Fr Francium

The synthesis of a series of peptides containing C-terminal 7-amino-4-methylcoumarin (AMC) for use in the thrombin generation test (TGT) is described. The lead structure in this project was H-Gly-Gly-Arg-AMC, of which the water solubility and kinetic parameters (K_M and k_cat) are greatly improved over those of the substrate in current use in the TGT: Cbz-Gly-Gly-Arg-AMC. A series of N-terminally substituted Gly-Gly-Arg-AMC derivatives were synthesized, as well as implementation of structural changes at either the P₂ or P₃ position of the peptide backbone. Furthermore, two substrates were synthesized that have structural similarities to the chromogenic thrombin substrate SQ68 or that contain a 1,2,3-triazole moiety in the peptide chain, mimicking an amide bond. To determine the applicability of newly synthesized fluorogenic substrates for monitoring continuous thrombin generation, the K_M and k_cat values of the conversion of these fluorogenic substrates by thrombin (FIIa) and factor Xa (FXa) were quantified. An initial selection was made on basis of these data, and suitable substrates were further evaluated as substrates in the thrombin generation assay. Assessment of the acquired data showed that several substrates, including the SQ68 derivative Et-malonate-Gly-Arg-AMC and N-functionalized Gly-Gly-Arg-AMC derivatives, are suitable candidates for replacement of the substrate currently in use.

An eye on thrombin: A series of fluorogenic peptidyl-AMC substrates were synthesized and subjected to a biological evaluation to determine their suitability in the thrombin generation test (TGT). Evaluation of the acquired thrombin generation curves showed that several of these substrates have excellent potential for replacement of the substrate in current use.

Highly multibranched gold nanostars were obtained by a room-temperature synthesis assisted by deep-eutectic solvents (DES). The concentration of the ascorbate ions and the presence of water in the solution were found to both have a profound influence on branch formation. A growth mechanism of the nanostar is therefore proposed from the analysis of the particle dimensions, the aspect ratio of their protuberances, and the gold crystal size. These spiky nanoparticles would find an application as conductive filler in polymeric piezoresistive composites, based on a tunneling conduction mechanism.

The dimension and morphology of gold nanostars, prepared through a room-temperature synthesis assisted by deep-eutectic solvents, can be tuned by varying the concentration of water and L-ascorbic acid. The obtained shapes fit with the requirements for the preparation of piezoresistive composites based on a tunneling conduction mechanism.

A series of ruthenium carboxylate complexes that contain two different anionic ligands was prepared. The complexes that bear iodide ligands exhibit remarkable chemical stability. Such complexes have a diminished tendency to undergo anionic ligand exchange and can be activated byvarious acids to form catalysts, which are active in olefinmetathesis reactions.

Ruthenium carboxylate complexes that contain an iodide ligand exhibit remarkable stability. Such complexes can be activated by various acids (HA) to form mixed ligand catalysts 12, which are active in metathesis reactions and possess a diminished tendency for anionic ligand exchange.

Double whammy! Small molecules that inhibit Staphylococcus aureus dehydrosqualene synthase (CrtM) or host squalene synthase (SQS) are of interest as novel, innate immunity-based therapeutics, blocking virulence or stimulating antibacterial neutrophil extracellular trap (NET) formation. The discovery of leads that do both represents a new route to treating staph infections.

