998 resultados para Non-nitroxide Intermediates
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The redox potentials of 25 cyclic nitroxides from four different structural classes (pyrrolidine, piperidine, isoindoline, and azaphenalene) were determined experimentally by cyclic voltammetry in acetonitrile, and also via high-level ab initio molecular orbital calculations. It is shown that the potentials are influenced by the type of ring system, ring substituents and/or groups surrounding the radical moiety. For the pyrrolidine, piperidine, and isoindolines there is excellent agreement (mean absolute deviation of 0.05 V) between the calculated and experimental oxidation potentials; for the azaphenalenes, however, there is an extraordinary discrepancy (mean absolute deviation of 0.60 V), implying that their one-electron oxidation might involve additional processes not considered in the theoretical calculations. This recently developed azaphenalene class of nitroxide represents a new variant of a nitroxide ring fused to an aromatic system and details of the synthesis of five derivatives involving differing aryl substitution are also presented.
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Halogen bonding has been observed for the first time between an isoindoline nitroxide and an iodoperfluorocarbon (see figure), which cocrystallize to form a discrete 2:1 supramolecular compound in which NO.⋅⋅⋅I halogen bonding is the dominant intermolecular interaction. This illustrates the potential use of halogen bonding and isoindoline nitroxide tectons for the assembly of organic spin systems...
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Background Type 1 Neurofibromatosis (NF1) is a genetic disorder linked to mutations of the NF1 gene. Clinical symptoms are varied, but hallmark features of the disease include skin pigmentation anomalies (café au lait macules, skinfold freckling) and dermal neurofibromas. Method These dermal manifestations of NF1 have previously been reported in a mouse model where Nf1+/− mice are topically treated with dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). We adopted this mouse model to test the protective effects of a nitroxide antioxidant, 5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl (CTMIO). Antioxidants have previously been shown to increase longevity in nf1-deficient fruitflies. Doses of 4 μM and 40 μM CTMIO provided ad libitum in drinking water were given to Nf1-deficient mice. Results Consistent with previous reports, Nf1-deficient mice showed a 4.7-fold increase in papilloma formation (P < 0.036). However, neither dose of CTMIO had any significant affect on papilloma formation. A non-significant decrease in skin pigmentation abnormalities was seen with 4 μM but not 40 μM CTMIO. Subsequent analysis of genomic DNA isolated from papillomas indicated that DMBA/TPA induced tumors did not exhibit a local loss of heterozygosity (LOH) at the Nf1 locus. Conclusion These data reveal that oral antioxidant therapy with CTMIO does not reduce tumor formation in a multistage cancer model, but also that this model does not feature LOH for Nf1.
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Changes to the redox status of biological systems have been implicated in the pathogenesis of a wide variety of disorders including cancer, Ischemia-reperfusion (I/R) injury and neurodegeneration. In times of metabolic stress e.g. ischaemia/reperfusion, reactive oxygen species (ROS) production overwhelms the intrinsic antioxidant capacity of the cell, damaging vital cellular components. The ability to quantify ROS changes in vivo, is therefore essential to understanding their biological role. Here we evaluate the suitability of a novel reversible profluorescent probe containing a redox-sensitive nitroxide moiety (methyl ester tetraethylrhodamine nitroxide, ME-TRN), as an in vivo, real-time reporter of retinal oxidative status. The reversible nature of the probe's response offers the unique advantage of being able to monitor redox changes in both oxidizing and reducing directions in real time. After intravitreal administration of the ME-TRN probe, we induced ROS production in rat retina using an established model of complete, acute retinal ischaemia followed by reperfusion. After restoration of blood flow, retinas were imaged using a Micron III rodent fundus fluorescence imaging system, to quantify the redox-response of the probe. Fluorescent intensity declined during the first 60 min of reperfusion. The ROS-induced change in probe fluorescence was ameliorated with the retinal antioxidant, lutein. Fluorescence intensity in non-Ischemia eyes did not change significantly. This new probe and imaging technology provide a reversible and real-time response to oxidative changes and may allow the in vivo testing of antioxidant therapies of potential benefit to a range of diseases linked to oxidative stress
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Novel profluorescent mono- and bis-isoindoline nitroxides linked to naphthalimide and perylene diimide structural cores are described. These nitroxide-fluorophore probes display strongly suppressed fluorescence in comparison to their corresponding non-radical diamagnetic methoxyamine derivs. The perylene-based probe possessing two isoindoline systems tethered through ethynyl linkages was shown to be the most photostable in soln., demonstrating significantly enhanced longevity over the 9,10-bis(phenylethynyl)anthracene fluorophore used in previous profluorescent nitroxide probes.
