Macrocyclic systems containing 2,6,9-trioxabicyclo[3.3.1]-nona-3,7-dienes as chiral spacer groups: Synthesis, stereochemical features and preliminary complexation properties

Novel 2:2-macrocycles bearing bridged concave 2,6,9-trioxabicyclo[3.3.1]nona-3,7-dienes as chiral spacer units were obtained by cyclocondensation reaction of the chiral bisacid chloride and the corresponding diols, while use of methylene diamines instead of diols afforded 1:1 macrocycles only. Applying the same, but now template-assisted, experimental procedure to the reaction of the bisacid chloride with triethylene glycol brought about a significant increase in yield as well as a suitable simplification of the work-up during preparation and separation of the corresponding 1:1 as well as 2:2 macrocycles, when compared to results reported previously. HPLC separation on chiral columns revealed the presence of diastereoisomers [RR(S,S)- and RS-(meso)-forms] for all 2:2 macrocycles, which was further evidenced by the CD spectrum of one of those species as an example. Preliminary ESI-MS experiments indicated strong complexation abilities of the sulphur-containing ligand towards Ag(I), Cu(II) and Au(III) ions.

Comparison of the binding of 3-fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines with their isosteric sulfonamides to the active site of phenylethanolamine N-methyltransferase

3-Fluoromethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines (14, 16, and 18-22) are highly potent and selective inhibitors of phenylethanolamine N-methyltransferase (PNMT). Molecular modeling studies with 3-fluoromethyl-7-(N-alkyl aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines, such as 16, suggested that the sulfonamide -NH-could form a hydrogen bond with the side chain of Lys57. However, SAR studies and analysis of the crystal structure of human PNMT (hPNMT) in complex with 7 indicated that the sulfonamide oxygens, and not the sulfonamide -NH-, formed favorable interactions with the enzyme. Thus, we hypothesized that replacement of the sulfonamide -NH-with a methylene group could result in compounds that would retain potency at PNMT and that would have increased lipophilicity, thus increasing the likelihood they will cross the blood brain barrier. A series of 3-fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines (23-30) were synthesized and evaluated for their PNMT inhibitory potency and affinity for the R2-adrenoceptor. A comparison of these compounds with their isosteric sulfonamides (14, 16, and 18-22) showed that the sulfones were more lipophilic but less potent than their corresponding sulfonamides. Sulfone 24 (hPNMT K-i = 1.3 mu M) is the most potent compound in this series and is quite selective for PNMT versus the R2-adrenoceptor, but 24 is less potent than the corresponding sulfonamide, 16 (hPNMT K-i = 0.13 mu M). We also report the crystal structure of hPNMT in complex with sulfonamide 15, from which a potential hydrogen bond acceptor within the hPNMT active site has been identified, the main chain carbonyl oxygen of Asn39. The interaction of this residue with the sulfonamide -NH-is likely responsible for much of the enhanced inhibitory potency of the sulfonamides versus the sulfones.

A PALAVRA DE JAVÉ EM JEREMIAS 7,1 8,3: UMA ANÁLISE DA PROFECIA COMO PORTADORA DE UM CONFLITO SOCIAL ORIUNDO DA COBRANÇA EXCESSIVA DE TRIBUTO

Esta pesquisa privilegia o enfoque histórico ao analisar o texto bíblico, como produto histórico-social, a partir do método sociológico. O material disposto ao longo desta investigação pretende ser uma ajuda para a compreensão de alguns textos do profeta Jeremias. Partindo do princípio de que o texto possui um vínculo com a sociedade na qual foi criado e fazendo uso da metodologia exegética, realiza-se uma análise histórico-sociológica da palavra de Javé em Jeremias 7,1 8,3 como portadora de um conflito social oriundo da cobrança excessiva de tributo em uma sociedade judaíta marcadamente tributária. Busca-se, por esse meio, o sentido do texto dentro do provável cenário histórico-social que permeia o escrito. Para isso, faz-se necessária a investigação dos aspectos preliminares que envolvem tanto o livro de Jeremias, sobretudo, os polêmicos caps. 7,1 8,3, como também a questão do estudo da pesquisa moderna acerca dessa magnífica obra. Vale a pena também salientar o conceito semiótico da poética sociológica que procura estudar a interação causal entre literatura e seu meio social. Além disso, avalia-se o âmbito histórico social da unidade literária alvo de nossa pesquisa, situando-a em seu provável contexto histórico social e determinando a datação, o cenário político e o modo de produção vigente nesse período. Não olvidando, contudo, do fator desencadeador do conflito social e o papel da religião nesse cenário. Além do mais, examina-se o sentido dos textos específicos ou unidades literárias concluídas (perícopes) presentes nos caps. 7,1 8,3, tendo como pressuposto o modelo teórico do modo de produção tributário e os passos da exegese histórico-social. O mecanismo socioanalítico do modo de produção tributário servirá como instrumento de análise da condição socioeconômica, centrando-se nos componentes externos incorporados na coletânea, não em sua história redacional, mas sim em sua formação social.

