Sphaeropsidin A C15-C16 Cross-Metathesis Analogues with Potent Anticancer Activity.

We recently discovered that sphaeropsidin A (SphA), a fungal metabolite from Diplodia cupressi, overcomes apoptosis resistance in cancer cells by inducing cellular shrinkage by impairing regulatory volume increase. Previously, we prepared a pyrene-conjugated derivative of SphA by a cross-metathesis reaction involving the phytotoxin's C15,C16-alkene. This derivative's evaluation in a cancer cell panel revealed a significant increase in potency, with the IC50 values 5-10× lower than those displayed by the original natural product. Herein, we describe the preparation and anticancer evaluation of fifteen novel C15,C16-alkene cross-metathesis analogues in which the pyrene moiety was replaced with other aromatic or non-aromatic hydrophobic groups. The idea for this replacement was to prepare a family of compounds that would not be predicted to be mutagenic compared with the original pyrene analogue. We predict several of our new compounds to be non-mutagenic, while retaining the high potency of the original pyrene-containing analogues. Examples of these potential lead compounds included those containing pentamethylphenyl and triphenylethylene pendant groups. As an additional feature of the current investigation, we prepared several deuterated pyrene-containing compounds to overcome intellectual property issues associated with non-patentability of the original pyrene derivative.

Synthetic Models for Nickel-Iron Hydrogenase Featuring Redox-Active Ligands.

The nickel-iron hydrogenase enzymes efficiently and reversibly interconvert protons, electrons, and dihydrogen. These redox proteins feature iron-sulfur clusters that relay electrons to and from their active sites. Reported here are synthetic models for nickel-iron hydrogenase featuring redox-active auxiliaries that mimic the iron-sulfur cofactors. The complexes prepared are NiII(µ-H)FeIIFeII species of formula [(diphosphine)Ni(dithiolate)(µ-H)Fe(CO)2(ferrocenylphosphine)]+ or NiIIFeIFeII complexes [(diphosphine)Ni(dithiolate)Fe(CO)2(ferrocenylphosphine)]+ (diphosphine = Ph2P(CH2)2PPh2 or Cy2P(CH2)2PCy2; dithiolate = -S(CH2)3S-; ferrocenylphosphine = diphenylphosphinoferrocene, diphenylphosphinomethyl(nonamethylferrocene) or 1,1'-bis(diphenylphosphino)ferrocene). The hydride species is a catalyst for hydrogen evolution, while the latter hydride-free complexes can exist in four redox states - a feature made possible by the incorporation of the ferrocenyl groups. Mixed-valent complexes of 1,1'-bis(diphenylphosphino)ferrocene have one of the phosphine groups unbound, with these species representing advanced structural models with both a redox-active moiety (the ferrocene group) and a potential proton relay (the free phosphine) proximal to a nickel-iron dithiolate.

Experience of total knee arthroplasty using a novel navigation system within the surgical field.

BACKGROUND: With the aim of improving component alignment and outcome in total knee arthroplasty (TKA), several computer-assisted devices (CAD) have been developed. METHODS: In February 2014, the present unit started to use a new imageless navigation system with accelerometric pods within the surgical field for all primary TKAs; there was no need for optical trackers or cameras. This paper presents the results of the first 72 TKAs using this iAssist system in 71 prospectively collected and retrospectively analyzed patients. It analyzed component positioning in standard and full-length leg x-rays. RESULTS: The mean age of the patients was 70years (range 52-88). The center of hip, knee and ankle (mechanical axes) deviated on average 0.5° (standard deviation (SD) of 1.8) valgus from the targeted straight alignment. Three TKAs had >3° deviation (i.e. four degree varus, five degree and seven degree valgus). The frontal tibial tray alignment was an average of 89.9° (range 86.4-100.1°, SD ±2.0) with the target being 90°, and the sagittal slope was as targeted at 85.0° (range 78.4-88.8°, SD ±1.7). CONCLUSIONS: This CAD facilitated good mechanical alignment and reproducible accuracy in component positioning. Pods clipped onto cutting jigs within the surgical field provided simple and accurate navigation, with little extra time needed for calibration and no need for optical trackers or pre-operative imaging.