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Research on the selective reduction of NOx with hydrocarbons under lean-burn conditions using non-zeolitic oxides and platinum group metal (PGM) catalysts has been critically reviewed. Alumina and silver-promoted alumina catalysts have been described in detail with particular emphasis on an analysis of the various reaction mechanisms that have been put forward in the literature. The influence of the nature of the reducing agent, and the preparation and structure of the catalysts have also been discussed and rationalised for several other oxide systems. It is concluded for non-zeolitic oxides that species that are strongly adsorbed on the surface, such as nitrates/nitrites and acetates, could be key intermediates in the formation of various reduced and oxidised species of nitrogen, the further reaction of which leads eventually to the formation of molecular nitrogen. For the platinum group metal catalysts, the different mechanisms that have been proposed in the literature have been critically assessed. It is concluded that although there is indirect, mainly spectroscopic, evidence for various reaction intermediates on the catalyst surface, it is difficult to confirm that any of these are involved in a critical mechanistic step because of a lack of a direct quantitative correlation between infrared and kinetic measurements. A simple mechanism which involves the dissociation of NO on a reduced metal surface to give N(ads) and O(ads), with subsequent desorption of N-2 and N2O and removal of O(ads) by the reductant can explain many of the results with the platinum group metal catalysts, although an additional contribution from organo-nitro-type species may contribute to the overall NOx reduction activity with these catalysts.
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Haigh, David; Birrell, Helen C.; Cantello, Barrie C. C.; Eggleston, Drake S.; Haltiwanger, R. Curtis; Hindley, Richard M.; Ramaswamy, Anantha; Stevens, Nicola C. Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, Essex, UK. Tetrahedron: Asymmetry (1999), 10(7), 1353-1367. Publisher: Elsevier Science Ltd., CODEN: TASYE3 ISSN: 0957-4166. Journal written in English. CAN 131:144537 AN 1999:369514 CAPLUS (Copyright (C) 2009 ACS on SciFinder (R)) Abstract Boron-mediated asym. aldol reactions of 4-[2-(2-benzoxazolylmethylamino)ethoxy]benzaldehyde with 2-oxyethanoyloxazolidinones contg. electron withdrawing, chelating, and bulky alkoxy and aryloxy groups, gave variable yields of syn-aldol adducts in high diastereoisomeric excess. These adducts were dehydroxylated in a sequence which complements the traditional Evans asym. alkylation strategy. Cleavage of the auxiliary from these intermediates afforded antihyperglycemic (S)-(-)-2-oxy-3-arylpropanoic acids in excellent enantiomeric excess. The target compds. were ?-alkoxy-4-[2-[(benzoxazolyl)amino]ethoxy]benzenepropanoic acid derivs. The biol. activity of the compds. thus prepd. was not reported here.
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Tese de doutoramento, Farmácia (Química Farmacêutica e Terapêutica), Universidade de Lisboa, Faculdade de Farmácia, 2014
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The [Ru(3)O(H(3)CCO(2))(6)(py)(2)(L)]PF(6) clusters, where L=methanol or dimethyl sulfoxide, can be activated by peroxide or oxygen donor species, such as tert-butyl hydroperoxide (TBHP) or iodosylbenzene (PhIO), respectively, generating reactive intermediates of the type [Ru(3)(IV,IV,III)=0](+). In this way, they catalyse the oxidation of cyclohexane or cyclohexene by TBHP and PhIO, via oxygen atom transfer, rather than by the alternative oxygen radical mechanism characteristic of this type of complexes. In addition to their ability to perform efficient olefin epoxydation catalysis, these clusters also promote the cleavage of the C-H bond in hydrocarbons, resembling the oxidation catalysis by metal porphyrins. (C) 2008 Elsevier Inc. All rights reserved.