Proteins sharing the same “2-His-1-carboxylate” structural motif have little amino acid sequence similarity and are able to perform many different reactions. Many factors have been cited to explain their different specificity and turnover rates, like protein environment, coordinated ligand geometry, electronic structure of the active site, etc. In this paper, we present a combined approach applying high-resolution XANES spectroscopy and theory simulations to different model complexes that mimic the binding modes of the amino acids to the metal site. Experiments were performed on three compounds showing three metal sites: ferrous hexacoordinate, ferric pentacoordinate and ferrous pentacoordinate. The first two compounds bear an N,N,O-tridentate 3,3-bis(1-alkylimidazol-2-yl)propionate ligand that features a monodentate carboxylate group. These complexes mimic the activity of extradiol dioxygenases but also exhibit intradiol cleavage activity. The third compound features a bidentate terphenylcarboxylate ligand and a sterically hindered bidentate N,N-donor, thus providing a good structural mimic of the ternary enzyme-tetrahydrobiopterin-substrate complex in pterin-dependent phenylalanine hydroxylase, which also contains a bidentate carboxylate. Modeling of high-resolution XANES on well-defined model complexes of different geometry can aid in protein structure elucidation. XANES gives the oxidation state and coordination number of the metal in the non-crystallized protein at natural pH. The accuracy of the results is limited by the core-hole and experimental broadenings. We found that high-resolution XANES experiments give increased resolution at the pre-edges, but limited improvement at the main edge. These high-resolution pre-edges can be accurately simulated by using crystal field multiplet theory (CFM). We show that by combining modelling and XANES simulations with FEFF8, detailed structural and chemical information can be obtained. We found that a short O2–metal distance for the carboxylate oxygen atom not bound to the metal causes a higher white line in Fe^II, which is similar to the results obtained for the pterin-dependent hydroxylase, tyrosine hydroxylase (TYH). Full-potential FDMNES simulations for each sample confirm the accuracy of the main results with muffin-tin approximation (FEFF8).

A combined spectroscopic and theoretical method to study the binding mode of amino acids to a metal is discussed. Three compounds showing three metal sites: ferrous hexacoordinate, ferric pentacoordinate and ferrous pentacoordinate were studied. The work shows the subtle correlation between structure and the absorption edge features.

Springer, Heidelberg 2011. xii+214 pp., softcover €42.75.—ISBN 978-1-4419-5628-6

Neurodegenerative disorders are becoming more prevalent given the increase in the aging population. This has inspired active research in the development of new drugs that could mark an important advance in the treatment of complex diseases such as Alzheimer′s and Parkinson′s. With the aim of finding new MAO-B-selective inhibitors, we report the synthesis, in vitro evaluation, and docking simulation of a new series of 3-arylcoumarins variously substituted at the 8-position. Most of the studied compounds show high affinity and selectivity for the hMAO-B isoform, with IC₅₀ values in the low micro- to nanomolar range. Some of them have greater hMAO-B inhibitory activity and selectivity than the reference compound, selegiline. Compounds 7 and 8 are the most active of this series, with compound 8 being fivefold more potent against MAO-B and severalfold more selective than selegiline. Docking experiments were carried out with hMAO-B crystal structures, providing new information about the enzyme–inhibitor interaction and the potential therapeutic application of the new 8-substituted 3-arylcoumarins.

B-selective! With the aim of finding new selective MAO-B inhibitors, herein we report the synthesis, in vitro evaluation, and a docking simulation of a new series of 3-arylcoumarins variously substituted at the 8-position as potential inhibitors of hMAO-A and B. Most of the studied compounds have high affinity and selectivity for hMAO-B, with IC₅₀ values in the low micro- to nanomolar range.

Isoprenoids form the largest family of compounds found in nature. Isoprenoids are often attached to other moieties such as aromatic compounds, indoles/tryptophan, and flavonoids. These reactions are catalyzed by three phylogenetically distinct prenyltransferases: soluble aromatic prenyltransferases identified mainly in actinobacteria, soluble indole prenyltransferases mostly in fungi, and membrane-bound prenyltransferases in various organisms. Fusicoccin A (FC A) is a diterpene glycoside produced by the plant-pathogenic fungus Phomopsis amygdali and has a unique O-prenylated glucose moiety. In this study, we identified for the first time, from a genome database of P. amygdali, a gene (papt) encoding a prenyltransferase that reversibly transfers dimethylallyl diphosphate (DMAPP) to the 6′-hydroxy group of the glucose moiety of FC A to yield an O-prenylated sugar. An in vitro assay with a recombinant enzyme was also developed. Detailed analyses with recombinant PAPT showed that the enzyme is likely to be a monomer and requires no divalent cations. The optimum pH and temperature were 8.0 and 50 °C, respectively. K_m values were calculated as 0.49±0.037 μM for FC P (a plausible intermediate of FC A biosynthesis) and 8.3±0.63 μM for DMAPP, with a k_cat of 55.3±3.3×10⁻³ s. The enzyme did not act on representative substrates of the above-mentioned three types of prenyltransferase, but showed a weak transfer activity of geranyl diphosphate to FC P.

