Alkali salts of amino acids as alkaline additives for neutralization of acidic corrosion inhibitors.

We present alkali salts of amino acids as functional, non-toxic, non-hazardous, non-volatile, chemically stable, and cheap alkaline additives for common acidic corrosion inhibitors. The resulting mixtures have been evaluated for Co, Ni, and Cu leaching and were analyzed by chip filter assay, potentiodynamic polarization measurements, electrochemical impedance measurements, and gravimetry for corrosion protection of iron and steel in aqueous environment at slightly alkaline pH. Leaching of Co and Ni was found to depend on the corresponding complex stabilities. Taurine (Tau) as well as aminohexanoic acid (AHX) leads to low leaching of Co and Ni. Particularly AHX is an attractive low leaching additive leading to lower Co and Ni concentrations in solution than currently used amino alcohols. Glu and Tau were found to synergistically interact with several acidic corrosion inhibitors of the carboxylic acid and the phosphonic acid type. Tau had a particularly positive impact on the protective properties of carboxyphosphonic acids. Glu had also a positive effect on the anti-corrosive properties of several acidic corrosion inhibitors and served as an anti-scalant. Alkali salts of Glu and Tau might thus serve as commercially and ecologically attractive substitutes for current alkaline additives to acidic corrosion inhibitors.

Contact-Biocide TiO2 Surfaces by Surface-Initiated Atom Transfer Radical Polymerization with Chemically Stable Phosphonate Initiators.

Surface-initiated atom transfer radical polymerization (SI-ATRP) is a powerful tool for grafting functional polymers from metal surfaces. It depends on the immobilization of suitable initiators on the surface before radical polymerization. Herein, we report a set of bifunctional initiators bearing a phosphonic acid group for surface binding and a bromoisobutyramide moiety for SI-ATRP. We have analyzed the impact of the connecting alkyl spacers on the grafting process of (vinylbenzyl)trimethylammonium chloride (VBTAC) from titanium as a base material. The thickness of the grafted polymer increased with the spacer length of the initiator. We obtained chemically stable polycationic surfaces with high charge densities of ∼1016 N+/cm2 leading to efficient contact activity of modified titanium coupons against S. aureus. Notably, SI-ATRP grafting was efficient with VBTAC as a styrene-derived ammonium compound. Thus, the reported protocol avoids post-grafting quaternization with toxic alkylating reagents.

Low-Fouling and Antibacterial Polymer Brushes via Surface-Initiated Polymerization of a Mixed Zwitterionic and Cationic Monomer.

The use of surface-grafted polymer brushes with combined low-fouling and antibacterial functionality is an attractive strategy to fight biofilm formation. This report describes a new styrene derivative combining a quaternary ammonium group with a sulfobetaine group in one monomer. Surface-initiated polymerization of this monomer on titanium and a polyethylene (PE) base material gave bifunctional polymer brush layers. Grafting was achieved via surface-initiated atom transfer radical polymerization from titanium or heat-induced free-radical polymerization from plasma-activated PE. Both techniques gave charged polymer layers with a thickness of over 750 nm, as confirmed by ToF-SIMS-SPM measurements. The chemical composition of the brush polymers was confirmed by XPS and FT-IR analysis. The surface charge, characterized by the ζ potential, was positive at different pH values, and the number of solvent-accessible excess ammonium groups was found to be ∼1016 N+/cm2. This led to strong antibacterial activity against Gram-positive and Gram-negative bacteria that was superior to a structurally related contact-active polymeric quaternary ammonium brush. In addition to this antibacterial activity, good low-fouling properties of the dual-function polymer brushes against Gram-positive and Gram-negative bacteria were found. This dual functionality is most likely due to the combination of antibacterial quaternary ammonium groups with antifouling sulfobetaines. The combination of both groups in one monomer allows the preparation of bifunctional brush polymers with operationally simple polymerization techniques.

Natural Product-Derived Phosphonic Acids as Corrosion Inhibitors for Iron and Steel.

Organic acids, typically derived from an oil-based value chain, are frequently used as corrosion inhibitors in industrial metal working fluids. The criteria for selection of these corrosion inhibitors have changed in the last decades, and are today not only performance-driven, but influenced by ecological considerations, toxicity and regulatory standards. We present scalable semisynthetic approaches to organic corrosion inhibitors based on phosphonic acids from renewable resources. They have been evaluated by chip filter assay, potentiodynamic polarization measurements, electrochemical impedance measurements and gravimetry for corrosion protection of iron and steel in an aqueous environment at slightly alkaline pH. The efficacy of several phosphonic acids tested was found to be strongly dependent on structural features influencing molecular self-assembly of protective layers, and the solubility of salts formed with di- and trivalent cations from the media or formed during corrosion. A carboxyphosphonic acid (derived from castor oil) was found to have remarkable anticorrosive effects in all media tested. We attribute the anticorrosion properties of this carboxyphosphonic acid to the formation of particularly stable protective layers on the metal surface. It might thus serve as a commercially attractive substitute for current acidic corrosion inhibitors, derived from renewable resources.

