On the Sachs bound in stress-induced phase transformations in polycrystalline scalar shape-memory alloys

We consider stress–induced transformations of polycrystalline shape–memory alloys which are so–called scalar materials. In this case the Sachs bound on the phase transformation yield stress turns out to be sharp. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)     

Analysis of isotopic signals in the Danube River water at Tulln,Austria, based on daily grab samples in 2012

Results of stable isotope measurements (δ²H, δ¹⁸O) of daily grab samples, taken from the Danube River at Tulln (river km 1963) during 2012, show seasonal and short-term variations depending on the climatic/hydrological conditions and changes in the catchment area (temperature changes, heavy rains and snow melt processes). Isotope ratios in river water clearly reflect the isotopic composition of precipitation water in the catchment area since evaporation influences play a minor role. Average δ²H and δ¹⁸O values in 2012 are?78‰ and?11.0‰, respectively, deuterium excess averages 10‰. The entire variation amounts to 1.8‰ in δ¹⁸O and 15‰ in δ²H. Quick changes of the isotopic composition within a few days emphasise the necessity of daily sampling for the investigation of hydrological events, while monthly grab sampling seems sufficient for the investigation of long-term hydro-climatic trends. ³H results show peaks (half-width 1–2 days, up to about 150 TU) exceeding the regional environmental level of about 9 TU, probably due to releases from nuclear power plants.     

A Modular Approach to Introduce Function into Single‐Chain Polymeric Nanoparticles

Here, a modular approach is reported to introduce a specific function into single‐chain polymeric nanoparticles (SCPNs). Hereto, an amphiphilic polymer with pendant benzene‐1,3,5‐tricarboxamide (BTA) units is mixed with a “free” BTA that contains a functional group, either a fluorescent naphthalimide or a catalytically active l ‐proline. Taking advantage of hydrophobic interactions and self‐recognition properties of the BTA units, the “free” BTAs are captured into the interior of the SCPN in water as evidenced by fluorescence studies. To illustrate that function can be readily introduced using a modular approach, l ‐proline‐based BTAs are incorporated to procure a catalytically active SCPN in water. The aldol reaction between p‐nitrobenzaldehyde and cyclohexanone shows good conversions at low catalyst loadings and substrate concentrations, and high stereoselectivities are obtained (de = 91% and ee = 98%).

     

An optimised small-molecule stabiliser of the 14-3-3-PMA2 protein-protein interaction

Modulation of protein-protein interactions (PPIs) is a highly demanding, but also a very promising approach in chemical biology and targeted drug discovery. In contrast to inhibiting PPIs with small, chemically tractable molecules, stabilisation of these interactions can only be achieved with complex natural products, like rapamycin, FK506, taxol, forskolin, brefeldin and fusicoccin. Fusicoccin stabilises the activatory complex of the plant H(+)-ATPase PMA2 and 14-3-3 proteins. Recently, we have shown that the stabilising effect of fusicoccin could be mimicked by a trisubstituted pyrrolinone (pyrrolidone1, 1). Here, we report the synthesis, functional activity and crystal structure of derivatives of 1 that stabilise the 14-3-3-PMA2 complex. With a limited compound collection three modifications that are important for activity enhancement could be determined: 1) conversion of the pyrrolinone scaffold into a pyrazole, 2) introduction of a tetrazole moiety to the phenyl ring that contacts PMA2, and 3) addition of a bromine to the phenyl ring that exclusively contacts the 14-3-3 protein. The crystal structure of a pyrazole derivative of 1 in complex with 14-3-3 and PMA2 revealed that the more rigid core of this molecule positions the stabiliser deeper into the rim of the interface, enlarging especially the contact surface to PMA2. Combination of the aforementioned features gave rise to a molecule (37) that displays a threefold increase in stabilising the 14-3-3-PMA2 complex over 1. Compound 37 and the other active derivatives show no effect on two other important 14-3-3 protein-protein interactions, that is, with CRaf and p53. This is the first study that describes the successful optimisation of a PPI stabiliser identified by screening.     

Stable-isotope dilution GC-MS method for ethanol in vapour ethanol and microdialysis systems based on carbonate-catalyzed extractive pentafluorobenzoylation

Common ethanol detection methods are not applicable to cell culture media and microdialysates due to interference with medium constituents including amino acids and pH indicators. We present a novel GC-MS method for the accurate and precise analysis of ethanol in cell cultures and microdialysates. The method is based on the carbonate-catalyzed extractive pentafluorobenzoylation of ethanol and deuterium-labelled ethanol serving as the internal standard and on their GC-MS analysis in the electron-capture negative-ion chemical ionization mode. The method was used to optimize experimental conditions in a custom-made ethanol vapour system utilized for studies examining ethanol influences on neuronal cell lines and in microdialysis.     

