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).

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].

Yes / We report an evaluation of the cytotoxicity of a series of electron-deficient (16-electron) half-sandwich precious metal complexes of ruthenium, osmium and iridium ([Os/Ru(η6-pcymene)( 1,2-dicarba-closo-dodecarborane-1,2-dithiolato)] (1/2), [Ir(η5-pentamethylcyclopentadiene)(1,2-dicarba-closo-dodecarborane- 1,2-dithiolato)] (3), [Os/Ru(η6-p-cymene)(benzene-1, 2-dithiolato)] (4/5) and [Ir(η5-pentamethylcyclopentadiene) (benzene-1,2-dithiolato)] (6)) towards RAW 264.7 murine macrophages and MRC-5 fibroblast cells. Complexes 3 and 6 were found to be non-cytotoxic. The anti-inflammatory activity of 1–6 was evaluated in both cell lines after nitric oxide (NO) production and inflammation response induced by bacterial endotoxin lipopolysaccharide (LPS) as the stimulus. All metal complexes were shown to exhibit dose-dependent inhibitory effects on LPS-induced NO production on both cell lines. Remarkably, the two iridium complexes 3 and 6 trigger a full anti-inflammatory response against LPS-induced NO production, which opens up new avenues for the development of non-cytotoxic anti-inflammatory drug candidates with distinct structures and solution chemistry from that of organic drugs, and as such with potential novel mechanisms of action. / We thank the Royal Society (University Research Fellowship No. UF150295 to NPEB), and the University of Bradford for financial support.

Une étude détaillée a été effectuée sur des composés organométalliques de carbènes N-hétérocycliques (NHC) de nickel(II), et plus particulièrement sur des complexes demi-sandwich nickel(II)−NHC. Ces complexes ont montré des activités sans précédent en catalyse homogène, notamment en α-arylation de cétones acycliques, où des charges en pré-catalyseur de seulement 1 mol% ont pu être utilisées. L' étude mécanistique de cette réaction tend à montrer l'implication d'intermédiaires radicalaires. De plus, ces complexes demi-sandwich se sont révélés être des pré-catalyseurs performants en hydrosilylation de dérivés carbonylés et d'imines. Les méthodologies qui en découlent fournissent de façon efficace et sélective les produits de réduction correspondants, dans des conditions réactionnelles douces. Un intermédiaire réactionnel demi-sandwich de type nickel−hydrure, agissant probablement comme le véritable précurseur catalytique, a en outre pu être isolé. D'autre part, la synthèse de nouveaux complexes Ni−NHC a remarquablement mené à une nouvelle méthodologie de substitution du ligand cyclopentadienyl dans des dérivés demi-sandwich alkyl,NHC−Ni. Enfin, l'utilisation de NHCs moins classiques, comme les NHCs possédant un squelette malonate, ou encore les carbènes (alkyl)(amine) cycliques, a mené à l'isolement de nouveaux complexes carbéniques de nickel(II), dont les premiers résultats catalytiques sont encourageants. / A detailed study has been conducted on organometallic compounds of N-heterocyclic carbenes (NHC) of nickel(II), in particular on half-sandwich nickel(II)−NHC complexes. These complexes showed unprecedented catalytic activity in homogeneous catalysis, especially in the α-arylation of acyclic ketones, where catalyst loadings as low as 1 mol% could be used. Mechanistic experiments suggest that radicals are implied. Furthermore, these half-sandwich complexes proved to be efficient pre-catalysts in the hydrosilylation of carbonyl compounds and imines, allowing the reduction processes to proceed under mild reaction conditions. During the course of these studies, a half-sandwich nickel−hydride intermediate that probably acts as the true pre-catalyst was isolated. Remarkably, the synthesis of new Ni−NHC complexes led to a methodology for cyclopentadienyl ligand substitution in stable 18-electron alkyl,NHC−Ni derivatives. Finally, the use of less common NHC ligands, such as NHCs possessing a malonate backbone, or else, the use of cyclic (alkyl)(amino) carbenes, led to the isolation of new nickel−carbene complexes, which gave encouraging preliminary catalytic results.

Die vorliegende Dissertation beschäftigt sich mit der Synthese und Charakterisierung von Übergangsmetallkomplexen und deren Anwendungen in der MOCVD (= metal-organic chemical vapor deposition), sowie als Precursoren zur Darstellung von Nanopartikeln und Nanokompositen. Ein Schwerpunkt dieser wissenschaftlichen Arbeit liegt dabei in der Entwicklung von Me-, tBu- und SiMe3-substituierten Manganhalbsandwichkomplexen für die Generierung dünner Mangan-basierter Schichten mittels MOCVD-Technik. Die gezielte strukturelle Veränderung des Cyclopentadienyl-Liganden beeinflusst die physikalischen und chemischen Eigenschaften dieser Verbindungen, welche systematisch untersucht werden. Ein weiteres zentrales Thema dieser Arbeit ist die Entwicklung von Bis(β-diketonato)- und Allyl-(β-diketonato)-palladium(II) Verbindungen als MOCVD-Precursoren. Hierbei dienen asymmetrische β-Diketonate des Typs CH3COCCO(CH2)n (n = 3, 4) als Liganden. Zudem wird durch Substitutionsreaktionen mit Me- und tBu-Gruppen am η3-Allyl-Liganden Einfluss auf die Stabilität der Verbindungen genommen. Die Abscheidung dieser Precursoren führt, in Abhängigkeit des verwendeten Reaktivgases, zur Bildung von Palladium- bzw. Palladiumoxid-Schichten. Zudem wird die Synthese und Charakterisierung von Co(II)-Carboxylaten des Typs [Co(CO2CRR´(OC2H4)nOMe)2] (n = 1, 2; R = H, R´ = Me; R = H, R´ = Ph) beschrieben. Stellvertretend wird eine Verbindung als Single-Source Precursor zur Darstellung von Co3O4-Nanopartikeln eingesetzt. Darüber hinaus wird die Inkorporation von Co3O4-Nanopartikel in organisch-anorganische Hybridmaterialien mittels Zwillingspolymerisation vorgestellt.