X-ray Fluorescence Uptake Measurement of Functionalized Gold Nanoparticles in Tumor Cell Microsamples.

Quantitative cellular in vitro nanoparticle uptake measurements are possible with a large number of different techniques, however, all have their respective restrictions. Here, we demonstrate the application of synchrotron-based X-ray fluorescence imaging (XFI) on prostate tumor cells, which have internalized differently functionalized gold nanoparticles. Total nanoparticle uptake on the order of a few hundred picograms could be conveniently observed with microsamples consisting of only a few hundreds of cells. A comparison with mass spectroscopy quantification is provided, experimental results are both supported and sensitivity limits of this XFI approach extrapolated by Monte-Carlo simulations, yielding a minimum detectable nanoparticle mass of just 5 pg. This study demonstrates the high sensitivity level of XFI, allowing non-destructive uptake measurements with very small microsamples within just seconds of irradiation time.

Exploring Rigid and Flexible Core Trivalent Sialosides for Influenza Virus Inhibition.

Herein, the chemical synthesis and binding analysis of functionalizable rigid and flexible core trivalent sialosides bearing oligoethylene glycol (OEG) spacers interacting with spike proteins of influenza A virus (IAV) X31 is described. Although the flexible Tris-based trivalent sialosides achieved micromolar binding constants, a trivalent binder based on a rigid adamantane core dominated flexible tripodal compounds with micromolar binding and hemagglutination inhibition constants. Simulation studies indicated increased conformational penalties for long OEG spacers. Using a systematic approach with molecular modeling and simulations as well as biophysical analysis, these findings emphasize on the importance of the scaffold rigidity and the challenges associated with the spacer length optimization.

Impact of S-adenosylmethionine decarboxylase 1 on pulmonary vascular remodeling.

BACKGROUND: Pulmonary hypertension (PH) is a life-threatening disease characterized by vascular remodeling and increased pulmonary vascular resistance. Chronic alveolar hypoxia in animals is often used to decipher pathways being regulated in PH. Here, we aimed to investigate whether chronic hypoxia-induced PH in mice can be reversed by reoxygenation and whether possible regression can be used to identify pathways activated during the reversal and development of PH by genome-wide screening. METHODS AND RESULTS: Mice exposed to chronic hypoxia (21 days, 10% O2) were reoxygenated for up to 42 days. Full reversal of PH during reoxygenation was evident by normalized right ventricular pressure, right heart hypertrophy, and muscularization of small pulmonary vessels. Microarray analysis from these mice revealed s-adenosylmethionine decarboxylase 1 (AMD-1) as one of the most downregulated genes. In situ hybridization localized AMD-1 in pulmonary vessels. AMD-1 silencing decreased the proliferation of pulmonary arterial smooth muscle cells and diminished phospholipase Cγ1 phosphorylation. Compared with the respective controls, AMD-1 depletion by heterozygous in vivo knockout or pharmacological inhibition attenuated PH during chronic hypoxia. A detailed molecular approach including promoter analysis showed that AMD-1 could be regulated by early growth response 1, transcription factor, as a consequence of epidermal growth factor stimulation. Key findings from the animal model were confirmed in human idiopathic pulmonary arterial hypertension. CONCLUSIONS: Our study indicates that genome-wide screening in mice from a PH model in which full reversal of PH occurs can be useful to identify potential key candidates for the reversal and development of PH. Targeting AMD-1 may represent a promising strategy for PH therapy.

Synthesis of tripodal catecholates and their immobilization on zinc oxide nanoparticles.

A common approach to generate tailored materials and nanoparticles (NPs) is the formation of molecular monolayers by chemisorption of bifunctional anchor molecules. This approach depends critically on the choice of a suitable anchor group. Recently, bifunctional catecholates, inspired by mussel-adhesive proteins (MAPs) and bacterial siderophores, have received considerable interest as anchor groups for biomedically relevant metal surfaces and nanoparticles. We report here the synthesis of new tripodal catecholates as multivalent anchor molecules for immobilization on metal surfaces and nanoparticles. The tripodal catecholates have been conjugated to various effector molecules such as PEG, a sulfobetaine and an adamantyl group. The potential of these conjugates has been demonstrated with the immobilization of tripodal catecholates on ZnO NPs. The results confirmed a high loading of tripodal PEG-catecholates on the particles and the formation of stable PEG layers in aqueous solution.

