O2 activation at bioinspired complexes: dinuclear copper systems and mononuclear non-heme iron compounds. Mechanisms and catalytic applications in oxidative transformations

L'activació d'oxigen que té lloc en els éssers vius constitueix una font d'inspiració pel desenvolupament d'alternatives als oxidants tradicionals, considerats altament tòxics i nocius. En aquesta treball s'utilitzen compostos sintètics com a models del centre actiu de proteïnes dinuclears de coure i mononuclears de ferro de tipus no-hemo que participen en l'activació d'oxigen en els éssers vius. Els sistemes dinuclears de coure mostren un centre de tipus coure(III) bis(oxo) que és capaç de dur a terme l'ortho-hidroxilació de fenols de manera similar a la reacció que catalitza la proteïna tirosinasa. Per altra banda, els sistemes de ferro desenvolupats en aquest treball actuen com a models de les dioxigenases de Rieske i poden dur a terme l'hidroxilació estereoespecífica d'alcans i l'epoxidació i cis-dihidroxilació d'olefines utilitzant peròxid d'hidrogen com a agent oxidant. Tot plegat demostra que el desenvolupament de sistemes model constitueix una bona estratègia per l'estudi dels sistemes naturals.

Immersive Projection for biochemical pattern matching

In all biological processes, protein molecules and other small molecules interact to function and form transient macromolecular complexes. This interaction of two or more molecules can be described by a docking event. Docking is an important phase for structure-based drug design strategies, as it can be used as a method to simulate protein-ligand interactions. Various docking programs exist that allow automated docking, but most of them have limited visualization and user interaction. It would be advantageous if scientists could visualize the molecules participating in the docking process, manipulate their structures and manually dock them before submitting the new conformations to an automated docking process in an immersive environment, which can help stimulate the design/docking process. This also could greatly reduce docking time and resources. To achieve this, we propose a new virtual modelling/docking program, whereby the advantages of virtual modelling programs and the efficiency of the algorithms in existing docking programs will be merged.

Ring-chain interconversion in high-performance polymer systems. 3. Cyclodepolymerization of poly(m-phenylene isophthalamide) (Nomex) and entropically driven ring-opening polymerization of the macrocyclic oligomers so produced

A homologous series of macrocyclic oligoamides has been prepared in high yield by reaction of isophthaloyl chloride with m-phenylenediamine under pseudo-high-dilution conditions. The products were characterized by infrared and H-1 NMR spectroscopies, matrix assisted laser desorption-ionization time-of-flight mass spectrometry, and gel permeation chromatography (GPC). A series of linear oligomers was prepared for comparison. The macrocycles ranged in size from the cyclic trimer up to at least the cyclic nonamer (90 ring atoms). The same homologous series of macrocyclic oligomers was prepared in high yield by the cyclodepolymerization of poly(m-phenylene isophthalamide) (Nomex). Cyclodepolymerization was best achieved by treating a 1% w/v solution of the polymer in dimethyl sulfoxide containing calcium chloride or lithium chloride with 3-4 mol % of sodium hydride or the sodium salt of benzanilide at 150 degreesC for 70 h. Treatment of a concentrated solution of the macrocyclic oligomers (25% w/v) with 4 mol % of sodium hydride or the sodium salt of benzanilide in a solution of lithium chloride in dimethyl sulfoxide at 170 degreesC for 6 h resulted in efficient entropically driven ring-opening polymerizations to give poly(m-phenylene isophthalamide), characterized by infrared and H-1 NMR spectroscopies and by GPC. The molecular weights obtained were comparable with those of the commercial polymer.

Alkene-arene meta photocycloadditions with a four-carbon-atom tether: efficient approach toward the polycyclic ring systems of aphidicolin and stemodinone

At the end of its tether! The fusion of a six-membered ring onto the four-carbon-atom tether of substrate 1 provides an efficient approach toward the polycyclic ring systems of the natural products aphidicolin and stemodinone. The reaction represents a unique example of a preference for product formation from an endo exciplex in an intramolecular system (exo:endo 2:3=1.0:1.2).

Synthesis of fused cyclic systems containing medium-sized rings through tandem ROM-RCM of norbornene derivatives embedded in a carbohydrate template

A general approach for the synthesis of fused cyclic systems containing medium-sized rings (7-9) has been developed. The key steps involve a diastereoface-selective Diels-Alder reaction of the dienophiles 4a-d attached to a furanosugar with cyclopentadiene and ring opening (ROM)-ring closing metathesis (RCM) of the resulting norbornene derivatives 10a-d and 11a-d. Diels-Alder reaction of the dienophiles 4a-d with cyclopentadiene in the absence of a catalyst produced 10a-d as the major product arising through addition of the diene to the unhindered Si-face. The most interesting and new aspect of the Diels-Alder reaction of these dienophiles is the accessibility of the Re-face that was blocked by the alkenyl chains under Lewis acid catalysis producing the diastereoisomers 11a-d exclusively. The reversal of facial selectivity from an uncatalyzed reaction to a catalyzed one is unprecedented. The observed stereochemical dichotomy is attributed to rotation of the enone moiety along the or bond linking the sugar moiety during formation of the chelate 13. This makes the Re-face of the enone moiety in 4a-d unhindered. Diels-Alder reaction of the carbocyclic analogue 15 under Lewis acid catalysis produced a 1: 1 mixture of the adducts 16 and 17 confirming the participation of sugar ring oxygen in chelate formation. Finally ROM-RCM of 10a-d and 11a-d with Grubbs' catalyst afforded the cis-syn-cis and cis-anti-cis bicyclo-annulated sugars 21a-d and 23a-d, respectively, containing 7-9 membered rings.

