SÍNTESE E DETERMINAÇÃO DA ESTEREOQUÍMICA RELATIVA DE UM NOVO EPÓXIDO ALDEÍDO CICLOPENTANO MONOTERPENÓIDE

In this study, we report the preparation of a new tetra-substituted epoxide aldehyde cyclopentane, which acts as a starting material for the synthesis of plinol, from (R)-(+)-epoxy-limonene. The synthesis was performed in three steps and resulted in a good yield. The structural determination was performed by 1H and 13C NMR, and the relative stereochemistry was defined by nuclear Overhauser effect (NOE) experiments with computer calculations of molecular modeling, particularly with respect to indirect coupling constant calculations.

Synthesis of Chiral Benzimidazolylidenes from 1,10-Phenathrolines and 1,10-Phenathroline-2,9-dione /

A^-heterocyclic carbenes (NHCs) have become the focus of much interest as ancillary ligands for transition metal catalysts in recent years. Their structural variability and strong cy-donation properties have led to the preparation of demonstrably useful organometallic catalysts. Among the three general structural types of NHCs (imidazolylidenes, imidazolinylidenes, and benzimidazolylidenes), benzimidazolylidenes are the least investigated because of the limitation of current synthetic approaches. The preparation of chiral analogues is even more challenging. Previously, our group has demonstrated an alternative approach to synthesizing benzimidazolylidenes with a tetracyclic framework in three steps from 1,10-phenanthroline. This thesis is focused on approaches to chiral benzimidazolylidenes derived from substituted 1,10-phenanthrolines. A key step in the preparation of these ligands involves a reduction of the pyridyl rings in 1,10-phenanthrolines. Chirality can be introduced to phenanthrolines before, during, or after the reduction as illustrated by three approaches: 1) de novo construction of the phenanthroline from chiral ketones with endo and exo faces to provide a degree of diastereoselectivity during subsequent reduction; 2) introduction of substituents into the 2- and 2,9- position of phenanthroline by nucleophilic aromatic substitution, followed by a reduction-resolution sequence; and 3) use of the protected octahydrophenanthroline as a substrate for chiral induction a to nitrogen.

Synthesis and evaluation of cyclic cationic peptides as antimicrobial agents for use in plant protection

Aquesta tesi doctoral se centra en l'estudi de l'aplicació de pèptids antimicrobians en la lluita contra agents patògens de cultius de plantes d'interès econòmic.L'estratègia sintètica s'ha portat a terme utilitzant metodologies convencionals de síntesi de pèptids en fase sòlida com l'estratègia tridimensional ortogonal Fmoc/tBut/Allyl. Ha calgut fer la recerca de les condicions òptimes per a l'eliminació del grup Allyl i la ciclació. D'entre els pèptids cíclics de 4-10 aminoacids sintetitzats, el decapèptid c(Lys-Leu-Lys-Leu-Lys-Phe-Lys-Lys-Leu-Gln) ha resultat ésser el més efectiu i s'ha pres com a base per al disseny d'una quimioteca de 56 pèptids. Dels resultats obtinguts s'ha sintetitzat una segona quimioteca basada en l'estructura general c(X1-X2-X3-X4-Lys-Phe-Lys-Lys-Leu-Gln) determinada com la que posseix el millor perfil d'activitat. Els pèptids més efectius obtinguts constituixen els primers exemples de pèptids cíclics actius contra E. amylovora i poden ser considerats com a bons candidats pel desenvolupament d'agents antimicrobians efectius en protecció vegetal.

Kinetic resolution of iodophenylethanols by Candida antarctica lipase and their application for the synthesis of chiral biphenyl compounds

The kinetic resolution of (+/-)-iodophenylethanols was carried out using lipase from Candida antarctica and in some cases the enantiomeric excesses were high (up to >98%). Enantiomerically enriched (S)-iodophenylethanols produced by the enzymatic resolution process were used in the synthesis of chiral biphenyl compounds by the Suzuki reaction with good yields (63-65%). (C) 2010 Elsevier Ltd. All rights reserved.