High-affinity carbohydrate binding by trimeric benzoboroxoles measured on carbohydrate arrays.

Carbohydrates are involved in a wide range of biological processes of pharmaceutical relevance. The selective recognition of carbohydrates is therefore of great interest in biology and medicine. In this study we present the synthesis of fluorescent multimeric benzoboroxoles and the analysis of multivalent binding processes to immobilized carbohydrate arrays by fluorescence spectroscopy. We observed high binding affinities of trimeric benzoboroxoles by determination of KDsurf values for their interaction with α-Gal on glass chips. The observed KDsurf values were in the mid-nM range (49 and 104 nM) and are comparable to the KDsurf values for binding of natural lectins, such as that of ConA to immobilized α-Man (79 nM). The array technology was found to be an excellent tool for studying the binding processes of multivalent lectin mimetics with respect to profiling and quantitation.

Variants of the prins cyclization for the synthesis of terpenoid spiroethers and oxabicyclo[3.3.1]nonane derivatives.

Terpenoid spiroethers are abundant natural flavors with significant impact, particularly in the food industry. We present in this article the synthesis of new derivatives of the well-known flavors theaspirane and vitispirane using a variant of the Prins cyclization starting from α,ß-unsaturated or heterocyclic ketones. When aromatic ketones were used as the starting materials for Lewis acid-mediated cyclizations, an alternative pathway involving a domino sequence of Prins cyclization, followed by an intramolecular Friedel-Crafts alkylation, gave benzoannelated oxabicyclo[3.3.1]nonane derivatives. Different reaction pathways may be triggered by the reaction temperature to give with good selectivity either tetrahydropyran derivatives as conventional Prins products or oxabicyclo[3.3.1]nonane derivatives.

Medicinal Chemistry of Drugs with N-Oxide Functionalities.

Molecules with N-oxide functionalities are omnipresent in nature and play an important role in Medicinal Chemistry. They are synthetic or biosynthetic intermediates, prodrugs, drugs, or polymers for applications in drug development and surface engineering. Typically, the N-oxide group is critical for biomedical applications of these molecules. It may provide water solubility or decrease membrane permeability or immunogenicity. In other cases, the N-oxide has a special redox reactivity which is important for drug targeting and/or cytotoxicity. Many of the underlying mechanisms have only recently been discovered, and the number of applications of N-oxides in the healthcare field is rapidly growing. This Perspective article gives a short summary of the properties of N-oxides and their synthesis. It also provides a discussion of current applications of N-oxides in the biomedical field and explains the basic molecular mechanisms responsible for their biological activity.

Decoration of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) with N-oxides increases the T1 relaxivity of Gd-complexes.

High complex stability and longitudinal relaxivity of Gd-based contrast agents are important requirements for magnetic resonance imaging (MRI) because they ensure patient safety and contribute to measurement sensitivity. Charged and zwitterionic Gd3+-complexes of the well-known chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) provide an excellent basis for the development of safe and sensitive contrast agents. In this report, we describe the synthesis of DOTA-NOx, a DOTA derivative with four N-oxide functionalities via "click" functionalization of the tetraazide DOTAZA. The resulting complexes Gd-DOTA-NOx and Eu-DOTA-NOx are stable compounds in aqueous solution. NMR-spectroscopic characterization revealed a high excess of the twisted square antiprismatic (TSAP) coordination geometry over square antiprismatic (SAP). The longitudinal relaxivity of Gd-DOTA-NOx was found to be r1=7.7 mm-1 s-1 (1.41 T, 37 °C), an unusually high value for DOTA complexes of comparable weight. We attribute this high relaxivity to the steric influence and an ordering effect on outer sphere water molecules surrounding the complex generated by the strongly hydrated N-oxide groups. Moreover, Gd-DOTA-NOx was found to be stable against transchelation with high excess of EDTA (200 eq) over a period of 36 h, and it has a similar in vitro cell toxicity as clinically used DOTA-based GBCAs.

Modified N-acyl-homoserine lactones as chemical probes for the elucidation of plant-microbe interactions.