Nickel-Iron Hydrogenases: High-Resolution Crystallography Resolves the Hydride, but Not the Debate.

An (X-ray) eye for detail: Modern high-resolution protein crystallography allows H atoms to be located. Applied to nickel-iron hydrogenase, X-ray structural analysis has finally confirmed the presence of an active-site hydride and thiol, as well as unveiling the intricate pathways that protons take to and from the active site.

Synthesis and vibrational spectroscopy of (57)Fe-labeled models of [NiFe] hydrogenase: first direct observation of a nickel-iron interaction.

A new route to iron carbonyls has enabled synthesis of (57)Fe-labeled [NiFe] hydrogenase mimic (OC)3(57)Fe(pdt)Ni(dppe). Its study by nuclear resonance vibrational spectroscopy revealed Ni-(57)Fe vibrations, as confirmed by calculations. The modes are absent for [(OC)3(57)Fe(pdt)Ni(dppe)](+), which lacks Ni-(57)Fe bonding, underscoring the utility of the analyses in identifying metal-metal interactions.

Protonation of nickel-iron hydrogenase models proceeds after isomerization at nickel.

Theory and experiment indicate that the protonation of reduced NiFe dithiolates proceeds via a previously undetected isomer with enhanced basicity. In particular, it is proposed that protonation of (OC)3Fe(pdt)Ni(dppe) (1; pdt(2-) = (-)S(CH2)3S(-); dppe = Ph2P(CH2)2PPh2) occurs at the Fe site of the two-electron mixed-valence Fe(0)Ni(II) species, not the Fe(I)-Ni(I) bond for the homovalence isomer of 1. The new pathway, which may have implications for protonation of other complexes and clusters, was uncovered through studies on the homologous series L(OC)2Fe(pdt)M(dppe), where M = Ni, Pd (2), and Pt (3) and L = CO, PCy3. Similar to 1, complexes 2 and 3 undergo both protonation and 1e(-) oxidation to afford well-characterized hydrides ([2H](+) and [3H](+)) and mixed-valence derivatives ([2](+) and [3](+)), respectively. Whereas the Pd site is tetrahedral in 2, the Pt site is square-planar in 3, indicating that this complex is best described as Fe(0)Pt(II). In view of the results on 2 and 3, the potential energy surface of 1 was reinvestigated with density functional theory. These calculations revealed the existence of an energetically accessible and more basic Fe(0)Ni(II) isomer with a square-planar Ni site.

Nickel-iron dithiolates related to the deactivated [NiFe]-hydrogenases.

Described herein are preparations of synthetic models for the deactivated Ni(II)Fe(II) states of the [NiFe]-hydrogenases. Iodination of the S = ½ species [(dppe)Ni(pdt)Fe(CO)(3)](+) afforded the diamagnetic iodo complex [(dppe)Ni(pdt)IFe(CO)(3)](+). Crystallographic analysis of this species confirmed the presence of square-pyramidal Ni linked to an octahedral Fe centre. The NiFe separation of 3.018 Å indicated the absence of metal-metal bonding. This complex could be reduced to give (dppe)Ni(pdt)Fe(CO)(3) and, in the presence of iodide, decarbonylated to afford (dppe)Ni(pdt)FeI(2). Derivatives of the type [(diphosphine)Ni(dithiolate)XFe(CO)(2)L](+) (X = Cl, Br, I) were prepared by halogenation of mixed-valence precursors [(diphosphine)Ni(dithiolate)Fe(CO)(2)L](+) (diphosphine = dppe, dcpe; L = tertiary phosphine or CO). The Fe(CO)(2)(PR(3))-containing derivatives are more robust than the related tricarbonyl derivatives. Exploiting this greater stability, we characterised examples of chloride and bromide derivatives. Related fluorides could be prepared by F(-) abstraction from BF(4)(-). Spectroscopic evidence is presented for the hydroperoxide [(dppe)Ni(pdt)(OOH)Fe(CO)(2)L](+), which represents a model for the Ni-SU state.