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Morphological caste differences and ovary conditions were analyzed in four colonies of Brachygastra augusti collected in different stages of the colony cycle. Differences between castes are distinct suggesting pre-imaginal determination. Many intermediates (non-inseminated ovary-developed females) were found. Because these intermediate females were morphologically similar to workers, it is suggested that they are young ovary-developed workers. Because there is a more evident overlap between queens and workers in the colony in pre-emergence of workers stage, and in three colonies in latter stages, especially in worker-production colonies, it is suggested that smaller queens are probably less viable than larger queens as observed in previously studied epiponines.
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The aspartic protease BACE1 (β-amyloid precursor protein cleaving enzyme, β-secretase) is recognized as one of the most promising targets in the treatment of Alzheimer's disease (AD). The accumulation of β-amyloid peptide (Aβ) in the brain is a major factor in the pathogenesis of AD. Aβ is formed by initial cleavage of β-amyloid precursor protein (APP) by β-secretase, therefore BACE1 inhibition represents one of the therapeutic approaches to control progression of AD, by preventing the abnormal generation of Aβ. For this reason, in the last decade, many research efforts have focused at the identification of new BACE1 inhibitors as drug candidates. Generally, BACE1 inhibitors are grouped into two families: substrate-based inhibitors, designed as peptidomimetic inhibitors, and non-peptidomimetic ones. The research on non-peptidomimetic small molecules BACE1 inhibitors remains the most interesting approach, since these compounds hold an improved bioavailability after systemic administration, due to a good blood-brain barrier permeability in comparison to peptidomimetic inhibitors. Very recently, our research group discovered a new promising lead compound for the treatment of AD, named lipocrine, a hybrid derivative between lipoic acid and the AChE inhibitor (AChEI) tacrine, characterized by a tetrahydroacridinic moiety. Lipocrine is one of the first compounds able to inhibit the catalytic activity of AChE and AChE-induced amyloid-β aggregation and to protect against reactive oxygen species. Due to this interesting profile, lipocrine was also evaluated for BACE1 inhibitory activity, resulting in a potent lead compound for BACE1 inhibition. Starting from this interesting profile, a series of tetrahydroacridine analogues were synthesised varying the chain length between the two fragments. Moreover, following the approach of combining in a single molecule two different pharmacophores, we designed and synthesised different compounds bearing the moieties of known AChEIs (rivastigmine and caproctamine) coupled with lipoic acid, since it was shown that dithiolane group is an important structural feature of lipocrine for the optimal inhibition of BACE1. All the tetrahydroacridines, rivastigmine and caproctamine-based compounds, were evaluated for BACE1 inhibitory activity in a FRET (fluorescence resonance energy transfer) enzymatic assay (test A). With the aim to enhancing the biological activity of the lead compound, we applied the molecular simplification approach to design and synthesize novel heterocyclic compounds related to lipocrine, in which the tetrahydroacridine moiety was replaced by 4-amino-quinoline or 4-amino-quinazoline rings. All the synthesized compounds were also evaluated in a modified FRET enzymatic assay (test B), changing the fluorescent substrate for enzymatic BACE1 cleavage. This test method guided deep structure-activity relationships for BACE1 inhibition on the most promising quinazoline-based derivatives. By varying the substituent on the 2-position of the quinazoline ring and by replacing the lipoic acid residue in lateral chain with different moieties (i.e. trans-ferulic acid, a known antioxidant molecule), a series of quinazoline derivatives were obtained. In order to confirm inhibitory activity of the most active compounds, they were evaluated with a third FRET assay (test C) which, surprisingly, did not confirm the previous good activity profiles. An