CONFLITO RELIGIOSO, MARTÍRIO E EXALTAÇÃO VISIONÁRIA: O CASO DE ESTEVÃO EM ATOS 6,1-8,3

Nesta dissertação nos propomos a fazer uma leitura da narrativa de Atos dos Apóstolos 6,1-8,3, considerando-a nos moldes de uma antiga tradição de martírio. Os Helenistas entram em conflito com os Hebreus, Estevão entra em atrito com os judeus da diáspora que se reúnem nas sinagogas, e é levado perante o Sinédrio e executado. O motivo de sua execução é a crítica à Lei e ao Templo. Depois de ter uma experiência de êxtase visionário ele é violentamente assassinado. Lucas, todavia, descreve Estevão como herói vitorioso. A realidade de conflitos, oposição, perseguição e martírio não se constitui em derrota, mas em fortalecimento da fé. A morte de Estevão é interpretada dentro desta tradição. A compreensão do caso de Estevão e dos Helenistas é fundamental para entender a continuação do movimento dos seguidores de Jesus e o início do desenvolvimento da Cristologia após o evento pascal.(AU)

Synthesis and iron binding studies of myo-inositol 1,2,3-trisphosphate and (+/-)-myo-inositol 1,2-bisphosphate, and iron binding studies of all myo-inositol tetrakisphosphates

The first syntheses of the natural products myo-inositol 1,2,3-trisphosphate and (+/-)-myo-inositol 1,2-bisphosphate are described. The protected key intermediates 4,5,6-tri-O-benzoyl-myo-inositol and (+/-)-3,4,5,6-tetra-O-benzyl-myo-inositol were phosphorylated with dibenzyl N,N-di-isopropylphosphoramidite in the presence of 1H-tetrazole and subsequent oxidation of the phosphite. The crystal structures of the synthetic intermediates (+/-)-1-O-(tert-butyldiphenylsilyl)-2,3,O-cyclohexylidene-myo-inos itol and (+/-)-4,5,6-tri-O-benzoyl-1-O-(tert-butyldiphenylsilyl)-2,3-O-cycl ohexylidene- myo-inositol are reported. myo-Inositol 1,2,3-trisphosphate (+/-)-myo-inositol 1,2-bisphosphate, and all isomeric myo-inositol tetrakisphosphates were evaluated for their ability to alter HO. production in the iron-catalysed Haber-Weiss reaction. The results demonstrated that a 1,2,3-grouping of phosphates in myo-inositol was necessary for inhibition also that (+/-)-myo-inositol 1,2-bisphosphate potentiated HO. production. myo-Inositol 1,2,3-trisphosphate resembled myo-inositol hexakisphosphate (phytic acid) in its ability to act as a siderophore by promoting iron-uptake into Pseudomonas aeruginosa.

The role of tissue transglutaminase in 1-methyl-4-phenylpyridinium (MPP+)-induced toxicity in differentiated human SH-SY5Y neuroblastoma cells

Tissue transglutaminase (TG2) can induce post-translational modification of proteins, resulting in protein cross-linking or incorporation of polyamines into substrates, and can also function as a signal transducing G protein. The role of TG2 in the formation of insoluble cross-links has led to its implication in some neurodegenerative conditions. Exposure of pre-differentiated SH-SY5Y cells to the Parkinsonian neurotoxin 1-methyl-4-phenylpyridinium ion (MPP+) resulted in significant dose-dependent reductions in TG2 protein levels, measured by probing Western blots with a TG2-specific antibody. Transglutaminase (TG) transamidating activity, on the other hand, monitored by incorporation of a polyamine pseudo-substrate into cellular proteins, was increased. Inhibitors of TG (putrescine) and TG2 (R283) exacerbated MPP+ toxicity, suggesting that activation of TG2 may promote a survival response in this toxicity paradigm.