Connecting [NiFe]- and [FeFe]-hydrogenases: mixed-valence nickel-iron dithiolates with rotated structures.

New mixed-valence iron-nickel dithiolates are described that exhibit structures similar to those of mixed-valence diiron dithiolates. The interaction of tricarbonyl salt [(dppe)Ni(pdt)Fe(CO)(3)]BF(4) ([1]BF(4), where dppe = Ph(2)PCH(2)CH(2)PPh(2) and pdt(2-) = -SCH(2)CH(2)CH(2)S-) with P-donor ligands (L) afforded the substituted derivatives [(dppe)Ni(pdt)Fe(CO)(2)L]BF(4) incorporating L = PHCy(2) ([1a]BF(4)), PPh(NEt(2))(2) ([1b]BF(4)), P(NMe(2))(3) ([1c]BF(4)), P(i-Pr)(3) ([1d]BF(4)), and PCy(3) ([1e]BF(4)). The related precursor [(dcpe)Ni(pdt)Fe(CO)(3)]BF(4) ([2]BF(4), where dcpe = Cy(2)PCH(2)CH(2)PCy(2)) gave the more electron-rich family of compounds [(dcpe)Ni(pdt)Fe(CO)(2)L]BF(4) for L = PPh(2)(2-pyridyl) ([2a]BF(4)), PPh(3) ([2b]BF(4)), and PCy(3) ([2c]BF(4)). For bulky and strongly basic monophosphorus ligands, the salts feature distorted coordination geometries at iron: crystallographic analyses of [1e]BF(4) and [2c]BF(4) showed that they adopt "rotated" Fe(I) centers, in which PCy(3) occupies a basal site and one CO ligand partially bridges the Ni and Fe centers. Like the undistorted mixed-valence derivatives, members of the new class of complexes are described as Ni(II)Fe(I) (S = ½) systems according to electron paramagnetic resonance spectroscopy, although with attenuated (31)P hyperfine interactions. Density functional theory calculations using the BP86, B3LYP, and PBE0 exchange-correlation functionals agree with the structural and spectroscopic data, suggesting that the spin for [1e](+) is mostly localized in a Fe(I)-centered d(z(2)) orbital, orthogonal to the Fe-P bond. The PCy(3) complexes, rare examples of species featuring "rotated" Fe centers, both structurally and spectroscopically incorporate features from homobimetallic mixed-valence diiron dithiolates. Also, when the NiS(2)Fe core of the [NiFe]-hydrogenase active site is reproduced, the "hybrid models" incorporate key features of the two major classes of hydrogenase. Furthermore, cyclic voltammetry experiments suggest that the highly basic phosphine ligands enable a second oxidation corresponding to the couple [(dxpe)Ni(pdt)Fe(CO)(2)L](+/2+). The resulting unsaturated 32e(-) dications represent the closest approach to modeling the highly electrophilic Ni-SI(a) state. In the case of L = PPh(2) (2-pyridyl), chelation of this ligand accompanies the second oxidation.

Mixed-valence nickel-iron dithiolate models of the [NiFe]-hydrogenase active site.

