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W-Cr-Zr systems with different compositions were oxidized in a mixed gas (Ar + 20 vol.% O2) atmosphere at 1000 °C. The power law which was used to describe the oxidation behaviour, indicates that W-11.2wt.%Cr-1.7wt.%Zr has an excellent oxidation behaviour. As analysed from the ten-hour exposure, W-Cr-Zr thin film oxidation shows a self-passivating stage followed by a linear oxidation stage. Furthermore, a study on the addition of zirconium indicates that zirconia particles act as diffusion barriers for the chromium cation diffusion and another function as the nucleation sites for the formation of the initial oxide scale.

Emission spectra of neural tungsten (W) sputtered by impact of argon (Ar) ions in a weakly magnetized ( The obtained energy distribution was found in a very good agreement with the Thompson distribution, even though deviations for lower impact energies are observed, e.g. the high-energy tail of sputtered particles demonstrates a faster drop compared to 1/E 2 at energies below 100 eV. Moreover, the standard cosine (Knudsen cosine law) distribution provides a rather good description of emission spectra in the energy range of study. Finally, the energy distribution was also compared with simulations carried out with the binary collision approximation (BCA) based Monte-Carlo code SDTrimSP. It shows a marginally worse description at low energies and better description of the high energy tail compared to the Thompson one. Furthermore, the model was used to determine in-situ the degree of light reflection at the W surface. The results are in excellent agreement with the literature data.

Tungsten (W) is a prime candidate as first wall armor material of future fusion power plants as W withstands extreme particle, heat, and radiation loads without forming long-lived radioactive waste. The release of radioactive material from the reactor to the environment should be suppressed in case of an accident such as a loss of coolant (LOCA) with simultaneous air ingress into the vacuum vessel. W oxidizes and sublimates in case of a LOCA. Therefore, oxidation resistant tungsten, chromium, yttrium (W–Cr–Y) alloys are developed to provide intrinsic safety in case of such an accident. In this paper, the optimization of the yttrium (Y) concentration is presented on bulk samples compacted by field assisted sintering technology (FAST). W with 11.4 weight (wt)% Cr and 0.6 wt% Y appears to be an optimum regarding the oxidation resistance. Further, first preparations for industrial upscaling, which may increase the impurity level, are addressed. The oxygen (O) content is varied systematically. It is shown that a good oxidation resistance requires a low O level. The exposure of the material to fusion neutrons is another issue addressed on W–Cr–Y alloys. In a non-activated environment it is shown that 1 wt% rhenium (Re) dramatically changes the oxidation kinetics: at 1273 K the mass gain of W–Cr–Y–Re follows a cubic rate law while W–Cr–Y follows a linear rate law for two days. Further, the influence of the alloying elements on the neutron transport and transmutation of W is studied by simulating the exposure of spatially heterogeneous high-resolution models of the W–Cr–Y alloys to 14 MeV fusion neutrons.

The dynamic behaviour of thermally driven segregation of Cr to the surface of WCrY smart alloy is studied with low energy ion scattering (LEIS). Sputtering the WCrY sample with 500 eV D$_2^+$ ions at room temperature results in preferential removal of the lighter alloy constituents and causes an almost pure W surface layer. At elevated temperatures above 700 K the segregation of Cr atoms towards the surface sets in and prevents the formation of a pure W layer. The simultaneous heating and sputtering of the sample leads to a surface state which reflects the balance between sputter removal and segregation flux, and deviates from the equilibrium due to thermally driven segregation. Stopping the sputter ion beam allows the system to relax and develop toward the segregation equilibrium. The time constants for the temporal changes of W and Cr surface coverage are obtained from a series of LEIS measurements. The segregation enthalpy is determined from the time constants obtained for various sample temperatures., 20 pages, 4 figures, Proceedings of the 23rd International Workshop on Inelastic Ion-Surface Collisions (IISC-23), submitted to Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms

The potential of papain-like cysteine proteases, such as cathepsin B, as drug discovery targets for systemic human diseases has prevailed over the past years. The development of potent and selective low-molecular cathepsin B inhibitors relies on the detailed expertise on preferred amino acid and inhibitor residues interacting with the corresponding specificity pockets of cathepsin B. Such knowledge might be obtained by mapping the active site of the protease with combinatorial libraries of peptidic substrates and peptidomimetic inhibitors. This review, for the first time, summarizes a wide spectrum of active site mapping approaches. It considers relevant X-ray crystallographic data and discloses propensities towards favorable protein-ligand interactions in case of the therapeutically relevant protease cathepsin B.

