

A new [PdPtL 4 ] 4+ heterobimetallic cage containing hydrazone linkages has been synthesised using the sub-component self-assembly approach. 1 H and DOSY nuclear magnetic resonance (NMR) spectroscopy and electrospray ionisation mass spectrometry (ESIMS) data were consistent with the formation of the [PdPtL 4 ] 4+ architecture. The cage was stimulus-responsive and could be partially disassembled and reassembled by the addition of dimethylaminopyridine (DMAP) and p -tolenesulfonic acid (TsOH), respectively. Additionally, the stability of the hydrazone cage against hydrolysis in the presence of water and nucleophilic decomposition in the presence of guest molecules was compared to a previously synthesised imine-containing [PdPtL 4 ] 4+ cage. It was established that the hydrazone linkage was more resistant to hydrolysis. Furthermore, the host-guest (HG) chemistry with a series of drug and drug-like molecules was examined. The hydrazone cage was shown to interact with cisplatin while the smaller imine cage was shown to interact with 5-fluorouracil and oxaliplatin in CD 3 CN. No HG interactions were observed in the more polar d 6 -DMSO. In vitro antiproliferative activity studies demonstrated both cages were active against the cancer cell lines tested and displayed half-maximal inhibitory (IC 50 ) values in the range of 25-35 μM. Most [PdPtL 4 ] 4+ -drug mixtures tested had higher IC 50 values than the hosts. However, the [PdPtL 4 ] 4+ cages, and [PdPtL 4 ] 4+ :drug mixtures were less cytotoxic than the well established anticancer drugs cisplatin, oxaliplatin and 5-fluorouracil.

The incorporation of the ferrocenyl moiety into a bioactive molecule may significantly alter the activity of the resulting conjugate. By applying this strategy, we designed ferrocenyl analogs of monastrol - the first low molecular weight kinesin spindle protein (KSP) inhibitor. The obtained compounds showed low micromolar antiproliferative activity towards a panel of sensitive and ABC-overexpressing cancer cells. Most cytotoxic compounds exhibited also higher KSP modulatory activity and ability for ROS generation compared to monastrol. The increased bioactivity of the studied compounds can be attributed to the presence of the ferrocenyl group.

Redox-modulating anticancer drugs allow the exploitation of altered redox biology observed in many cancer cells. We discovered dinuclear RhIII(Cp*) and IrIII(Cp*) complexes that have in vitro anticancer activity superior to cisplatin and the investigational drug IT-139, while being less toxic in haemolysis and in vivo zebrafish models. The mode of action appears to be related to DNA damage and ROS-mediated stress pathways.

Correction for 'Unexpected arene ligand exchange results in the oxidation of an organoruthenium anticancer agent: the first X-ray structure of a protein-Ru(carbene) adduct' by Matthew P. Sullivan et al., Chem. Commun., 2018, 54, 6120-6123.

The first X-ray structures of adducts formed between a RuII(N-heterocyclic carbene)(η6-p-cymene) compound and a protein are reported. Coordination to the protein induced the cleavage of the cymene ligand and EPR spectroscopy demonstrated the oxidation of the Ru centre.

Ru(arene) compounds have many desirable features making them promising candidates for further development in anticancer drug research. While a lot of emphasis has been placed on the modification of the ancillary ligands, there are not many examples of arene ligands bearing functional groups. Herein, we report the preparation of [Ru(arene)(8-oxyquinolinato)Cl] complexes with the arene being a protected form of the amino acid l-phenylalanine and 8-oxyquinolinato ligand substituted with halogens. With this approach we aimed to alter the pharmacological properties of the complexes and address issues with the aqueous solubility of the analogous p-cymene complexes. The complexes were shown to be stable in DMSO and water and reacted readily with l-histidine and 9-ethylguanine as protein and DNA models, respectively. Assaying the antiproliferative activity in cancer cells gave IC 50 values in the low μM range. While the lipophilicity of the p-cymene analogues correlated well with their in vitro cytotoxicity, the potency of the complexes with the l-phenylalanine-derived arene was independent of lipophilicity.

The reaction of the para-quinone 6,7-dichloroquinoline-5,8-dione with various transition metal dimers led to the unexpected formation of quinoline-ortho-quinone metal complexes. Systematic variation of the reaction conditions helped identify the solvent as the source of the carbonyl oxygen.

A novel capillary zone electrophoresis-mass spectrometry (CZE-MS) approach allows the simultaneous characterization and quantification of the binding of metal-based anticancer agents to biomolecules. Moreover, for the first time, oligonucleotide metallation was resolved at single-nucleotide resolution by MS.