Increased glucose synthesis in renal tubule fragments from hyperthyroid rats

Rates of glucose synthesis from several substrates were examined in renal tubule fragments from hyperthyroid rats. A hyperthyroid state was induced by daily intraperitoneal injections of thyroxine (T-4) (100 mu g/100 g body weight) for 14 days. At the end of the experimental period, plasma triiodothyronine and T-4 levels were six and eight times higher, respectively, than initial values. Hyperthyroid rats gained less weight and had lower blood glucose despite an increased food intake. In both control and hyperthyroid rats, rates of glucose production by renal tubule fragments were higher with glutamine and glycerol than with lactate, alanine, or glutamate. T-4 treatment induced a significant increase in the de novo glucose synthesis from all substrates, except glutamine. The highest percent increase was obtained with alanine (64%), compared with 31-40% for glutamate, lactate, and glycerol. The T-4 treatment induced increase in glucose synthesis by renal tubule fragments suggests that renal gluconeogenesis contributes to enhance glucose production in hyperthyroidism.

The effects of copper ions on the synthesis of periplasmic and membrane proteins in Acidithiobaeillus ferrooxidans as analyzed by SDS-PAGE and 2D-PAGE

The effects of 200 mM copper ions on the synthesis of membrane and periplasmic proteins were investigated in iron-grown cells of Acidithiobacillus ferrooxidans (At. ferrooxidans). Total membrane protein profiles of cells grown in the absence of copper ions (unadapted cells) and in the presence of copper ions (copper-adapted cells) were compared by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE). Crude preparations of outer membrane and periplasmic proteins were analyzed by SDS-PAGE. The synthesis of proteins was diminished or increased in the presence of copper ions. Low molecular weight proteins (< 14 kDa) were significantly repressed by copper. These proteins are probably acidic proteins located in the outer membrane. An over-expression of a periplasmic protein of about 17 kDa was detected in the copper-adapted cells and was assumed to be rusticyanin, a 16.5-kDa periplasmic copper protein present in At. ferrooxidans cells and involved in the electron-transport chain of the iron oxidation pathway. To our knowledge, this is the first report of a possible involvement of the rusticyanin and outer membrane proteins in the mechanism of copper resistance in At. ferrooxidans. (C) 2003 Elsevier B.V. All rights reserved.

Thiobacillus ferrooxidans response to copper and other heavy metals: growth, protein synthesis and protein phosphorylation

Respirometric experiments demonstrated that the oxygen uptake by Thiobacillus ferrooxidans strain LR was not inhibited in the presence of 200 mM copper. Copper-treated and untreated cells from this T. ferrooxidans strain were used in growth experiments in the presence of cadmium, copper, nickel and zinc. Growth in the presence of copper was improved by the copper-treated cells. However, no growth was observed for these cells, within 190 h of culture, when cadmium, nickel and zinc were added to the media. Changes in the total protein synthesis pattern were detected by two-dimensional polyacrylamide gel electrophoresis for T. ferrooxidans LR cells grown in the presence of different heavy metals. Specific proteins were induced by copper (16, 28 and 42 kDa) and cadmium (66 kDa), whereas proteins that had their synthesis repressed were observed for all the heavy metals tested. Protein induction was also observed in the cytosolic and membrane fractions from T. ferrooxidans LR cells grown in the presence of copper. The level of protein phosphorylation was increased in the presence of this metal.