Antioxidant properties of malt model systems

The aim of this study was to investigate the effect of kilning and roasting temperatures on antioxidant activity of malt model systems prepared from combinations of glucose, proline, and ferulic acid. Model systems (initial a(w) = 0.09, 6 % moisture) were heated at 60 degrees C for up to 24 h, at 90 degrees C for up to 120 min, and at 220 degrees C for up to 15 min. The antioxidant activity of the glucose-proline-ferulic acid model system increased significantly on heating at 60 degrees C; for 24 h or at 90 degrees C for 120 min. In contrast, the glucose-proline, ferulic acid-glucose, and ferulic acid-proline systems presented either nonsignificantly increased or unchanged antioxidant activity. The antioxidant activity of both the glucose-proline-ferulic acid and glucose-proline model systems increased significantly after heating at 220 degrees C for 10 min, followed by a significant decrease at 15 min. The data suggest that (1) at 60 degrees C, ferulic acid reacts with Maillard reaction products, resulting in a significant increase in antioxidant activity; (2) at 90 degrees C, the antioxidant activity of the glucose-proline-ferulic system comes from both ferulic acid and Maillard reaction products; and (3) at 220 degrees C, the major contributors to antioxidant activity in glucose-proline-ferulic acid and glucose-proline systems are glucose-proline reaction products.

The reaction of flavonoid metabolites with peroxynitrite

There is much interest in the bioactivity of in vivo flavonoid metabolites. We report for the first time the hierarchy of reactivity of flavonoid metabolites with peroxynitrite and characterise novel reaction products. O-Methylation of the B-ring catechol containing flavonoids epicatechin and quercetin, and O-glucuronidation of all flavonoids reduced their reactivity with peroxynitrite. The reaction of the flavanones hesperetin and naringenin and their glucuronides resulted in the formation of multiple mono-nitrated and nitrosated products. In contrast, the catechol-containing flavonoids epicatechin and quercetin yielded oxidation products which when trapped with glutathione led to the production of glutathionyl-conjugates. However, the O-methylated metabolites of epicatechin yielded both mono-and di-nitrated products and nitrosated metabolites. The 3'-O-methyl metabolite of quercetin also yielded a nitrosated species, although its counterpart 4'-O-methyl quercetin yielded only oxidation products. Such products may represent novel metabolic products in vivo and may also express cellular activity. (c) 2006 Elsevier Inc. All rights reserved.

Investigations on the effect of amino acids on acrylamide, pyrazines, and Michael addition products in model systems

Acrylamide and pyrazine formation, as influenced by the incorporation of different amino acids, was investigated in sealed low-moisture asparagine-glucose model systems. Added amino acids, with the exception of glycine and cysteine and at an equimolar concentration to asparagine, increased the rate of acrylamide formation. The strong correlation between the unsubstituted pyrazine and acrylamide suggests the promotion of the formation of Maillard reaction intermediates, and in particular glyoxal, as the determining mode of-action. At increased amino acid concentrations, diverse effects were observed. The initial rates of acrylamide formation remained high for valine, alanine, phenylalanine, tryptophan, glutamine, and Ieucine, while a significant mitigating effect, as evident from the acrylamide yields after 60 min of heating at 160 degrees C, was observed for proline, tryptophan, glycine, and cysteine. The secondary amine containing amino acids, proline and tryptophan, had the most profound mitigating effect on acrylamide after 60 min of heating. The relative importance of the competing effect of added amino acids for alpha-dicarbonyls and acrylamide-amino, acid alkylation reactions is discussed and accompanied by data on the relative formation rates of selected amino acid-AA adducts.

Fermentation of heated gluten systems by gut microflora

The Maillard reaction causes changes to protein structure and occurs in foods mainly during thermal treatment. Melanoidins, the final products of the Maillard reaction, may enter the gastrointestinal tract, which is populated by different species of bacteria. In this study, melanoidins were prepared from gluten and glucose. Their effect on the growth of faecal bacteria was determined in culture with genotype and phenotype probes to identify the different species involved. Analysis of peptic and tryptic digests showed that low molecular mass products are formed from the degradation of melanoidins. Results showed a change in the growth of bacteria. This in vitro study demonstrated that melanoidins, prepared from gluten and glucose, affect the growth of the gut microflora.