Metalation of hen egg white lysozyme (HEWL) with organometallics was studied with physicochemical methods in solid state, solution and the gas phase. While metalation did not affect the crystal structure of HEWL significantly, protein destabilisation was detected in gas phase and solution.

Anticancer active metal complexes with biologically active ligands have the potential to interact with more than one biological target, which could help to overcome acquired and/or intrinsic resistance of tumors to small molecule drugs. In this paper we present the preparation of 2-hydroxy-[1,4]-naphthoquinone-derived ligands and their coordination to a Ru(II)(η(6)-p-cymene)Cl moiety. The synthesis of oxime derivatives resulted in the surprising formation of nitroso-naphthalene complexes, as confirmed by X-ray diffraction analysis. The compounds were shown to be stable in aqueous solution but reacted with glutathione and ascorbic acid rather than undergoing reduction. One-electron reduction with pulse radiolysis revealed different behavior for the naphthoquinone and nitroso-naphthalene complexes, which was also observed in in vitro anticancer assays.

The clinical development of anticancer metallodrugs is often hindered by the elusive nature of their molecular targets. To identify the molecular targets of an antimetastatic ruthenium organometallic complex based on 1,3,5-triaza-7-phosphaadamantane (RAPTA), we employed a chemical proteomic approach. The approach combines the design of an affinity probe featuring the pharmacophore with mass-spectrometry-based analysis of interacting proteins found in cancer cell lysates. The comparison of data sets obtained for cell lysates from cancer cells before and after treatment with a competitive binder suggests that RAPTA interacts with a number of cancer-related proteins, which may be responsible for the antiangiogenic and antimetastatic activity of RAPTA complexes. Notably, the proteins identified include the cytokines midkine, pleiotrophin and fibroblast growth factor-binding protein 3. We also detected guanine nucleotide-binding protein-like 3 and FAM32A, which is in line with the hypothesis that the antiproliferative activity of RAPTA compounds is due to induction of a G 2 /M arrest and histone proteins identified earlier as potential targets.

Emerging evidence indicates that levels of advanced glycation end-products (AGEs) correlate with age- and diabetes-related organ damage and may play a causative role in such damage. Increased chelation of Cu(II) ions appears to play an important role in this process, however, the precise relationship between formation of AGEs and accumulation of Cu(II) is yet to be determined. The interaction between AGEs and Cu(II) has been investigated using a collagenous peptide that has been site-specifically modified by a key AGE. Potentiometric titration showed that introduction of this AGE increased the capacity of the host-peptide to bind Cu(II). This result was confirmed by mass spectrometric characterisation of the AGE-modified peptide-Cu(II) system.

Chemotherapeutics for the treatment of tumorigenic conditions that feature novel modes of action are highly sought after to overcome the limitations of current chemotherapies. Herein, we report the conjugation of the alkylating agent chlorambucil to the RAPTA scaffold, a well-established pharmacophore. While chlorambucil is known to alkylate DNA, the RAPTA complexes are known to coordinate to amino acid side chains of proteins. Therefore, such a molecule combines DNA and protein targeting properties in a single molecule. Several chlorambucil-tethered RAPTA derivatives were prepared and tested for their cytotoxicity, stability in water and reactivity to protein and DNA substrates. The anticancer activity of the complexes is widely driven by the cytotoxicity of the chlorambucil moiety. However, especially in the cisplatin-resistant A2780R cells, the chlorambucil-functionalized RAPTA derivatives are in general more cytotoxic than chlorambucil and also a mixture of chlorambucil and the parent organoruthenium RAPTA compound. In a proof-of-principle experiment, the cross-linking of DNA and protein fragments by a chlorambucil-RAPTA derivative was observed.

A water-stable phosphoramidate Ru(arene) metallodrug shows antiproliferative activity comparable to KP1019 in human cancer cell lines. This novel compound can cross-link the peptide backbone of cytochrome c, but features low apoptosis inducing properties.