A series of inhibitors targeting human cathepsins have been designed and synthesized following a combinatorial approach. The compounds bear an α,β-unsaturated phenyl vinyl sulfone or ethyl acrylate warhead and a peptidomimetic portion aligned to the non-primed binding region. Biochemical evaluation toward four human cathepsins was carried out and the kinetic characterization confirmed an irreversible mode of inhibition. Compound 6c combining the most advantageous building blocks for cathepsin S inhibition was identified as a potent cathepsin S inactivator exhibiting a second-order rate constant of 30600 M-1 s-1.

In this paper the impact of steady state pure D plasma on WCrY smart alloys at ion energies of 120 and 220 eV is reported. For this purpose a comparison with simultaneously exposed pure W samples is drawn. Different analysis techniques employed for pre- and post-plasma sample analysis hint at a significant depletion of Cr and enrichment of W for lower ion energies. Preferential sputtering leads to enhanced volumetric loss at 220 eV. Analysis of redeposited material indicated local redeposition of Cr. Modelling the ion irradiation with SDTrimSP is used to further interpret experimental results. Depending on the sample temperature during plasma exposure and the magnitude of the ion flux, diffusion of Cr towards the surface is a determining factor for erosion of smart alloys for higher ion energies. Keywords: Smart alloys, Plasma-wall-interaction, Plasma ion irradiation, DEMO, W-based alloys

Tungsten (W) currently is the main candidate as plasma-facing armour material for the first wall of future fusion reactors, like DEMO. Advantages of W include a high melting point, high thermal conductivity, low tritium retention, and low erosion yield. However, in case of an accident, air ingress into the vacuum vessel can occur and the temperature of the first wall can reach 1200 K to 1450 K due to nuclear decay heat. In the absence of cooling, the temperature will remain in that range for several weeks. At these temperatures the radioactive tungsten oxide volatilizes. Therefore, ‘smart’ W alloys are developed that aim to preserve the properties of W during plasma operation coupled with suppressed tungsten oxide formation in case of an accident.This study focusses on oxidation studies at 1273 K of samples produced by mechanical alloying followed by field assisted sintering. In a first step the sintering is optimized for tungsten (W) – chromium (Cr) -yttrium (Y) alloys. It is shown that the best oxidation resistance is achieved with submicron grain sizes. This yields a closed, protective oxide layer. In a second step the influence of the grinding process during sample preparation is analysed. It is shown that scratches initiate failure of the protective oxide. In a third step the oxidation and sublimation is measured for weeks – for the first time the sublimation is directly measured in order to determine the potential hazard in comparison to pure W. It is shown that the oxidation is suppressed in comparison to pure W. However, sublimation at a rate of 1×10−6mgcm−2s−1 starts after a few days. Nevertheless, the progess in smart alloys is evident: sublimation is delayed by about two days and complete mechanical destruction of the first wall is avoided. Keywords: W-based alloys, W–Cr–Y alloys, Oxidation resistance, DEMO

