100 years of metal coordination chemistry: from Alfred Werner to anticancer metallodrugs

YesAlfred Werner was awarded the Nobel Prize in Chemistry just over 100 years ago. We recall briefly the era in which he was working, his co-workers, and the equipment he used in his laboratories. His ideas were ground breaking: not only does a metal ion have a primary valency (“hauptvalenz”, now the oxidation state), but also a secondary valency, the coordination number (“nebenvalenz”). At that time some refused to accept this idea, but he realised that his new thinking would open up new areas of research. Indeed it did. We illustrate this for the emerging field of medicinal metal coordination chemistry, the design of metal-based therapeutic and diagnostic agents. The biological activity of metal complexes depends intimately not only on the metal and its oxidation state, but also on the type and number of coordinated ligands, and the coordination geometry. This provides a rich platform in pharmacological space for structural and electronic diversity. It is necessary to control both the thermodynamics (strengths of metal-ligand bonds) and kinetics of ligand substitution reactions to provide complexes with defined mechanisms of action. Outer-sphere interactions can also play a major role in target recognition. Our current interest is focussed especially on relatively inert metal complexes which were very familiar to Werner (RuII, OsII, RhIII, IrIII, PtII, PtIV).We thank the Leverhulme Trust (Early Career Fellowship No. ECF-2013-414 to NPEB), the University of Warwick (Grant No. RDF 2013-14 to NPEB) the ERC (Grant No. 247450 to PJS), EPSRC (Grant No. EP/F034210/1) and EC COST Action CM1105 for support

Halide Control of N,N-Coordination versus N,C-Cyclometalation and Stereospecific Phenyl Ring Deuteration of Osmium(II) p-Cymene Phenylazobenzothiazole Complexes

YesWe report the synthesis of halido Os(II) p-cymene complexes bearing bidentate chelating phenylazobenzothiazole (AZBTZ) ligands. Unlike the analogous phenylazopyridine (AZPY) complexes, AZBTZ-NMe2 is capable of both N,N-coordination to Os(II) and cyclometalation to form N,C-coordinated species. N,C-Coordination occurs via an azo nitrogen and an ortho carbon on the aniline ring, as identified by 1H NMR and X-ray crystallography of [Os(p-cym)(N,N-AZBTZ-NMe2)Cl]PF6 (1a), [Os(p-cym)(N,N-AZBTZ-NMe2)Br]PF6 (2a), [Os(p-cym)(N,C-AZBTZ-NMe2)Br] (2b), and [Os(p-cym)(N,C-AZBTZ-NMe2)I] (3b). The N,C-coordinated species is more stable and is not readily converted to the N,N-coordinated complex. Analysis of the crystal structures suggests that their formation is influenced by steric interactions between the p-cym and AZBTZ-NMe2 ligands: in particular, larger monodentate halide ligands favor N,C-coordination. The complexes [Os(p-cym)(N,N-Me2-AZBTZ-NH2)Cl]PF6 (4) and [Os(p-cym)(N,N-Me2-AZBTZ-NH2)I]PF6 (5) were synthesized with methyl groups blocking the ortho positions on the aniline ring, forcing an N,N-coordination geometry. 1H NMR NOE experiments confirmed hindered rotation of the arene ligand and steric crowding around the metal center. Complex 2b exhibited unexpected behavior under acidic conditions, involving regiospecific deuteration of the aniline ring at the meta position, as observed by 1H NMR and high-resolution ESI-MS. Deuterium exchange occurs only under acidic conditions, suggesting an associative mechanism. The calculated partial charges on 2b show that the meta carbon is significantly more negatively charged, which may account for the regiospecificity of deuterium exchange.ERC, EPSRC, The Royal Societ

Excited-State Dynamics of a Two-Photon-Activatable Ruthenium Prodrug

We present a new approach to investigate how the photodynamics of an octahedral ruthenium(II) complex activated through two-photon absorption (TPA) differ from the equivalent complex activated through one-photon absorption (OPA). We photoactivated a RuII polypyridyl complex containing bioactive monodentate ligands in the photodynamic therapy window (620–1000 nm) by using TPA and used transient UV/Vis absorption spectroscopy to elucidate its reaction pathways. Density functional calculations allowed us to identify the nature of the initially populated states and kinetic analysis recovers a photoactivation lifetime of approximately 100 ps. The dynamics displayed following TPA or OPA are identical, showing that TPA prodrug design may use knowledge gathered from the more numerous and easily conducted OPA studies

Potent organometallic osmium compounds induce mitochondria-mediated apoptosis and S-phase cell cycle arrest in A549 non-small cell lung cancer cells

YesThe problems of acquired resistance associated with platinum drugs may be addressed by chemotherapeutics based on other transition metals as they offer the possibility of novel mechanisms of action. In this study, the cellular uptake and induction of apoptosis in A549 human non-small cell lung cancer cells of three promising osmium(II) arene complexes containing azopyridine ligands,[Os(Z6-arene)( p-R-phenylazopyridine)X]PF6, where arene is p-cymene or biphenyl, R is OH or NMe2, and X is Cl or I, were investigated. These complexes showed time-dependent (4–48 h) potent anticancer activity with highest potency after 24 h (IC50 values ranging from 0.1 to 3.6 mM). Cellular uptake of the three compounds as quantified by ICP-MS, was independent of their log P values (hydrophobicity). Furthermore, maximum cell uptake was observed after 24 h, with evident cell efflux of the osmium after 48 and 72 h of exposure, which correlated with the corresponding IC50 values. The most active compound 2, [Os(Z6-p-cymene)(NMe2-phenylazopyridine)I]PF6, was taken up by lung cancer cells pre-dominately in a temperature-dependent manner indicating that energy-dependent mechanisms are important in the uptake of 2. Cell fractionation studies showed that all three compounds accumulated mainly in cellular membranes. Furthermore, compound 2 induced apoptosis and caused accumulation in the S-phase of the cell cycle. In addition, 2 induced cytochrome c release and alterations in mito-chondrial membrane potential even after short exposure times, indicating that mitochondrial apoptotic pathways are involved. This study represents the first steps towards understanding the mode of action of this promising class of new osmium-based chemotherapeutics