A series of mixed-valence nickel-iron dithiolates is described. Oxidation of (diphosphine)Ni(dithiolate)Fe(CO)(3) complexes 1, 2, and 3 with ferrocenium salts affords the corresponding tricarbonyl cations [(dppe)Ni(pdt)Fe(CO)(3)](+) ([1](+)), [(dppe)Ni(edt)Fe(CO)(3)](+) ([2](+)) and [(dcpe)Ni(pdt)Fe(CO)(3)](+) ([3](+)), respectively, where dppe = Ph(2)PCH(2)CH(2)PPh(2), dcpe = Cy(2)PCH(2)CH(2)PCy(2), (Cy = cyclohexyl), pdtH(2) = HSCH(2)CH(2)CH(2)SH, and edtH(2) = HSCH(2)CH(2)SH. The cation [2](+) proved unstable, but the propanedithiolates are robust. IR and EPR spectroscopic measurements indicate that these species exist as C(s)-symmetric species. Crystallographic characterization of [3]BF(4) shows that Ni is square planar. Interaction of [1]BF(4) with P-donor ligands (L) afforded a series of substituted derivatives of type [(dppe)Ni(pdt)Fe(CO)(2)L]BF(4) for L = P(OPh)(3) ([4a]BF(4)), P(p-C(6)H(4)Cl)(3) ([4b]BF(4)), PPh(2)(2-py) ([4c]BF(4)), PPh(2)(OEt) ([4d]BF(4)), PPh(3) ([4e]BF(4)), PPh(2)(o-C(6)H(4)OMe) ([4f]BF(4)), PPh(2)(o-C(6)H(4)OCH(2)OMe) ([4g]BF(4)), P(p-tol)(3) ([4h]BF(4)), P(p-C(6)H(4)OMe)(3) ([4i]BF(4)), and PMePh(2) ([4j]BF(4)). EPR analysis indicates that ethanedithiolate [2](+) exists as a single species at 110 K, whereas the propanedithiolate cations exist as a mixture of two conformers, which are proposed to be related through a flip of the chelate ring. Mössbauer spectra of 1 and oxidized S = 1/2 [4e]BF(4) are both consistent with a low-spin Fe(I) state. The hyperfine coupling tensor of [4e]BF(4) has a small isotropic component and significant anisotropy. DFT calculations using the BP86, B3LYP, and PBE0 exchange-correlation functionals agree with the structural and spectroscopic data, suggesting that the SOMOs in complexes of the present type are localized in an Fe(I)-centered d(z(2)) orbital. The DFT calculations allow an assignment of oxidation states of the metals and rationalization of the conformers detected by EPR spectroscopy. Treatment of [1](+) with CN(-) and compact basic phosphines results in complex reactions. With dppe, [1](+) undergoes quasi-disproportionation to give 1 and the diamagnetic complex [(dppe)Ni(pdt)Fe(CO)(2)(dppe)](2+) ([5](2+)), which features square-planar Ni linked to an octahedral Fe center.

Dinuclear bis-beta-diketonato ligand derivatives of iron(III) and copper(II) and use of the latter as components for the assembly of extended metallo-supramolecular structures.

A range of 1,3-aryl linked, bis-beta-diketone derivatives (LH2) has been employed to synthesise neutral bis(ligand), dinuclear complexes incorporating square-planar copper(II) and tris(ligand) dinuclear helical derivatives containing octahedral iron(III). The 1H NMR spectra of the free ligands contain singlet peaks at ca. 16.2 ppm, indicative of enolic protons, confirming that the (bis) enol tautomer is present in solution. An X-ray structure of a ligand from the series incorporating tert-butyl terminal substituents confirms that the same tautomer persists in the solid and that the relative orientation of the bis-beta-diketone fragments is such that the coordination vectors lie at approximately 120 degrees to each other. The planar, dinuclear copper complexes form 1 : 2 adducts with pyridine and 4-(dimethylamino)pyridine, confirmed by X-ray structures, that incorporate five-coordinate metal centres. Based on this behaviour, the prospect of linking copper centres in the dinuclear complexes using the difunctional heterocyclic bases, 4,4'-bipyridine, 4,4'-trans-azopyridine and pyrazine as co-ligands has been probed. However, 4,4'-bipyridine was observed to coordinate through only one of its heterocyclic nitrogen atoms in the solid state to form a 1 : 2 ([Cu2(L)2]: 4,4'-bipyridine) adduct, analogous to the structures obtained with the above mono-functional nitrogen bases. Nevertheless, an X-ray structure determination shows that the related difunctional base, 4,4'-trans-azopyridine, coordinates in a bridging fashion via both its heterocyclic nitrogen atoms on alternate sides of each planar [Cu2(L)2] unit to produce an infinite one dimensional metallo chain. In contrast, with pyrazine, a new neutral, discrete assembly of type [Cu4(L)4(pyrazine)2] is formed. The X-ray structure shows that two planar dinuclear complexes are linked by two pyrazine molecules in a sandwich arrangement such that the coordination environment of each copper ion is approximately square pyramidal with the overall tetranuclear structure thus taking the form of a 'dimer of dimers'.