Gram-negative bacteria often use N-acyl-homoserine lactones (AHLs) as signal molecules to monitor their local population densities and to regulate gene-expression in a process called "Quorum Sensing" (QS). This cell-to-cell communication allows bacteria to adapt to environmental changes and to behave as multicellular communities. QS plays a key role in both bacterial virulence towards the host and symbiotic interactions with other organisms. Plants also perceive AHLs and respond to them with changes in gene expression or modifications in development. Herein, we report the synthesis of new AHL-derivatives for the investigation and identification of AHL-interacting proteins. We show that our new compounds are still recognised by different bacteria and that a novel biotin-tagged-AHL derivative interacts with a bacterial AHL receptor.

Elucidation of the regio- and chemoselectivity of enzymatic allylic oxidations with Pleurotus sapidus - conversion of selected spirocyclic terpenoids and computational analysis.

Allylic oxidations of olefins to enones allow the efficient synthesis of value-added products from simple olefinic precursors like terpenes or terpenoids. Biocatalytic variants have a large potential for industrial applications, particularly in the pharmaceutical and food industry. Herein we report efficient biocatalytic allylic oxidations of spirocyclic terpenoids by a lyophilisate of the edible fungus Pleurotus sapidus. This ''mushroom catalysis'' is operationally simple and allows the conversion of various unsaturated spirocyclic terpenoids. A number of new spirocyclic enones have thus been obtained with good regio- and chemoselectivity and chiral separation protocols for enantiomeric mixtures have been developed. The oxidations follow a radical mechanism and the regioselectivity of the reaction is mainly determined by bond-dissociation energies of the available allylic CH-bonds and steric accessibility of the oxidation site.

Synthesis of Modular Desferrioxamine Analogues and Evaluation of Zwitterionic Derivatives for Zirconium Complexation.

The natural siderophore desferrioxamine B (DFOB) has been used for targeted PET imaging with 89 Zr before. However, Zr-DFOB has a limited stability and a number of derivatives have been developed with improved chelation properties for zirconium. We describe the synthesis of pseudopeptidic analogues of DFOB with azido side chains. These are termed AZA-DFO (hexadentate) and AZA-DFO* (octadentate) and are assembled via a modular synthesis from Orn-ß-Ala and Lys-ß-Ala. Nine different chelators have been conjugated to zwitterionic moieties by copper-catalyzed azide-alkyne cycloaddition (CuAAC). The resulting water-soluble chelators form Zr complexes under mild conditions (room temperature for 90 min). Transchelation assays with 1000-fold excess of EDTA and 300-fold excess of DFOB revealed that a short spacing of hydroxamates in (Orn-ß-Ala)3-4 leads to improved complex stability compared to a longer spacing in (Lys-ß-Ala)3-4 . We found that the alignment of amide groups in the pseudopeptide backbone and the presence of zwitterionic sidechains did not compromise the stability of the Zr-complexes with our chelators. We believe that the octadentate derivative AZA-DFO* is particularly valuable for the preparation of new Zr-chelators for targeted imaging which combine tunable pharmacokinetic properties with high complex stability and fast Zr-complexation kinetics.

Zwitterionic surface modification of polyethylene via atmospheric plasma-induced polymerization of (vinylbenzyl-)sulfobetaine and evaluation of antifouling properties.

Zwitterionic polymer brushes were grafted from bulk polyethylene (PE) by air plasma activation of the PE surface followed by radical polymerization of the zwitterionic styrene derivative (vinylbenzyl)sulfobetaine (VBSB). Successful formation of dense poly-(VBSB)-brush layers was confirmed by goniometry, IR spectroscopy, XPS and ToF-SIMS analysis. The resulting zwitterionic layers are about 50-100 nm thick and cause extremely low contact angles of 10° (water) on the material. Correspondingly we determined a high density of > 1.0 × 1016 solvent accessible zwitterions/cm2 (corresponding to 2,0 *10-8 mol/cm2) by a UV-based ion-exchange assay with crystal violet. The elemental composition as determined by XPS and characteristic absorption bands in the IR spectra confirmed the presence of zwitterionic sulfobetaine polymer brushes. The antifouling properties of the resulting materials were evaluated in a bacterial adhesion test against gram-positive bacteria (S. aureus). We observed significantly reduced cellular adhesion of the zwitterionic material compared to pristine PE. These microbiological tests were complemented by tests in natural seawater. During a test period of 21 days, confocal microscopy revealed excellent antifouling properties and confirmed the operating antifouling mechanism. The procedure reported herein allows the efficient surface modification of bulk PE with zwitterionic sulfobetaine polymer brushes via a scalable approach. The resulting modified PE retains important properties of the bulk material and has excellent and durable antifouling properties.