Besides their extracellular activity crucial for several pathophysiological conditions, human cysteine cathepsins, in particular cathepsins K and S, represent important intracellular targets for drug development. In the present study, a prototypic dipeptide nitrile inhibitor structure was equipped with a coumarin moiety to function as a fluorescent reporter group. In a second inhibitor, a PEG linker was introduced between the dipeptide nitrile and the fluorophore. These tool compounds 6 and 7 were characterized by kinetic investigations as covalent reversible inhibitors of human cathepsins L, S, K and B. Probe 6 showed a pronounced inhibitory activity against cathepsins K and S, which was corroborated by modeling of inhibition modes. Probe 7 was highly potent (Ki = 93 nM) and selective for cathepsin S. To examine the ability of both probes to enter living cells, human embryonic kidney 293 cells were targeted. At a concentration of 10 μM, cellular uptake of probe 6 was demonstrated by fluorescence measurement after an incubation time of 30 min and 3 h, respectively. The probe's concentration in cell lysates was ascertained on the basis of the emission at 492 nm upon excitation at 450 nm, and the results were expressed as concentrations of probe 6 relative to the protein concentration originating from the lysate. After incubation of 10 μM of probe 6 for 3 h, the cellular uptake was confirmed by fluorescence microscopy. HPLC was used to assess the probes’ lipophilicity, and the obtained

Nitrile-type inhibitors are known to interact with cysteine proteases in a covalent-reversible manner. The chemotype of 3-cyano-3-aza-β-amino acid derivatives was designed in which the N-cyano group is centrally arranged in the molecule to allow for interactions with the nonprimed and primed binding regions of the target enzymes. These compounds were evaluated as inhibitors of the human cysteine cathepsins K, S, B, and L. They exhibited slow-binding behavior and were found to be exceptionally potent, in particular toward cathepsin K, with second-order rate constants up to 52 900 × 10(3) M(-1) s(-1).

A series of dipeptide nitriles with different P3 substituents was designed to explore the S3 binding pocket of cathepsin S. Racemic 7-16 and the enantiopure derivative (R)-22 proved to be potent inhibitors of human cathepsin S and exhibited notable selectivity over human cathepsins L, K, and B. Inhibition of cathepsin F, the functional synergist of cathepsin S, was not observed. The azadipeptide analogue of 22, compound 26, was highly potent but nonselective.

Diethyl 2-alkyl-2-(benzyloxycarbonylamino)malonates were saponified, activated with oxalyl chloride, and treated with primary aromatic amines. This gave 3,5-disubstituted hydantoin-5-carboxamides. As second products, 2-alkyl-2-formamido-N 1,N 3-bis(aryl)malonamides were isolated. The formation of both types of products is expected to include a cyclization to 2-alkoxyoxazol-5(4H)-ones, acting as precursor for the hydantoins, or a further transformation to N-carboxy anhydrides, their chloride-promoted ring opening, and subsequent conversion to give the bis(aryl)malon­amides.

Cysteine cathepsins are lysosomal cysteine proteases which play roles in many physiological processes. Cathepsin F is predominantly expressed in macrophages. Major histocompatibility complex class II molecules (MHC-II) are expressed by antigen-presenting cell types including macrophages, B cells, and dendritic cells. The cleavage of the invariant chain is the key event in the pathway of MHC-II complexes. Cathepsin S was described as the major processing enzyme of the invariant chain, but it was shown that cathepsin F can adopt its role in cathepsin S deficient mice.[1] Low molecular weight inhibitors for cathepsin F have not been investigated so far. We have chosen the dipeptide nitrile[2] chemotype to develop covalent-reversible inhibitors for this target. An active site mapping with a library of 52 nitrile-based cathepsin inhibitors was performed at human cathepsin F to draw structure-activity relationships. With the kinetic data in hand, new compounds with optimized residues in P1, P2 and P3 position were synthesized and evaluated. With all dipeptide nitriles including the newly synthesized derivatives, a 3D activity landscape was generated to visualize similarity-activity relationships of this series of cathepsin F inhibitors. References [1] Shi GP, Bryant RA, Riese R, Verhelst S, Driessen C, Li Z, Bromme D, Ploegh HL, Chapman HA. J. Exp. Med. 2000, 191, 1177-1186. [2] Frizler M, Stirnberg M, Sisay MT, Gutschow M. Curr. Top. Med. Chem. 2010, 10, 294-322.