Fabrication of crystals from single metal atoms

YesMetal nanocrystals offer new concepts for the design of nanodevices with a range of potential applications. Currently the formation of metal nanocrystals cannot be controlled at the level of individual atoms. Here we describe a new general method for the fabrication of multi-heteroatom-doped graphitic matrices decorated with very small, ångström-sized, three-dimensional (3D)-metal crystals of defined size. We irradiate boron-rich precious-metal-encapsulated self-spreading polymer micelles with electrons and produce, in real time, a doped graphitic support on which individual osmium atoms hop and migrate to form 3D-nanocrystals, as small as 15 Å in diameter, within 1 h. Crystal growth can be observed, quantified and controlled in real time. We also synthesize the first examples of mixed ruthenium–osmium 3D-nanocrystals. This technology not only allows the production of ångström-sized homo- and hetero-crystals, but also provides new experimental insight into the dynamics of nanocrystals and pathways for their assembly from single atoms.We thank the Leverhulme Trust (Early Career Fellowship No. ECF-2013-414 to NPEB), the University of Warwick (Grant No. RDF 2013-14 to NPEB), the Swiss National Science Foundation (Grant No. PA00P2_145308 to NPEB and PBNEP2_142949 to APB), the ERC (Grant No. 247450 to PJS), EPSRC (EP/G004897/1 to RKOR, and EP/F034210/1 to PJS) and Science City (AWM/ERDF) for support. We thank the Wellcome Trust (Grant No. 055663/Z/98/Z) for funding the Electron Microscopy Facility, School of Life Sciences, University of Warwick. We also thank COST Action CM1105 for stimulating discussions, Thomas Wilks for supplying the micelle image for Figure 1, and the Australian Synchrotron and the University of Monash for allocation of time on the SAXS/ WAXS beamline and funding. The 2000FX Gatan Orius digital TEM camera used in this research was funded by Science City: Creating and Characterizing Next Generation Advanced Materials, with support from Advantage West Midlands and part funded by the European Regional Development Fund

Controlled fabrication of osmium nanocrystals by electron, laser and microwave irradiation and characterisation by microfocus X-ray absorption spectroscopy

YesOsmium nanocrystals can be fabricated by electron (3–50 nm, formed by atom migration), 785–815 nm laser (20–50 nm, in micelle islands), and microwave (ca. 1 nm in arrays, >100 mg scale) irradiation of a polymer-encapsulated OsII carborane; microfocus X-ray absorption studies at the Os LIII-edge show differences between the three preparation methods, suggesting that the electron-beam irradiated materials have a significant support interaction and/or surface oxidation, while the laser and microwave samples are more like metallic osmium.Royal Society (University Research Fellowship No. UF150295 to NPEB), the Leverhulme Trust (Early Career Fellowship No. ECF-2013-414 to NPEB), the ERC (Grant No. 247450 to PJS), EPSRC (Grant No. EP/F034210/1 to PJS and EP/ J007153/1 to VGS), Diamond Light Source (Beam-time grant number SP11314)

Precision Pion-Proton Elastic Differential Cross Sections at Energies Spanning the Delta Resonance

A precision measurement of absolute pi+p and pi-p elastic differential cross sections at incident pion laboratory kinetic energies from T_pi= 141.15 to 267.3 MeV is described. Data were obtained detecting the scattered pion and recoil proton in coincidence at 12 laboratory pion angles from 55 to 155 degrees for pi+p, and six angles from 60 to 155 degrees for pi-p. Single arm measurements were also obtained for pi+p energies up to 218.1 MeV, with the scattered pi+ detected at six angles from 20 to 70 degrees. A flat-walled, super-cooled liquid hydrogen target as well as solid CH2 targets were used. The data are characterized by small uncertainties, ~1-2% statistical and ~1-1.5% normalization. The reliability of the cross section results was ensured by carrying out the measurements under a variety of experimental conditions to identify and quantify the sources of instrumental uncertainty. Our lowest and highest energy data are consistent with overlapping results from TRIUMF and LAMPF. In general, the Virginia Polytechnic Institute SM95 partial wave analysis solution describes our data well, but the older Karlsruhe-Helsinki PWA solution KH80 does not.Comment: 39 pages, 22 figures (some with quality reduced to satisfy ArXiv requirements. Contact M.M. Pavan for originals). Submitted to Physical Review

The roles of the formal and informal sectors in the provision of effective science education

For many years, formal school science education has been criticised by students, teachers, parents and employers throughout the world. This article presents an argument that a greater collaboration between the formal and the informal sector could address some of these criticisms. The causes for concern about formal science education are summarised and the major approaches being taken to address them are outlined. The contributions that the informal sector currently makes to science education are identified. It is suggested that the provision of an effective science education entails an enhanced complementarity between the two sectors. Finally, there is a brief discussion of the collaboration and communication still needed if this is to be effective

Organizational and Leadership Implications for Transformational Development

Transformational development is a concept of change that originated in the Christian context but has now become generally used in the work of both secular and faith-based organizations. The growing use of the concept by organizations that are fundamentally different has naturally led to some confusion about what the concept means and what it takes to effectively implement it. In this article, we describe the key features of the concept and how they are important in determining the organizational requirements for its effective implementation. Drawing on a few cases, the paper highlights the centrality of faith in transformational development work