Combined muta- and semisynthesis: a powerful synthetic hybrid approach to access target specific antitumor agents based on ansamitocin P3

Access of four new tumor specific folic acid/ansamitocin conjugates is reported that relies on a synthetic strategy based on the combination of mutasynthesis and semisynthesis. Two bromo‐ansamitocin derivatives were prepared by mutasynthesis or by a modified fermentation protocol, respectively, that served as starting point for the semisynthetic introduction of an allyl amine linker under Stille conditions. A sequence of standard coupling steps introduced the pteroic acid/glutamic acid/cysteine unit to the modified ansamitocins. All new derivatives, including those that are expected to be generated after internalization of the folic acid/ansamitocin conjugates into the cancer cell and reductive cleavage of the disulfide linkage showed good to strong antiproliferative activity (IC₅₀ <10 nM ) for different cancer cell lines. Finally, the four conjugates were exposed to two cancer cell lines [cervix carcinoma, KB‐3‐1 (FR+) and lung carcinoma, A‐459 (FR?)], the latter devoid of the membrane‐bound folic acid receptor (FR?). All four conjugates showed strong antiproliferative activity for the FR+ cancer cell line but were inactive against the FR? cell line. The synthetic strategy pursued is based on the combination of mutasynthesis and semisynthesis and proved to be powerful for accessing new ansamitocin derivatives that are difficult to prepare by total synthesis.     

STM manipulation of a subphthalocyanine double-wheel molecule on Au(111)

A new class of double-wheel molecules is manipulated on a Au(111) surface by the tip of a scanning tunneling microscope (STM) at low temperature. The double-wheel molecule consists of two subphthalocyanine wheels connected by a central rotation carbon axis. Each of the subphthalocyanine wheels has a nitrogen tag to monitor its intramolecular rolling during an STM manipulation sequence. The position of the tag can be followed by STM, allowing us to distinguish between the different lateral movements of the molecule on the surface when manipulated by the STM tip.     

Cellular uptake of a fluorescent vanadyl sulfonylcalix[4]arene

Vanadyl bearing calix[4]arene ligands have undergone evaluation against several cell lines, and show varying degrees of toxicity. For vanadyl complexed to a sulfonylcalix[4]arene, monitoring of the strong blue fluorescence revealed slow uptake kinetics. The complex is exclusively found in the cytoplasm of the cells and uptake is not due to active endocytotic mechanisms.     

An Optimised Small‐Molecule Stabiliser of the 14‐3‐3–PMA2 Protein–Protein Interaction

Modulation of protein–protein interactions (PPIs) is a highly demanding, but also a very promising approach in chemical biology and targeted drug discovery. In contrast to inhibiting PPIs with small, chemically tractable molecules, stabilisation of these interactions can only be achieved with complex natural products, like rapamycin, FK506, taxol, forskolin, brefeldin and fusicoccin. Fusicoccin stabilises the activatory complex of the plant H⁺‐ATPase PMA2 and 14‐3‐3 proteins. Recently, we have shown that the stabilising effect of fusicoccin could be mimicked by a trisubstituted pyrrolinone (pyrrolidone1, 1 ). Here, we report the synthesis, functional activity and crystal structure of derivatives of 1 that stabilise the 14‐3‐3–PMA2 complex. With a limited compound collection three modifications that are important for activity enhancement could be determined: 1) conversion of the pyrrolinone scaffold into a pyrazole, 2) introduction of a tetrazole moiety to the phenyl ring that contacts PMA2, and 3) addition of a bromine to the phenyl ring that exclusively contacts the 14‐3‐3 protein. The crystal structure of a pyrazole derivative of 1 in complex with 14‐3‐3 and PMA2 revealed that the more rigid core of this molecule positions the stabiliser deeper into the rim of the interface, enlarging especially the contact surface to PMA2. Combination of the aforementioned features gave rise to a molecule ( 37 ) that displays a threefold increase in stabilising the 14‐3‐3–PMA2 complex over 1 . Compound 37 and the other active derivatives show no effect on two other important 14‐3‐3 protein–protein interactions, that is, with CRaf and p53. This is the first study that describes the successful optimisation of a PPI stabiliser identified by screening.