A novel sugar prenyltansferase, PAPT, from the fungus Phomopsis amygdali has been cloned and characterized. This enzyme transfers dimethylallyl diphosphate to the 6′-hydroxy group of the glucose moiety of fusicoccin (FC) A, a diterpene glucoside. To the best of our knowledge, this is the first enzyme to catalyze prenylation of a hydroxyl group in a glucose moiety.

Hydroxyapatite (HAP) microspheres composed of nanorods have successfully been prepared by a facile co-precipitation method without any template. We propose the formation mechanism of the microspheres to be a four-step process on the basis of the evolution of their morphology as a function of reaction time. We investigate the competitive sorption of the HAP microspheres for Pb²⁺, Cu²⁺, Cd²⁺, Zn²⁺, and Ni²⁺ to show that HAP microspheres are a highly selective adsorbent for Pb²⁺ in wastewater.

Hierarchically structured microspheres self-assembled from hydroxyapatite nanorods have successfully been prepared by a simple co-precipitation method without any template. The as-prepared materials exhibit high selective adsorption for Pb²⁺ in wastewater.

The tBu₂Sn-bridged [1]troticenophane [(η⁷-C₇H₆)Ti(η⁵-C₅H₄)]SntBu₂ (2) has been synthesized by low-temperature salt elimination reaction between stoichiometric amounts of the dilithiated troticene [(η⁷-C₇H₆Li)Ti(η⁵-C₅H₄Li)]·pmdta (1; pmdta = N,N′,N′,N″,N″-pentamethyltriethylenetriamine) and tBu₂SnCl₂. Compound 2 was isolated as a blue-green crystalline solid in moderate yield and characterized by multinuclear ¹H, ¹³C and ¹¹⁹Sn NMR spectroscopy, UV/Vis spectroscopy and elemental analysis. Compound 2 and the co-crystal 2·[(pmdta)LiCl] were characterized in the solid state by X-ray diffraction analyses. The dihedral angles between the planes of the C₅H₄ and C₇H₆ rings are 16.3(3) and 17.2(1)°, respectively, for 2 and its co-crystal. Compound 2 is the first monocrystalline structurally characterized heteroleptic stanna[1]troticenophane. The reaction of 2 with [Pt(PEt₃)₃] afforded the platinastanna[2]troticenophane 3, in which the Pt⁰ fragment was inserted by regioselective cleavage of the ipso-C₇H₆–Sn bond, as evidenced by ¹³C NMR spectroscopy and X-ray diffraction analysis. Compound 2 underwent thermal ring-opening polymerization in the solid state to form poly(troticenylstannane) 4. In solution and in the presence of nBuLi as initiator, 2 opens and reassembles to form the metallopolymer 5. The polymeric nature of both 4 and 5 was determined by gel permeation chromatography.

The synthesis of a tBu₂Sn-bridged ansa-cycloheptatrienyl-cyclopentadienyl titanium sandwich complex is presented. As a result of its tilted structure, this strained stanna[1]troticenophane is easily converted into poly(troticenylstannanes) by ring-opening polymerization and undergoes regioselective insertion of platinum(0) into the ipso-C₇H₆–Sn bond upon reaction with [Pt(PEt₃)₃].