A coumarin-tetrahydroquinoline hydride 8 was synthesized as a chemical tool for fluorescent labeling. The rigidified tricyclic coumarin structure was chosen for its suitable fluorescence properties. The connection of 8 with a vinyl sulfone building block was accomplished by convergent synthesis thereby leading to the coumarin-based, tripeptidomimetic activity-based probe 10, containing a Gly-Phe-Gly motif. Probe 10 was evaluated as inactivator of the therapeutically relevant human cysteine cathepsins S, L, K, and B: it showed particularly strong inactivation of cathepsin S. The detection of recombinant and native cathepsin S was demonstrated by applying 10 to in-gel fluorescence imaging.

Freidinger lactams, possessing a peptide bond configuration locked to Z, are important key elements of conformationally restricted peptidomimetics. In the present work, the C(α)H(i+1) unit has been replaced by N, leading to novel aza-Freidinger lactams. A synthesis to corresponding building blocks and their E-locked analogs is introduced. The versatile buildings blocks reported here are expected to serve as useful elements in peptide synthesis.

Trisubstituted hydantoins (VI) are obtained in low yields from malonic acid derivative (IV) via activation with oxalyl dichloride and subsequent treatment with aromatic amines.

Tungsten (W) is deemed as the main candidate for the first wall armor material of future fusion power plants such as DEMO. Advantages of W include a high melting point, low erosion yield, low tritium retention, and a high thermal conductivity. One issue concerning W is the oxidation resistance in case of a loss-of-coolant accident with simultaneous air ingress. The major challenge in such a scenario is to suppress the sublimation which is responsible for a release of radioactivity. This work studies an alloy containing tungsten (W), 12 weight % chromium (Cr), and 0.6 weight % yttrium (Y) in DEMO-relevant conditions: a temperature in the range of 1100 K to 1473 K in humid air. The sublimation rates are measured for the first time in humid air. Tungsten oxide sublimates at a rate of 1.4 × 10−4 mg cm−2 s−1 at 1273 K in humid air. At the same conditions the alloy suppresses sublimation by more than one order of magnitude as compared to that of pure W. This suppression is achieved due to the formation of a protective chromium oxide layer on the surface of the sample. Details about the protection mechanisms are presented and discussed. Testing is performed for up to 10 days.

The first wall armor of a DEMOnstration fusion power plant (DEMO) is planned to be built from tungsten. However, in case of loss-of-coolant accident with air ingress, the temperature of the first wall may exceed 1000 °C due to nuclear decay heat. At such temperatures, tungsten forms volatile radioactive oxides, which may be mobilized into the environment at a rate of 10–600 kg per hour. Advanced “smart” tungsten alloys adjust their properties to the environment: during the plasma operation, preferential sputtering will form almost pure tungsten surface facing the plasma. In case of an accident, the remaining alloying elements form a protective layer, preventing tungsten mobilization. The new smart alloys contain tungsten (W), chromium (Cr) and yttrium (Y). The first bulk smart alloys produced using field-assisted sintering technique, revealed excellent oxidation resistance for a timescale of 10–20 hours. W-Cr-Y systems underwent combined plasma and oxidation test. During plasma exposure, smart alloys demonstrated nearly the same mass loss as the reference pure tungsten samples. Subsequent oxidation confirmed superior oxidation resistance of new alloys compared to the former W-Cr-Ti systems. Experiments attaining oxidation times and plasma fluence required for DEMO, are started. First results show necessity in further improvement of W-Cr-Y alloys.

WCrY Smart Alloys are developed as first wall material of future fusion devices such as DEMO. They aim at behaving like pure W during plasma operation due to depletion of the alloying elements Cr and Y. The Cr concentration gradients induced by preferential plasma sputtering cause Cr-diffusion. The exposure of WCrY and W samples to pure D plasma, with a plasma ion energy of 220 eV , is simulated using the dynamic version of SDTrimSP. Cr-diffusion is included into the model. Simulation results are compared with experimental results. At sample temperatures of more than 600∘C and sputtering by D plus residual oxygen in the plasma ion flux, the Cr-transport to the surface leads to enhanced erosion for WCrY samples. A diffusion coefficient for Cr in WCrY of the order of 1 ⋅ 10 − 17 m 2 / s is determined. The suitability of WCrY as first wall armour and the influence of further effects, considering especially Cr-diffusion, is discussed.