evaluation study of kinetic parameters of the three assays revealed that method C is endowed with the best specificity and enzymatic efficiency. Biological evaluation of the modified 2,4-diamino-quinazoline derivatives measured through the method C, allow to obtain a new lead compound bearing the trans-ferulic acid residue coupled to 2,4-diamino-quinazoline core endowed with a good BACE1 inhibitory activity (IC50 = 0.8 mM). We reported on the variability of the results in the three different FRET assays that are known to have some disadvantages in term of interference rates that are strongly dependent on compound properties. The observed results variability could be also ascribed to different enzyme origin, varied substrate and different fluorescent groups. The inhibitors should be tested on a parallel screening in order to have a more reliable data prior to be tested into cellular assay. With this aim, preliminary cellular BACE1 inhibition assay carried out on lipocrine confirmed a good cellular activity profile (EC50 = 3.7 mM) strengthening the idea to find a small molecule non-peptidomimetic compound as BACE1 inhibitor. In conclusion, the present study allowed to identify a new lead compound endowed with BACE1 inhibitory activity in submicromolar range. Further lead optimization to the obtained derivative is needed in order to obtain a more potent and a selective BACE1 inhibitor based on 2,4-diamino-quinazoline scaffold. A side project related to the synthesis of novel enzymatic inhibitors of BACE1 in order to explore the pseudopeptidic transition-state isosteres chemistry was carried out during research stage at Università de Montrèal (Canada) in Hanessian's group. The aim of this work has been the synthesis of the δ-aminocyclohexane carboxylic acid motif with stereochemically defined substitution to incorporating such a constrained core in potential BACE1 inhibitors. This fragment, endowed with reduced peptidic character, is not known in the context of peptidomimetic design. In particular, we envisioned an alternative route based on an organocatalytic asymmetric conjugate addition of nitroalkanes to cyclohexenone in presence of D-proline and trans-2,5-dimethylpiperazine. The enantioenriched obtained 3-(α-nitroalkyl)-cyclohexanones were further functionalized to give the corresponding δ-nitroalkyl cyclohexane carboxylic acids. These intermediates were elaborated to the target structures 3-(α-aminoalkyl)-1-cyclohexane carboxylic acids in a new readily accessible way.
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Stabile organische Radikale mit zusätzlichen Funktionalitäten wie Donor/Akzepotor Eigenschaften und Ligandeneignung für Übergangsmetallkomplexierung repräsentieren eine synthetische Herausforderung beim Streben nach der Konstruktion hochdimensionaler heterospin Strukturen. In diesem Hinblick wurden acht neue Hochspinbiradikal-Moleküle zusammen mit ihren Monoradikal- Pendants in dieser Arbeit hergestellt. Die Wahl der Liganden als organische Distanzhalter der Radikaleinheiten wurde auf stickstoffhaltige Heterozyklen (Pyridin und Pyrazol) gelenkt. Diese wurden weiterhin mit den stabilen Spinträgern Nitronylnitroxid- (NN) und Iminonitroxidfragmenten (IN) dekoriert. Ihre Synthese beinhaltete mehrstufige Umsetzungen (Brominierung, Iodierung, N- und Carbaldehyd Schutzgruppen, Stille-Kupplung, Grignard Reaktion, etc.) um die Mono- und Dicarbaldehyd-heterocyclenderivate als Schlüsselvorläufer der Radikaleinheiten zu gewinnen. Die Carbaldehyd-Zwischenstufen wurden Kondensationsreaktionen mit 2,3-Dimethyl-2,3-bis(hydroxylamino)-butan unterworfen (üblicherweise in Dioxan unter Argon für ~ 7 Tage), gefolgt von der Oxidation der Bis-hydroxylimidazolidin-Vorläufer unter Phasentransferkatalyse (NaIO4/H2O). Die Radikalmoleküle wurden mit verschiedenen spektroskopischen Methoden untersucht (FT/IR, UV/Vis/ EPR etc.) und ihre Einkristalle mit Röntgenstrahlbeugung gemessen. Die UV/VIS- Lösungsspektren zeigten in einem breiten Bereich verschiedener Lösungsmittelpolaritäten keine spezifische Wechselwirkung zwischen Lösungsmittel und Radikaleinheit, während ihre Stabilitäten in protischen Lösunsgmitteln wie MeOH stark abnahmen. Als Pulver konnten sie jedoch im Kühlschrank an der Luft für eine Jahr gelagert werden, ohne sich zu zersetzen. Die