Yes / The functionalisation of the 16-electron complex [Os(η6-p-cymene)(1,2-dicarba-closo-dodecarborane- 1,2-dithiolato)] (1) with a series of Lewis bases to give the 18-electron complexes of general formula [Os(η6-p-cymene)(1,2-dicarba-closo-dodecarborane-1,2-dithiolato)(L)] (L = pyridine (2), 4-dimethylaminopyridine (3), 4-cyanopyridine (4), 4-methoxypyridine (5), pyrazine (6), pyridazine (7), 4,4’-bipyridine (8) and triphenylphosphine (9)) is reported. All 18-electron complexes are in equilibrium in solution with the 16-electron precursor, and thermochromic properties are observed in some cases (2, 3, 5, 8, and 9). The binding constants and Gibbs free energies of the equilibria are determined using UV-visible titrations and their stabilities investigated. Synthetic routes for forcing the formation of the 18-electron species are proposed, and analytical methods to characterise the equilibria are described. / We thank the Leverhulme Trust (Early Career Fellowship No. ECF-2013-414 to NPEB), and the University of Warwick (Grant No. RD14102 to NPEB).

The synthesis of two types of metallocenophanes is described: strained, ring-tilted [1]metallocenophanes with Al and Ga in bridging positions and Fe and Ru as transition elements and unstrained [1.1]ferrocenophanes with Al, Ga and In in bridging positions. [1]Metallocenophanes are potential monomers for the synthesis of organometallic polymers via ring-opening polymerization (ROP). After the successful synthesis of various starting monomers using the concept of intramolecular coordinating ligands, four different pathways of ROP were investigated. However, only one of these pathways proved successful in obtaining polymeric material. The starting monomers showed a surprising stability against commonly used initiators. This was attributed to an overly steric protection by the intramolecular coordinating ligands, thereby blocking the initiators, and a reduced ring strain, a consequence of the size of the bridging element.<p>[1.1]Ferrocenophanes belong to a class of dinuclear complexes where the two redox-active iron atoms are in close proximity with restricted flexibility. [1.1]Ferrocenophanes with Al, Ga and In in bridging positions were investigated. The redox properties of previously published [1.1]ferrocenophanes showed a fully reversible, stepwise, one-electron oxidation (FeII/FeII → FeII/FeIII → FeIII/FeIII). After the initial oxidation of the first iron center, a stable, mixed-valent monocationic species is created. The removal of a second electron from the second iron center therefore is more difficult, and occurs at higher potential to create the dicationic species. The difference in potential for the stepwise oxidation is directly related to the delocalization of the charge in the mixed-valent species. This delocalization mainly depends on the electronic properties of the bridging element. Depending on the bridging group 13 element, very different electrochemical properties were observed. For the alumina[1.1]ferrocenophane, no delocalization was detected, and a one-step, two-electron oxidation at the same potential was observed. For the inda[1.1]ferrocenophane, a more complex electrochemistry was observed that we attributed to an isomerization of the compound in solution. Only the investigated galla[1.1]ferrocenophane showed the expected stepwise oxidation-reduction behavior.

The synthesis of two types of metallocenophanes is described: strained, ring-tilted [1]metallocenophanes with Al and Ga in bridging positions and Fe and Ru as transition elements and unstrained [1.1]ferrocenophanes with Al, Ga and In in bridging positions. [1]Metallocenophanes are potential monomers for the synthesis of organometallic polymers via ring-opening polymerization (ROP). After the successful synthesis of various starting monomers using the concept of intramolecular coordinating ligands, four different pathways of ROP were investigated. However, only one of these pathways proved successful in obtaining polymeric material. The starting monomers showed a surprising stability against commonly used initiators. This was attributed to an overly steric protection by the intramolecular coordinating ligands, thereby blocking the initiators, and a reduced ring strain, a consequence of the size of the bridging element.<p>[1.1]Ferrocenophanes belong to a class of dinuclear complexes where the two redox-active iron atoms are in close proximity with restricted flexibility. [1.1]Ferrocenophanes with Al, Ga and In in bridging positions were investigated. The redox properties of previously published [1.1]ferrocenophanes showed a fully reversible, stepwise, one-electron oxidation (FeII/FeII → FeII/FeIII → FeIII/FeIII). After the initial oxidation of the first iron center, a stable, mixed-valent monocationic species is created. The removal of a second electron from the second iron center therefore is more difficult, and occurs at higher potential to create the dicationic species. The difference in potential for the stepwise oxidation is directly related to the delocalization of the charge in the mixed-valent species. This delocalization mainly depends on the electronic properties of the bridging element. Depending on the bridging group 13 element, very different electrochemical properties were observed. For the alumina[1.1]ferrocenophane, no delocalization was detected, and a one-step, two-electron oxidation at the same potential was observed. For the inda[1.1]ferrocenophane, a more complex electrochemistry was observed that we attributed to an isomerization of the compound in solution. Only the investigated galla[1.1]ferrocenophane showed the expected stepwise oxidation-reduction behavior.