Bis(azidophenyl)phosphole building block for extended π-conjugated systems

Novel bis(azidophenyl)phosphole sulfide building block 8 has been developed to give access to a plethora of phosphole-containing π-conjugated systems in a simple synthetic step. This was explored for the reaction of the two azido moieties with phenyl-, pyridyl- and thienylacetylenes, to give bis(aryltriazolyl)-extended π-systems, having either the phosphole sulfide (9) or the phosphole (10) group as central ring. These conjugated frameworks exhibit intriguing photophysical and electrochemical properties that vary with the nature of the aromatic end-group. The λ3-phospholes 10 display blue fluorescence (λem = 460–469 nm) with high quan-tum yield (ΦF = 0.134–0.309). The radical anion of pyridylsubstituted phosphole sulfide 9b was observed with UV/Vis spectroscopy. TDDFT calculations on the extended π-systems showed some variation in the shape of the HOMOs, which was found to have an effect on the extent of charge transfer, depending on the aromatic end-group. Some fine-tuning of the emission maxima was observed, albeit subtle, showing a decrease in conjugation in the order thienyl � phenyl � pyridyl. These results show that variations in the distal ends of such π-systems have a subtle but significant effect on photophysical properties.

The integration of proteomics and systems approaches to map regulatory mechanisms underpinning platelet function.

Platelets in the circulation are triggered by vascular damage to activate, aggregate and form a thrombus that prevents excessive blood loss. Platelet activation is stringently regulated by intracellular signalling cascades, which when activated inappropriately lead to myocardial infarction and stroke. Strategies to address platelet dysfunction have included proteomics approaches which have lead to the discovery of a number of novel regulatory proteins of potential therapeutic value. Global analysis of platelet proteomes may enhance the outcome of these studies by arranging this information in a contextual manner that recapitulates established signalling complexes and predicts novel regulatory processes. Platelet signalling networks have already begun to be exploited with interrogation of protein datasets using in silico methodologies that locate functionally feasible protein clusters for subsequent biochemical validation. Characterization of these biological systems through analysis of spatial and temporal organization of component proteins is developing alongside advances in the proteomics field. This focused review highlights advances in platelet proteomics data mining approaches that complement the emerging systems biology field. We have also highlighted nucleated cell types as key examples that can inform platelet research. Therapeutic translation of these modern approaches to understanding platelet regulatory mechanisms will enable the development of novel anti-thrombotic strategies.

The role of rules-based compliance systems in the new EU regulatory landscape: perspectives of institutional change and agency

The financial crisis of 2007-2009 and the subsequent reaction of the G20 have created a new global regulatory landscape. Within the EU, change of regulatory institutions is ongoing. The research objective of this study is to understand how institutional changes to the EU regulatory landscape may affect corresponding institutionalized operational practices within financial organizations and to understand the role of agency within this process. Our motivation is to provide insight into these changes from an operational management perspective, as well as to test Thelen and Mahoney?s (2010) modes of institutional change. Consequently, the study researched implementations of an Investment Management System with a rules-based compliance module within financial organizations. The research consulted compliance and risk managers, as well as systems experts. The study suggests that prescriptive regulations are likely to create isomorphic configurations of rules-based compliance systems, which consequently will enable the institutionalization of associated compliance practices. The study reveals the ability of some agents within financial organizations to control the impact of regulatory institutions, not directly, but through the systems and processes they adopt to meet requirements. Furthermore, the research highlights the boundaries and relationships between each mode of change as future avenues of research.

Divergent evolution of the activity and regulation of the glutamate decarboxylase systems in Listeria monocytogenes EGD-e and 10403S : roles in virulence and acid tolerance

The glutamate decarboxylase (GAD) system has been shown to be important for the survival of Listeria monocytogenes in low pH environments. The bacterium can use this faculty to maintain pH homeostasis under acidic conditions. The accepted model for the GAD system proposes that the antiport of glutamate into the bacterial cell in exchange for γ-aminobutyric acid (GABA) is coupled to an intracellular decarboxylation reaction of glutamate into GABA that consumes protons and therefore facilitates pH homeostasis. Most strains of L. monocytogenes possess three decarboxylase genes (gadD1, D2 & D3) and two antiporter genes (gadT1 & gadT2). Here, we confirm that the gadD3 encodes a glutamate decarboxylase dedicated to the intracellular GAD system (GADi), which produces GABA from cytoplasmic glutamate in the absence of antiport activity. We also compare the functionality of the GAD system between two commonly studied reference strains, EGD-e and 10403S with differences in terms of acid resistance. Through functional genomics we show that EGD-e is unable to export GABA and relies exclusively in the GADi system, which is driven primarily by GadD3 in this strain. In contrast 10403S relies upon GadD2 to maintain both an intracellular and extracellular GAD system (GADi/GADe). Through experiments with a murinised variant of EGD-e (EGDm) in mice, we found that the GAD system plays a significant role in the overall virulence of this strain. Double mutants lacking either gadD1D3 or gadD2D3 of the GAD system displayed reduced acid tolerance and were significantly affected in their ability to cause infection following oral inoculation. Since EGDm exploits GADi but not GADe the results indicate that the GADi system makes a contribution to virulence within the mouse. Furthermore, we also provide evidence that there might be a separate line of evolution in the GAD system between two commonly used reference strains.