spektroskopischen Fingerabdrücke der Radikale wurden eindeutig identifiziert and erschienen stark abhängig vom Typ des pi-Ringsystems an das die Spinträger gekoppelt wurden. Basierend auf diesen Informationen wurde ein schnelles Protokoll etabliert, das eine direkte Zuordnung der Art der Radikale und ihrer Anzahl ermöglicht, sowie ihre Reinheit und Verunreinigungen zu definieren. In Lösung bestätigte die Analyse der EPR Spektren der Biradikale die starke Austauschwechselwirkung J zwischen den Radikalfragmenten über die Kopplungseinheiten (J >> an, an ist die Stickstoffhyperfeinkopplungskonstante). Dies wurde weiter unterstützt durch die Beobachtungen in gefrorener Lösung über die Nullfeldaufspaltungen und verbotenen Halbfeldübergänge (Δms = 2). Die Temperaturabhängigkeiten der Δms = 2 - EPR Signale wurden bis herunter auf 4 K gemessen und das exakte Vorzeichen und die Größe von J ermittelt. Diese Arbeit unterstreicht die Möglichkeit über synthetische Chemie eine Feineinstellung der „through bond“ Austauschwechselwirkung zwischen verwandten pi- und sigma- konjugierten Heterozyklen zu erreichen, in denen der S = 1 Grundzustand angenommen wird. Zusätzlich zeigten diese Resultate, dass die Übertragung der Spinpolarisation durch verschiedene Koppler sehr effektiv war.
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We have investigated the microstructure and bonding of two biomass-based porous carbon chromatographic stationary phase materials (alginic acid-derived Starbon® and calcium alginate-derived mesoporous carbon spheres (AMCS) and a commercial porous graphitic carbon (PGC), using high resolution transmission electron microscopy, electron energy loss spectroscopy (EELS), N2 porosimetry and X-ray photoelectron spectroscopy (XPS). The planar carbon sp -content of all three material types is similar to that of traditional nongraphitizing carbon although, both biomass-based carbon types contain a greater percentage of fullerene character (i.e. curved graphene sheets) than a non-graphitizing carbon pyrolyzed at the same temperature. This is thought to arise during the pyrolytic breakdown of hexauronic acid residues into C5 intermediates. Energy dispersive X-ray and XPS analysis reveals a homogeneous distribution of calcium in the AMCS and a calcium catalysis mechanism is discussed. That both Starbon® and AMCS, with high-fullerene character, show chromatographic properties similar to those of a commercial PGC material with extended graphitic stacks, suggests that, for separations at the molecular level, curved fullerene- like and planar graphitic sheets are equivalent in PGC chromatography. In addition, variation in the number of graphitic layers suggests that stack depth has minimal effect on the retention mechanism in PGC chromatography. © 2013 Elsevier Ltd. All rights reserved.
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The main objective of this research was to investigate pyrolysis and torrefaction of forest biomass species using a micropyrolysis instrument. It was found that 30-45% of the original sample mass remained as bio-char in the pyrolysis temperature range of 500 - 700˚C for aspen, balsam, and switchgrass. The non-char mass was converted to gaseous and vapor products, of which 10-55% was water and syngas, 2-12% to acetic acid, 2-12% to hydroxypropanone, 1-3% to furaldehyde, and 5-15% to various phenolic compounds. In addition, several general trends in the evolution of gaseous species were indentified when woody feedstocks were pyrolyzed. With increasing temperature it was observed that: (1) the volume of gas produced increased, (2) the volume of CO2 decreased and the volumes of CO and CH4 increased, and (3) the rates of gas evolution increased. In the range of torrefaction temperature (200 - 300˚C), two mechanistic models were developed to predict the rates of CO2 and acetic acid product formation. The models fit the general trend of the experimental data well, but suggestions for future improvement were also noted. Finally, it was observed that using torrefaction as a pre-curser to pyrolysis improves the quality of bio-oil over traditional pyrolysis by reducing the acidity through removal of acetic acid, reducing the O/C ratio by removal of some oxygenated species, and removing a portion of the water.