Chalcopyrite and bornite differentially affect protein synthesis in planktonic cells of Acidithiobacillus ferrooxidans

Acidithiobacillus ferrooxidans is used in bioleaching industrial operations to recover metal ions from mineral sulfides. Chalcopyrite and bornite are copper sulfides that have the same elemental composition, but differ in their susceptibility to the bioleaching process. Our objective was to identify differentially expressed proteins in A. ferrooxidans LR cells exposed to chalcopyrite or bornite, as a sole energy source, for 24 hours. Compared to the control (without minerals), proteins were induced or repressed in planktonic cells after contact with chalcopyrite or bornite by 24 hours. These results demonstrated that the time of exposure to the copper minerals was enough to trigger distinct responses in the A. ferrooxidans metabolism. © 2007 Trans Tech Publications.

Síntese e modelagem molecular do novo derivado indolinônico como candidato a antiinflamatório COX-2 seletivo

Anti-inflammatory drugs are known to be the most widely-marketed drugs in the world, despite their serious side effects, mainly on the gastrointestinal tract. Thus, there are constant efforts to discover new prototypes with improved therapeutic activity and safety for the patient. Since the advent of the computational chemistry, the theoretical study of the physiological behavior of a new compound and hence an understanding of its supposed mechanism of action have been made a lot more accessible. Thus, molecule-receptor mathematical modeling was applied to compound I (1-(2,6-dichlorophenyl)indolin-2-one), to predict theoretically its ability to inhibit, selectively, the COX-2 isoform of prostaglandin endoperoxide synthase (PGHS-2), and the best positions to introduce chemical groups and to make molecular modifications.

Identidade e estudos organizacionais: em direção a um novo paradigma?

This paper aimes to contribute to the analyzes of Caldas and Wood Jr (1997) concerning to the concept of identity. That concept has been developed in Organization Studies under the propositions of Albert and Whetten (1985). In that way, identity concept has been defined by the following characteristics: centrality, distinctiveness and continuity. Nevertheless, a new paradigm has been emerging within social science. In this paper, we present a synthesis on how the concept of identity has been discussed in Social Psychology and Cultural Studies. For both theoretical perspectives, the ideas of centrality and durability are put into doubt, as identity is seen as dynamic and fragmentary. Besides that, we intend to show how the new paradigm is getting formed within Organizational Studies, especially considering international context. Considering that the emerging organizational ideas concerning identity show proximity with those proposed by Social Psychology and Cultural Studies, we raise possible questions that the new paradigm will have to face.

Desenvolvimento e validação de método bioanalítico aplicado em estudo de farmacocinética pré-clínica e ensaio preliminar de segurança de novo derivado de tiazolidinodiona com atividade antiinflamatória - LYSO-07

Pós-graduação em Ciências Farmacêuticas - FCFAR

Desenvolvimento e validação de método bioanalítico aplicado em estudo de farmacocinética pré-clínica e ensaio preliminar de segurança de novo derivado de tiazolidinodiona com atividade antiinflamatória - LYSO-07

Pós-graduação em Ciências Farmacêuticas - FCFAR

De Novo Design of Foldamers for Preparation of Nanostructured Materials

This thesis deals with the synthesis and the conformation analysis of hybrid foldamers containing the 4-carboxyoxazolidin-2-one unit or related molecules, in which an imido-type function is obtained by coupling the nitrogen of the heterocycle with the carboxylic acid moiety of the next unit. The imide group is characterized by a nitrogen atom connected to an endocyclic and an exocyclic carbonyl, which tend always to adopt the trans conformation. As a consequence of this locally constrained disposition effect, these imide-type oligomers are forced to fold in ordered conformations. The synthetic approach is highly tuneable with endless variations, so, simply by changing the design and the synthesis, a wide variety of foldamers with the required properties may be prepared “on demand”. Thus a wide variety of unusual secondary structures and interesting supramolecular materials may be obtained with hybrid foldamers. The behaviour in the solid state of some of these compounds has been analyzed in detail, thus showing the formation of different kinds of supramolecular materials that may be used for several applications. A winning example is the production of a bolaamphiphilic gelators that may also be doped with small amounts of dansyl containing compounds, needed to show the cellular uptake into IGROV-1 cells, by confocal laser scanning microscopy. These gels are readily internalized by cells and are biologically inactive, making them very good candidates in the promising field of drug delivery. In the last part of the thesis, a particular attention was directed to the search of new scaffolds that behave as constrained amino acid mimetics, showing that tetramic acids derivatives could be good candidates for the synthesis and applications of molecules having an ordered secondary structure.