Ru(II)(η(6)-arene) complexes, especially with bioactive ligands, are considered to be very promising compounds for anticancer drug design. We have shown recently that Ru(II)(η(6)-p-cymene) complexes with 3-hydroxyflavone ligands exhibit very high in vitro cytotoxic activities correlating with a strong inhibition of topoisomerase IIα. In order to expand our knowledge about the structure-activity relationships and to determine the impact of lipophilicity of the arene ligand and of the hydrolysis rate on anticancer activity, a series of novel 3-hydroxyflavone derived Ru(II)(η(6)-arene) complexes were synthesised. Furthermore, the impact of the heteroatom in the bioactive ligand backbone was studied by comparing the cytotoxic activity of Ru(II)(η(6)-p-cymene) complexes of 3-hydroxyquinolinone ligands with that of their 3-hydroxyflavone analogues. To better understand the behaviour of these Ru(II) complexes in aqueous solution, the stability constants and pK(a) values for complexes and the corresponding ligands were determined. Furthermore, the interaction with the DNA model 5'-GMP and with a series of amino acids was studied in order to identify potential biological target structures.

Organometallic Ru(II), Os(II) and Rh(III) complexes of lapachol induce apoptosis in human tumour cell lines in the low μM range by a mode of action involving oxidative stress, especially in the case of the ruthenium compound.

Ru(II)(arene)-flavonoids with high in vitro antitumour activity were synthesised. These compounds are capable of inhibiting human topoisomerase IIα and binding covalently to DNA., (This journal is © The Royal Society of Chemistry 2012)

Ru(II)(arene) anticancer compounds with maleimide functionality were prepared to allow selective interaction with thiol-containing biomolecules and thereby enforcing the selective delivery of the compounds to the tumour., (This journal is © The Royal Society of Chemistry 2012)

The synthesis and in vitro anticancer activity of Os(II)-arene complexes with carbohydrate-derived phosphite co-ligands are reported. The compounds were characterized by standard methods and the molecular structure of dichlorido(eta(6)-p-cymene)(3,5,6-bicyclophosphite-1,2-O-isopropylidene-alpha-D-glucofuranoside)osmium(II) was determined by X-ray diffraction analysis. Complexes with chlorido leaving groups undergo hydrolysis by consecutive formation of aqua compounds, followed by cleavage of a P-O bond of sugar phosphite ligands, as demonstrated by NMR studies. These observations are similar to those of analogous Ru(II)-arene complexes; however the rate of hydrolysis is very slow for osmium compounds. The complexes with oxalato leaving groups resist hydrolysis; no hydrolytic species were detected by (31)P{(1)H} NMR spectroscopy over several days. Within this series of Os compounds, in vitro anticancer activity is highest for the most lipophilic chlorido complex dichlorido(eta(6)-p-cymene)(3,5,6-bicyclophosphite-1,2-O-cyclohexylidene-alpha-D-glucofuranoside)osmium(II).

A series of nitrile-functionalized pyrrolidinium-based ionic liquids have been prepared and characterized by spectroscopic methods and X-ray crystallography. The application of these new ionic liquids as reaction media for Suzuki and Stille C-C cross-coupling reactions has been investigated and compared with related imidazolium and pyridinium systems (including those with and without nitrile functionalities). The nature of the ionic liquid strongly influences the catalyzed reaction and it would appear that, in addition to the nitrile group, the strength of anion-cation pairing in the ionic liquid and the viscosity of the ionic liquid play critical roles. Nanoparticles are also detected following catalysis and their role, and the influence of the ionic liquid on them, is assessed. The ability to use the nitrile-functionalized pyrrolidinium-based ionic liquids diluted in other (non-functionalized) ionic liquids is also described.

Cellular uptake is being widely investigated in the context of diverse biological activities of metal compounds on the cellular level. However, the applied techniques differ considerably, and a validated methodology is not at hand. Therefore, we have varied numerous aspects of sample preparation of the human colon carcinoma cell line SW480 exposed in vitro to the tumor-inhibiting metal complexes cisplatin and indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(iii)] (KP1019) prior to analysis with ICP-MS, and the results were found to be tremendously influenced by adsorption to the culture dishes. Adsorption to culture plates increases linearly with the concentration of KP1019, depends on the protein content of the medium, the duration of contact to protein-containing medium prior to drug addition and the hydrophilicity/lipophilicity of the compound. For varying degrees of cell confluence, adsorption of Ru hardly differs from cell-free experiments. Desorption from the plates contributes to total Ru detected in dependence on the cell harvesting method. Desorption kinetics for lysis in HNO(3) and tetramethylammonium hydroxide (TMAH) are comparable, but TMAH is a more potent desorbant. Sample storage conditions prior to analysis influence significantly the recovery of analyte. Protocols using cell lysis in the culture plate without proper corrections run the risk of producing artefacts resulting from metal adsorption/desorption to an extent comparable with the actual cellular content. However, experimental protocols reported in the literature frequently do not contain information whether adsorption or blank correction were performed and should be regarded with caution, especially if lysis was performed directly in the culture dishes.

