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.

Yes / Carbon monoxide (CO) is both a substance hazardous to health and a side product of a number of industrial processes, such as methanol steam reforming and large-scale oxidation reactions. The separation of CO from nitrogen (N2) in industrial processes is considered to be difficult because of the similarities of their electronic structures, sizes, and physicochemical properties (e.g., boiling points). Carbon monoxide is also a major poison in fuel cells because of its adsorption onto the active sites of the catalysts. It is therefore of the utmost economic importance to discover new materials that enable effective CO capture and release under mild conditions. However, methods to specifically absorb and easily release CO in the presence of contaminants, such as water, nitrogen, carbon dioxide, and oxygen, at ambient temperature are not available. Here, we report the simple and versatile fabrication of a new class of hybrid materials that allows capture and release of carbon monoxide under mild conditions. We found that carborane-containing metal complexes encapsulated in networks made of poly(dimethylsiloxane) react with CO, even when immersed in water, leading to dramatic color and infrared signature changes. Furthermore, we found that the CO can be easily released from the materials by simply dipping the networks into an organic solvent for less than 1 min, at ambient temperature and pressure, which not only offers a straightforward recycling method, but also a new method for the “on-demand” release of carbon monoxide. We illustrated the utilization of the on-demand release of CO from the networks by carrying out a carbonylation reaction on an electron-deficient metal complex that led to the formation of the CO-adduct, with concomitant recycling of the gel. We anticipate that our sponge-like materials and scalable methodology will open up new avenues for the storage, transport, and controlled release of CO, the silent killer and a major industrial poison. / The Royal Society, The Romanian Ministry of Education and Research, The University of Bradford, European Regional Development Fund of the European Union / Research Development Fund Publication Prize Award winner.

No / 4-Chloro-2(H)-pyran-2-one undergoes thermal Diels−Alder cycloaddition with electron-deficient dienophiles to afford, without any significant selectivity, 6-endo- and 5-endo-substituted bicyclic lactone cycloadducts. In contrast to 3- and 5-bromo-2(H)-pyran-2-one, 4-chloro-2(H)-pyran-2-one does not undergo thermal cycloadditions with electron-rich dienophiles. The regio- and stereochemical preferences of the cycloadditions of 4-chloro-2(H)-pyran-2-one and other related 2(H)-pyran-2-ones are investigated computationally. Calculations were carried out on the transition states leading to the four possible regio- and stereoisomeric cycloadducts using density functional theory (B3LYP/6-31G*). These studies allow prediction of the regio- and stereoselectivity in these reactions which are in line with experimental observations.