Peroxisome proliferator-activated receptor {gamma} coactivator 1{alpha} (PGC-1{alpha}) promotes skeletal muscle lipid refueling in vivo by activating de novo lipogenesis and the pentose phosphate pathway

Exercise induces a pleiotropic adaptive response in skeletal muscle, largely through peroxisome proliferator-activated receptor coactivator 1 (PGC-1 ). PGC-1 enhances lipid oxidation and thereby provides energy for sustained muscle contraction. Its potential implication in promoting muscle refueling remains unresolved, however. Here, we investigated a possible role of elevated PGC-1 levels in skeletal muscle lipogenesis in vivo and the molecular mechanisms that underlie PGC-1 -mediated de novo lipogenesis. To this end, we studied transgenic mice with physiological overexpression of PGC-1 and human muscle biopsies pre- and post-exercise. We demonstrate that PGC-1 enhances lipogenesis in skeletal muscle through liver X receptor -dependent activation of the fatty acid synthase (FAS) promoter and by increasing FAS activity. Using chromatin immunoprecipitation, we establish a direct interaction between PGC-1 and the liver X receptor-responsive element in the FAS promoter. Moreover, we show for the first time that increased glucose uptake and activation of the pentose phosphate pathway provide substrates for RNA synthesis and cofactors for de novo lipogenesis. Similarly, we observed increased lipogenesis and lipid levels in human muscle biopsies that were obtained post-exercise. Our findings suggest that PGC-1 coordinates lipogenesis, intramyocellular lipid accumulation, and substrate oxidation in exercised skeletal muscle in vivo.

De novo ceramide biosynthesis is associated with resveratrol-induced inhibition of ornithine decarboxylase activity

Previous studies could demonstrate, that the naturally occuring polyphenol resveratrol inhibits cell growth of colon carcinoma cells at least in part by inhibition of protooncogene ornithine decarboxylase (ODC). The objective of this study was to provide several lines of evidence suggesting that the induction of ceramide synthesis is involved in this regulatory mechanisms. Cell growth was determined by BrdU incorporation and crystal violet staining. Ceramide concentrations were detected by HPLC-coupled mass-spectrometry. Protein levels were examined by Western blot analysis. ODC activity was assayed radiometrically measuring [(14)CO(2)]-liberation. A dominant-negative PPARgamma mutant was transfected in Caco-2 cells to suppress PPARgamma-mediated functions. Antiproliferative effects of resveratrol closely correlate with a dose-dependent increase of endogenous ceramides (p<0.001). Compared to controls the cell-permeable ceramide analogues C2- and C6-ceramide significantly inhibit ODC-activity (p<0.001) in colorectal cancer cells. C6-ceramide further diminished protein levels of protooncogenes c-myc (p<0.05) and ODC (p<0.01), which is strictly related to the ability of ceramides to inhibit cell growth in a time- and dose-dependent manner. These results were further confirmed using inhibitors of sphingolipid metabolism, where only co-incubation with a serine palmitoyltransferase (SPT) inhibitor could significantly counteract resveratrol-mediated actions. These data suggest that the induction of ceramide de novo biosynthesis but not hydrolysis of sphingomyelin is involved in resveratrol-mediated inhibition of ODC. In contrast to the regulation of catabolic spermidine/spermine acetyltransferase by resveratrol, inhibitory effects on ODC occur PPARgamma-independently, indicating independent pathways of resveratrol-action. Due to our findings resveratrol could show great chemopreventive and therapeutic potential in the treatment of colorectal cancers.