Yes / An evaluation of the in vitro cytotoxicity of nine electron-deficient half-sandwich metal complexes towards two colorectal cancer cell lines (HCT116 p53+/+, HCT116 p53-/-) and one normal prostate cell line (PNT2) is presented herein. Three complexes were found to be equally cytotoxic towards both colorectal cancer cell lines, suggesting a p53-independent mechanism of action. These complexes are 12 to 34  more potent than cisplatin against HCT116 p53+/+ and HCT116 p53-/- cells. Furthermore, they were found to exhibit little or no cytotoxicity towards PNT2 normal cells, with selectivity ratios greater than 50. To gain an insight into the potential mechanisms of action of the most active compounds, their effects on the expression levels of a panel of genes were measured using qRT-PCR against treated HCT116 p53+/+ and HCT116 p53-/- cells, and cell cycle analysis was carried out. / The Royal Society grant UF150295, The Academy of Medical Sciences grant SFB003\1170

Yes / The synthesis, characterisation and evaluation of the in vitro cytotoxicity of four indole-based half-sandwich metal complexes towards two ovarian cancer cell lines (A2780 and A2780cisR) and one normal prostate cell line (PNT2) are presented herein. Although capable of inducing catalytic oxidation of NADH and able to reduce NAD+ with high turnover frequencies, in cells and in the presence of sodium formate, these complexes also strongly interact with biomolecules such as glutathione. This work highlights that efficient out-of-cells catalytic activity might lead to higher reactivity towards biomolecules, thus inhibiting the in-cells catalytic processes.

Yes / The synthesis, characterisation, and evaluation of the in vitro cytotoxicity of five maleonitriledithiolate-based ruthenium metal complexes bearing various phosphine ligands towards two ovarian cancer cell lines (A2780 and A2780cisR), one non-small-cell lung cancer cell line (H460) and one normal prostate cell line (PNT2) are presented herein. These 18-electron complexes were designed with four water-soluble phosphine ligands to increase the water-solubility character of the corresponding electron-deficient ruthenium complex which showed great in vitro promises, and triphenylphosphine for comparison. The complexes with triphenylphosphine-3,3',3''trisulfonic acid and triphenylphosphine present similar cytotoxicity compared to the 16-electron precursor, with equal cytotoxicity to both A2780 and A2780cisR. Hints at the mechanism of action suggest an apoptotic pathway based on ROS production. No toxicity was observed in preliminary in vivo pilot studies for these two complexes in subcutaneous A2780 and A2780cisR xenograft models, with some evidence of tumour growth delay. / The support of the Royal Society (University Research Fellowship No. URF150295, and RGF\EA\201001), the Academy of Medical Sciences/ The Wellcome Trust/ The Government Department of Business, Energy and Industrial/ The British Heart Foundation Springboard Award (SBF003\1170), and the CNRS is acknowledged. LRP is supported by a PhD studentship funded by the University of Bradford.

No / Half-sandwich complexes of precious metals are a versatile class of organometallic compounds. Their accessibility, robustness, and air-stability are examples of the unique properties that allow their applications in various fields of chemistry (e.g. catalysis), and as anticancer drug candidates. Half-sandwich complexes generally follow the 18-electron rule, although some stable 16-electron (16-e) complexes have been isolated. The latter are generally coordinatively unsaturated leading to potential applications in catalysis and as precursors for 18-electron (18-e) complexes. Six 16-e complexes [Ru(η6-p-cymene)(1,2-benzene-1,2-dithiolato)] (1), [Os(η6-p-cymene) (1,2-benzene-1,2-dithiolato)] (2), [Ir(η5-pentamethylcyclopentadiene) (1,2-benzene-1,2-dithiolato)] (3), [Ru(η6-p-cymene)(1,2-dicarba-closo- dodecaborane-1,2-dithiolato)] (4), [Os(η6-p-cymene)(1,2-dicarba-closo- dodecaborane-1,2-dithiolato)] (5), and [Ir(η5-pentamethylcyclopentadiene)(1,2-dicarba-closo-dodecaborane-1,2-dithiolato)] (6) were synthesised by reactions between 1,2-benzenedithiol (1, 2, 3) or 1,2-dicarba-closo-dodecaborane-1,2-dithiol (4, 5, 6) and the corresponding metal dimers. In solution (10-4 M) at ambient temperature, the six complexes are stable electron-deficient 16-electron monomers, although the formation of a more electronically stable 18-electron dimer is observed for complex 1 at millimolar concentrations. The six complexes exhibit dramatic differences in reactivity towards electron-donor molecule. The in-vitro anti-inflammatory activities of the 16-e complexes 1 – 6 were investigated on MRC 5-fibroblast and lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. Cells were exposed for 24h to the 16-e complexes 1 – 6 in the concentrations range of 10, 20, 50 and 100uM. After this, drugs were removed and nitric oxide (NO) concentration in the cultured medium was determined by the Griess reaction. Cells were then washed and placed in fresh growth medium for a further 24h as a recovery period. Cell viability was then assessed by MTT assay. Our preliminary data showed that complex 1 – 6 showed some anti-inflammatory effect on both lines, but with slightly differences between them, suggesting that the M-S2C2 scaffold of the electron-deficient complexes is the main structural moiety responsible for such effect. Further studies will focus on the matching these effects with their structures. / Abstract of conference paper.