Extracellular loops 1 and 3 and their associated transmembrane regions of the calcitonin receptor-like receptor are needed for CGRP receptor function

The first and third extracellular loops (ECL) of G protein-coupled receptors (GPCRs) have been implicated in ligand binding and receptor function. This study describes the results of an alanine/leucine scan of ECLs 1 and 3 and loop-associated transmembrane (TM) domains of the secretin-like GPCR calcitonin receptor-like receptor which associates with receptor activity modifying protein 1 to form the CGRP receptor. Leu195Ala, Val198Ala and Ala199Leu at the top of TM2 all reduced aCGRP-mediated cAMP production and internalization; Leu195Ala and Ala199Leu also reduced aCGRP binding. These residues form a hydrophobic cluster within an area defined as the "minor groove" of rhodopsin-like GPCRs. Within ECL1, Ala203Leu and Ala206Leu influenced the ability of aCGRP to stimulate adenylate cyclase. In TM3, His219Ala, Leu220Ala and Leu222Ala have influences on aCGRP binding and cAMP production; they are likely to indirectly influence the binding site for aCGRP as well as having an involvement in signal transduction. On the exofacial surfaces of TMs 6 and 7, a number of residues were identified that reduced cell surface receptor expression, most noticeably Leu351Ala and Glu357Ala in TM6. The residues may contribute to the RAMP1 binding interface. Ile360Ala impaired aCGRP-mediated cAMP production. Ile360 is predicted to be located close to ECL2 and may facilitate receptor activation. Identification of several crucial functional loci gives further insight into the activation mechanism of this complex receptor system and may aid rational drug design.

Fluorescent probe:complexation of Fe3+ with the myo-inositol 1,2,3-trisphosphate motif

Natural myo-inositol phosphate antioxidants containing the 1,2,3-trisphosphate motif bind Fe3+ in the unstable penta-axial conformation.

Conformational analysis of the natural iron chelator myo-inositol 1,2,3-trisphosphate using a pyrene-based fluorescent mimic

myo-Inositol phosphates possessing the 1,2,3-trisphosphate motif share the remarkable ability to completely inhibit iron-catalysed hydroxyl radical formation. The simplest derivative, myo-inositol 1,2,3-trisphosphate [Ins(1,2,3)P3], has been proposed as an intracellular iron chelator involved in iron transport. The binding conformation of Ins(1,2,3)P3 is considered to be important to complex Fe3+ in a 'safe' manner. Here, a pyrene-based fluorescent probe, 4,6-bispyrenoyl-myo-inositol 1,2,3,5-tetrakisphosphate [4,6-bispyrenoyl Ins(1,2,3,5)P4], has been synthesised and used to monitor the conformation of the 1,2,3-trisphosphate motif using excimer fluorescence emission. Ring-flip of the cyclohexane chair to the penta-axial conformation occurs upon association with Fe3+, evident from excimer fluorescence induced by π-π stacking of the pyrene reporter groups, accompanied by excimer formation by excitation at 351 nm. This effect is unique amongst biologically relevant metal cations, except for Ca 2+ cations exceeding a 1:1 molar ratio. In addition, the thermodynamic constants for the interaction of the fluorescent probe with Fe3+ have been determined. The complexes formed between Fe 3+ and 4,6-bispyrenoyl Ins(1,2,3,5)P4 display similar stability to those formed with Ins(1,2,3)P3, indicating that the fluorescent probe acts as a good model for the 1,2,3-trisphosphate motif. This is further supported by the antioxidant properties of 4,6-bispyrenoyl Ins(1,2,3,5)P4, which closely resemble those obtained for Ins(1,2,3)P3. The data presented confirms that Fe3+ binds tightly to the unstable penta-axial conformation of myo-inositol phosphates possessing the 1,2,3-trisphosphate motif. © 2010 The Royal Society of Chemistry.

Noise in gallium nitride-based quantum well structures used for nanometer devices in the frequency range 1 Hz--3 Mhz and temperature range 77K--324K

Electronic noise has been investigated in AlxGa1−x N/GaN Modulation-Doped Field Effect Transistors (MODFETs) of submicron dimensions, grown for us by MBE (Molecular Beam Epitaxy) techniques at Virginia Commonwealth University by Dr. H. Morkoç and coworkers. Some 20 devices were grown on a GaN substrate, four of which have leads bonded to source (S), drain (D), and gate (G) pads, respectively. Conduction takes place in the quasi-2D layer of the junction (xy plane) which is perpendicular to the quantum well (z-direction) of average triangular width ∼3 nm. A non-doped intrinsic buffer layer of ∼5 nm separates the Si-doped donors in the AlxGa1−xN layer from the 2D-transistor plane, which affords a very high electron mobility, thus enabling high-speed devices. Since all contacts (S, D, and G) must reach through the AlxGa1−xN layer to connect internally to the 2D plane, parallel conduction through this layer is a feature of all modulation-doped devices. While the shunting effect may account for no more than a few percent of the current IDS, it is responsible for most excess noise, over and above thermal noise of the device. ^ The excess noise has been analyzed as a sum of Lorentzian spectra and 1/f noise. The Lorentzian noise has been ascribed to trapping of the carriers in the AlxGa1−xN layer. A detailed, multitrapping generation-recombination noise theory is presented, which shows that an exponential relationship exists for the time constants obtained from the spectral components as a function of 1/kT. The trap depths have been obtained from Arrhenius plots of log (τT2) vs. 1000/T. Comparison with previous noise results for GaAs devices shows that: (a) many more trapping levels are present in these nitride-based devices; (b) the traps are deeper (farther below the conduction band) than for GaAs. Furthermore, the magnitude of the noise is strongly dependent on the level of depletion of the AlxGa1−xN donor layer, which can be altered by a negative or positive gate bias VGS. ^ Altogether, these frontier nitride-based devices are promising for bluish light optoelectronic devices and lasers; however, the noise, though well understood, indicates that the purity of the constituent layers should be greatly improved for future technological applications. ^