Triggered by the resounding success of cisplatin, the past decades have seen tremendous efforts to produce clinically beneficial analogues. The recent achievement of oxaliplatin for the treatment of colon cancer should, however, not belie the imbalance between a plethora of investigated complexes and a very small number of clinically approved platinum drugs. Strategies opening up new avenues are increasingly being sought using complexes of metals other than platinum such as ruthenium or gallium. Based on the chemical differences between these metals, the spectrum of molecular mechanisms of action and potential indications can be broadened substantially. Other approaches focus on complexes with tumour-targeting properties, thereby maximizing the impact on cancer cells and minimizing the problem of adverse side effects, and complexes with biologically active ligands.

The antitumour activity of the organometallic ruthenium(ii)-arene mixed phosphine complexes, [Ru(eta(6)-p-cymene)Cl(PTA)(PPh(3))]BF(4) and [Ru(eta(6)-C(6)H(5)CH(2)CH(2)OH)Cl(PTA)(PPh(3))]BF(4) (PTA = 1,3,5-triaza-7-phosphaadamantane), have been evaluated in vitro and compared to their RAPTA analogues, [Ru(eta(6)-p-cymene)Cl(2)(PTA)] and [Ru(eta(6)-C(6)H(5)CH(2)CH(2)OH)Cl(2)(PTA)] . The results show that the addition of the PPh(3) ligand to increases the cytotoxicity towards the TS/A adenocarcinoma cancer cells, which correlates with increased uptake, but also increases cytotoxicity to non-tumourigenic HBL-100 cells, thus decreasing selectivity. The decrease in selectivity has been correlated to increased DNA interactions relative to proteins, demonstrated by reactivity of the compounds with a 14-mer oligonucleotide and the model proteins ubiquitin and cytochrome-c.

Biotransformation of ruthenium(III) anticancer complexes as hypothesized in the activation-by-reduction theory is the central topic of the present paper. The redox behavior of tetrachlorobis(azole)ruthenate(III)-type complexes was studied by NMR spectroscopy and square wave voltammetry. The influence of reducing agents on the binding behavior toward the DNA-modeling nucleotide GMP was determined by capillary electrophoresis, accompanied by identification of arising peaks by online coupling to electrospray ionization mass spectrometry. The determination of redox potentials revealed that the biologically relevant reductants ascorbic acid and glutathione are capable of reducing the studied Ru(III) complexes under physiological conditions. Characteristic differences in reduction kinetics dependent on the pH value can be explained by higher reduction strength of ascorbic acid and glutathione at higher pH compared to the pH-independent redox response of ruthenium(III) complexes. Binding behavior of (H2ind)[trans-RuCl4(Hind)2] (Hind = 1H-indazole) toward GMP was found to be increased upon addition of two equivalents of glutathione but not of ascorbic acid. In contrast, only a minor influence on the GMP-binding under reductive conditions was found for (H2im)[trans-RuCl4(Him)2] (KP418, Him = 1H-imidazole).

(SP-4-2)-Bis[(R)-(-)-2-aminobutanol-kappaN]dichloroplatinum(II) and (SP-4-2)-bis[(R)-(-)-2-aminobutanolato-kappa2N,O]platinum(II) are promising cytotoxic agents exhibiting a strongly pH-dependent rate of reaction with the DNA-modeling nucleotide guanosine 5'-monophosphate (GMP). This potential mode-of-action binding, directly correlating with cytotoxicity, is influenced by the intramolecular chelation of bifunctional aminoalcohol ligands which was examined by means of micellar electrokinetic chromatography (MEKC) and nuclear magnetic resonance (NMR). While NMR clearly proves the existence of equilibrium between the ring-opened and ring-closed species, no such transformation was observed under MEKC conditions. In a kinetic study performed by MEKC, the half-lives of GMP bound to the platinum complexes were determined and compared to the kinetic data acquired by capillary zone electrophoresis. An appreciable increase in binding in the presence of sodium dodecyl sulfate (SDS) micelles was explained in terms of activation of (SP-4-2)-bis[(R)-(-)-2-aminobutanol-kappaN]dichloroplatinum(II). This apparently takes place due to the shifting of the equilibrium towards the ring-opened species, induced by adduct formation between SDS and the platinum complex that was confirmed by electrospray ionization mass spectrometry.