Yes / Ruthenium compounds have been shown to be promising alternatives to platinum(II) drugs. However, their clinical success depends on achieving mechanisms of action that overcome Pt-resistance mechanisms. Electron-deficient organoruthenium complexes are an understudied class of compounds that exhibit unusual reactivity in solution and might offer novel anticancer mechanisms of action. Here, we evaluate the in vitro and in vivo anticancer properties of the electron-deficient organoruthenium complex [(p-cymene)Ru(maleonitriledithiolate)]. This compound is found to be highly cytotoxic: 5 to 60 times more potent than cisplatin towards ovarian (A2780 and A2780cisR), colon (HCT116 p53+/+ and HCT116 p53−/−), and non-small cell lung H460 cancer cell lines. It shows no cross-resistance and is equally cytotoxic to both A2780 and A2780cisR cell lines. Furthermore, unlike cisplatin, the remarkable in vitro antiproliferative activity of this compound appears to be p53-independent. In vivo evaluation in the hollow-fibre assay across a panel of cancer cell types and subcutaneous H460 non-small cell lung cancer xenograft model hints at the activity of the complex. Although the impressive in vitro data are not fully corroborated by the in vivo follow-up, this work is the first preclinical study of electron-deficient half-sandwich complexes and highlights their promise as anticancer drug candidates. / UF150295/Royal Society; University of Bradford; Government Department of Business, Energy and Industrial Strategy; SBF003\1170/British Heart Foundation Springboard Award; AMS_/Academy of Medical Sciences/United Kingdom

Yes / Electron‐deficient half‐sandwich complexes are a class of under‐studied organometallics with demonstrated potential as metallodrug candidates. The present study investigates the effect of two 16‐electron organoruthenium complexes ([( p‐ cym)Ru(benzene‐1,2‐dithiolato)] ( 1 ) and [( p ‐cym)Ru(maleonitriledithiolate)] ( 2 )) on the cell viability of non‐immortalised human lymphocytes from healthy individuals. The genotoxic effects of 1 and 2 in lymphocytes using the Comet and cytokinesis‐block micronucleus assays is also investigated. Gene expression studies were carried out on a panel of genes involved in apoptosis and DNA damage repair response. Results show that the two 16‐electron complexes do not have significant effect on the cell viability of human lymphocytes from healthy individuals. However, an increase in DNA damage is induced by both compounds, presumably through oxidative stress production. / This project was supported by the Royal Society (University Research Fellowship No. UF150295 to NPEB), the University of Bradford (RDF Award), and by the Academy of Medical Sciences/the Wellcome Trust/ the Government Department of Business, Energy and Industrial Strategy/ the British Heart Foundation Springboard Award [SBF003\1170 to NPEB].

No / Two new complexes, [Fe3(μ3-O)(inicH)6(H2O)3][Gd(NO3)6]·(NO3)4·nH2O (1) and [Fe3(μ3-O)(inicH)6(H2O)3][Dy(NO3)5 (H2O)]·(NO3)5·n(H2O) (2) with two isolated complex moieties, were generated when isonicotinic acid was treated with iron(III) nitrate and the corresponding lanthanide(III) nitrate in water. The structures were determined by single-crystal X-ray diffraction studies. In these compounds, the anionic lanthanide complexes are encapsulated by trinuclear [Fe3(μ3-O)(inicH)6(H2O)3]7+ cationic cluster units, which is facilitated by hydrogen-bonding interactions. Investigation of the magnetic properties reveals that 2 shows slow relaxation of magnetization at low magnetic field (Hdc = 1.0 kOe), with an energy barrier of 23 K originating from a single [Dy(NO3)5(H2O)]2– anion. / Errata: 2014(25): 4228 (http://onlinelibrary.wiley.com/enhanced/doi/10.1002/ejic.201402684)