Análise comparativa da imunoexpressão de GLUT-1, GLUT-3 e M-CSF em lesão periférica e central de células gigantes

The peripheral giant cell lesion ( PG CL ) and the central giant cell lesion ( CGC L) are lesions histologically similar affecting the head and neck region . The study aimed to analyze the immunohistochemical expression of markers GLUT - 1 , GLUT - 3 and M - CSF in a series of cases of PGCL and CGCL , in trying to understand the different biological behavior of these pathologies . The sample consisted of 20 tissue specimens of PGCL 20 central lesion of not aggressive giant cell ( CLNAGC) and 20 central lesi on of aggressive giant cell ( CLAGC), coming from the Pathology Unit of Oral Pathology of the Department of Dentistry of UFRN . W as performed the s emi - quantitative and qualitative analysis of immunohistochemical expression of the markers in giant cells and m ononuclear cells . In relation to the GLUT - 1, it was found a statistically significant difference (p < 0.05) in the number of mononuclear cells immunomarked between the PGCL and the CLNAGC and between the PGCL and CLAGC . Regarding the intensity of staining w as also observed a statistically significant difference both at the mononuclear cells as in giant cells between PL and CLNAGC and between PGCL and CLAGC , at the giant cells there was also a statistically significant difference between the CLNAGC and CLAGC . In relation to GLUT - 3 , was found a statistically significant difference between PGCL and CLAGC and between CLAGC and CLNAGC in amount of mononuclear cells immunomarked . Regarding the intensity of labeling for such protein was found a statistically signifi cant difference at the giant cells between PL and CLAGC . To the M - CSF was observed only a statistically significant difference in the intensity of labeling at the mononuclear cells between PGCL and CLNAGC and between PGCL and CLAGC . Based on these results, we can conclude the participation of GLUT - 1, GLUT - 3 and M - CSF in the pathogenesis of the lesions studied. The bigger immunostaining of these proteins in mononuclear cells show that these cells perform a higher metabolic activity and osteoclastogenic, espe cially in CLAGC . It was found that the mononuclear cells were more related to the pathogenesis of the studied lesions than properly the giant s cell s.

Mid-infrared spectroscopy of lensed galaxies at 1 < z < 3: The nature of sources near the MIPS confusion limit

We present Spitzer IRS mid-infrared spectra for 15 gravitationally lensed, 24 μm-selected galaxies, and combine the results with four additional very faint galaxies with IRS spectra in the literature. The median intrinsic 24 μm flux density of the sample is 130 μJy, enabling a systematic survey of the spectral properties of the very faint 24 μm sources that dominate the number counts of Spitzer cosmological surveys. Six of the 19 galaxy spectra (32%) show the strong mid-IR continuua expected of AGNs; X-ray detections confirm the presence of AGNs in three of these cases, and reveal AGNs in two other galaxies. These results suggest that nuclear accretion may contribute more flux to faint 24 μm-selected samples than previously assumed. Almost all the spectra show some aromatic (PAH) emission features; the measured aromatic flux ratios do not show evolution from z = 0. In particular, the high signal-to-noise mid-IR spectrum of SMM J163554.2+661225 agrees remarkably well with low-redshift, lower luminosity templates. We compare the rest-frame 8 μm and total infrared luminosities of star-forming galaxies, and find that the behavior of this ratio with total IR luminosity has evolved modestly from z = 2 to z = 0. Since the high aromatic-to-continuum flux ratios in these galaxies rule out a dominant contribution by AGNs, this finding implies systematic evolution in the structure and/or metallicity of infrared sources with redshift. It also has implications for the estimates of star-forming rates inferred from 24 μm measurements, in the sense that at z ~ 2, a given observed frame 24 μm luminosity corresponds to a lower bolometric luminosity than would be inferred from low-redshift templates of similar luminosity at the corresponding rest wavelength.