Synthesis of multivalent host and guest molecules for the construction of multithreaded diamide pseudorotaxanes.

A series of di-, tri- and tetravalent axles and wheels for the synthesis of pseudorotaxanes bearing the tetralactam macrocycle/diamide axle binding motif was prepared. Starting from iodinated monovalent precursors, Sonogashira cross-coupling reactions were utilized to couple the binding sites to appropriate spacer groups. Through this "Lego" or "toolbox" approach, the convergent synthesis of host and guests with a well-defined number of the binding sites is possible. In addition, the spatial arrangement of the binding sites can be controlled through the quite rigid connections between linker and binding sites. Although a quantitative assessment of binding strengths was not possible by NMR titration experiments, typical and significant shifts of the signals of the diamide moiety indicate qualitatively the formation of pseudorotaxanes from the axle and wheel precursors.

A biomimetic principle for the chemical modification of metal surfaces: synthesis of tripodal catecholates as analogues of siderophores and mussel adhesion proteins.

By following a biomimetic design principle, tetravalent scaffolds based on an adamantyl and trisalkylmethyl core structure have been synthesized. These scaffolds have been coupled to three catecholamines, thus resembling the characteristic tripodal recognition motif of many natural metal binders, such as mussel adhesion proteins and siderophores, for example, enterobactin. Besides this tripodal recognition element, our scaffolds provide a fourth position for the conjugation of effector molecules. These effectors can be conjugated through biocompatible conjugation techniques to the scaffold and can be used to tailor the properties of different metal surfaces for a range of applications, for example, in implant engineering. Herein, we describe the synthesis of several tripodal metal binders and their immobilization on TiO(2) surfaces by using a simple dip-coating procedure. Furthermore, we demonstrate the conjugation of our surface binders to the dye eosin Y as an effector molecule by peptide coupling. The resulting surfaces have been analyzed by using ellipsometry, time-of-flight secondary ion mass spectrometry, IR spectroscopy, and contact-angle measurements to confirm the specific loading on TiO(2) films and nanoparticles with our trivalent surface binders. As a proof of concept, we have demonstrated the functionalization of TiO(2) nanoparticles with the eosin Y dye.

Regulation of dual leucine zipper kinase activity through its interaction with calcineurin.

Hyperglycemia enhancing the intracellular levels of reactive oxygen species (ROS) contributes to dysfunction and progressive loss of beta cells and thereby to diabetes mellitus. The oxidation sensitive calcium/calmodulin dependent phosphatase calcineurin promotes pancreatic beta cell function and survival whereas the dual leucine zipper kinase (DLK) induces apoptosis. Therefore, it was studied whether calcineurin interferes with DLK action. In a beta cell line similar concentrations of H2O2 decreased calcineurin activity and activated DLK. DLK interacted via its φLxVP motif (aa 362-365) with the interface of the calcineurin subunits A and B. Mutation of the Val prevented this protein protein interaction, hinting at a distinct φLxVP motif. Indeed, mutational analysis revealed an ordered structure of DLK's φLxVP motif whereby Val mediates the interaction with calcineurin and Leu maintains an enzymatically active conformation. Overexpression of DLK wild-type but not the DLK mutant unable to bind calcineurin diminished calcineurin-induced nuclear localisation of the nuclear factor of activated T-cells (NFAT), suggesting that both, DLK and NFAT compete for the substrate binding site of calcineurin. The calcineurin binding-deficient DLK mutant exhibited increased DLK activity measured as phosphorylation of the downstream c-Jun N-terminal kinase, inhibition of CRE-dependent gene transcription and induction of apoptosis. These findings show that calcineurin interacts with DLK; and inhibition of calcineurin increases DLK activity. Hence, this study demonstrates a novel mechanism regulating DLK action. These findings suggest that ROS through inhibition of calcineurin enhance DLK activity and thereby lead to beta cell dysfunction and loss and ultimately diabetes mellitus.

X-ray-Based Techniques to Study the Nano-Bio Interface.

X-ray-based analytics are routinely applied in many fields, including physics, chemistry, materials science, and engineering. The full potential of such techniques in the life sciences and medicine, however, has not yet been fully exploited. We highlight current and upcoming advances in this direction. We describe different X-ray-based methodologies (including those performed at synchrotron light sources and X-ray free-electron lasers) and their potentials for application to investigate the nano-bio interface. The discussion is predominantly guided by asking how such methods could better help to understand and to improve nanoparticle-based drug delivery, though the concepts also apply to nano-bio interactions in general. We discuss current limitations and how they might be overcome, particularly for future use in vivo.