N-aminopyrroledione-hydrazonoketene-pyrazolium oxide-pyrazolone rearrangements and pyrazolone tautomerism

Flash vacuum thermolysis (FVT) of 1-(dimethylamino)pyrrole-2,3-diones 5 causes extrusion of CO with formation of transient hydrazonoketenes 7. The transient ketenes 7 are observable in the form of weak bands at 2130 (7a) or 2115 cm(-1) (7b) in the Ar matrix IR spectra resulting from either FVT or photolysis of either 5 or 1,1- dimethylpyrazolium-5- oxides 8, and these absorptions are in excellent agreement with B3LYP/6-31G* frequency calculations. Under FVT conditions the ketenes 7 cyclize to pyrazolium oxides 8, which undergo 1,4-migration of a methyl group to yield 1,4-dimethyl-3-phenylpyrazole-5(4H)-one 9a and 1,4,4-trimethyl-3-phenylpyrazole-5(4H)-one 9b. All three tautomers of 9a have been characterized, viz. the CH form 9a (most stable form in the gas phase, the solid state and solvents of low polarity), the OH form 9a' (metastable solid at room temperature) and the NH form 9a (stable in aprotic dipolar solvents). The isomeric 1,4-dimethyl-5-phenylpyrazole-3(2H)-one 12 tautomerizes to the 3-hydroxypyrazole 12'. The crystal structure of the hydrochloride 14 of 9a'/9a is reported, representing the first structurally characterised example of a protonated 5-hydroxypyrazole.

Synthesis and biological evaluation of mono and bis-naphthalimide derivatives against SH-SY5Y, human brain cancer cells

Dissertação de mestrado em Medicinal Chemistry

Controle químico do crescimento vegetativo de Murraya paniculata

A utilização de inibidores do crescimento de plantas tem sido uma prática interessante para a manutenção de sebes em condições adequadas por períodos mais longos de tempo após a realização da poda. Para se determinar a melhor concentração de hidrazida maleica que promovesse inibição no desenvolvimento da cerca viva de Murraya paniculata, aplicou-se, sob a forma de pulverização, 30 dias depois da poda, MH-30 (sal dietanolamina de 6-hidroxi-3-(2H)-piridazinona) nas dosagens de 500, 750, 1000 e 1250 ppm, além do controle. Com a finalidade de estabelecer as variações promovidas pelo inibidor de crescimento, efetuou-se a poda das plantas 130 dias após a aplicação do regulador de crescimento, determinando-se o peso da materia seca da folhagem cortada. Os resultados obtidos mostraram que MH 1000 e 1250 ppm reduziram significativamente o desenvolvimento das plantas em relação ao controle, sendo que as concentrações de 500 e 750 ppm não promoveram variações no crescimento da folhagem comparativamente às plantas não tratadas. Estes resultados sugerem a possibilidade da utilização da hidrazida maleica como uma prática que poderia substituir o controle mecânico do crescimento na manutenção de sebes, desde que aplicada em concentrações inibitórias ao desenvolvimento mas que não promovam sintomas de fitotoxidade.

Utilização de fito-reguladores de crescimento em morangueiro(Fragaria spp.): influência no ciclo da cultura e na produção final

O presente trabalho, conduzido em área experimental da Escola Superior de Agricultura "Luiz de Queiroz", em Piracicaba, SP., teve como finalidade estudar as influências de diferentes fitoreguladores no ciclo da cultura e produção final, em dois cultivares de morangueiro (Fragaria spp.), 'Campinas' e 'Monte Alegre'. Foram aplicados os fito-reguladores: ácido indolil-3-acetico (IAA), 30 ppm; ácido 2-(3-clorofenoxi) propiônico (CPA), 75 ppm; ácido giberelico (GA3), 30 ppm; cloreto de (2-cloroetil) trimetilamônico (CCC), 1500 ppm; sal potássio de 6-hidroxi-3-(2H) piridazinone (MH), 900 ppm; e ácido succínico-2,2-dimetilhidrazida -(SADH), 900 ppm; sendo que essas dosagens foram subdivididas, e aplicadas em 3 vezes, com intervalo de uma semana, iniciando-se, a 3 semanas após o transplante das plantas de morangueiro para o local definitivo. Através dos estudos realizados, concluiuse que: as maiores produções foram alcançadas com a utilização de GA3, CPA e IAA; o CCC veio logo a seguir, induzindo a plantas menores, mais compactas, mas com frutos médios a grandes; posteriormente, o SADH, e a menor produção foi com MH. Plantas tratadas com GA3, CPA e IAA foram mais precoces na produção de frutos, sendo que GA3 e CPA produziram maior numero de frutos mas de menor peso e volume médios; os produtos CCC, SADH e MH retardaram o inicio de produção. Todos os produtos utilizados, induziram as plantas a continuarem a produzir por mais tempo, em relação às parcelas não tratadas. Com relação aos cultivares estudados, 'Monte Alegre' produziu maior número de frutos que 'Campinas', mas não diferiram entre si com relação à produção total, pois 'Campinas' produziu frutos maiores e mais pesados. 'Campinas' iniciou a produção de frutos antes da 'Monte Alegre' (mais precoce), mas este último continuou a produzir por mais tempo.

Análise quantitativa de crescimento vegetal em cultivares de morangueiro (Fragarta spp.), sob a influência de fito-reguladores de crescimento

O presente trabalho, conduzido em área experimental da Escola Superior de Agricultura "Luiz de Queiroz", em Piracicaba, SP, teve como finalidade estudar as influências de diferentes fito-reguladores no crescimento de cultivares ('Campinas' e 'Monte Alegre') de morangueiro (Fragaria spp·). Foram aplicados os fito-reguladores: ácido indolil 3-acetico (IAA), 30 ppm; ácido 2-(3-clorofenoxi) propiônico (CPA), 75 ppm; ácido giberélico (GA3), 30 ppm; cloreto de (2-cloroetil) trimetil amônio (CCC), 1.500 ppm; sal potássico de 6-hidroxi-3-(2H)-piridazinone (MH), 900 ppm; e ácido succínico-2,2 - dimetilhidrazida (SADH), 900 ppm; sendo que essas dosagens foram subdivididas, e aplicadas em tres vezes, com intervalo de uma semana, iniciando-se, a três semanas após o transplante das plantas de morangueiro para o local definitivo Para ser executada a análise quantitativa de crescimento vegetal dos cultivares estudados, a cada 14 dias, com início uma semana após a aplicação da última sub-dose dos fito-reguladores, e terminando quando as plantas iniciavam a emissão de estolhos, foram colhidas plantas e determinadas a área foliar e peso da matéria seca produzida. Através dos estudos realizados, concluise que os produtos GA3, IAA e CPA conferiram as plantas, um maior. crescimento, pois induziram a uma maior relação parte aérea/sistema radicular (RPAR) , maior índice de área foliar (IAF), maior taxa de produção de matéria seca (TPMS), e maior eficiência de conversão da energia solar (Ec); CCC e SADH induziram a valores médios desses parâmetros, portanto médio crescimento e razoável produção; e, os menores índices de crescimento foram obtidos com MH, portanto reduzindo o crescimento e a produção do morangueiro. A análise de crescimento mostrou que 'Campinas' possui maior taxa de crescimento relativo (TCR), maior taxa de assimilação líquida (TAL), maior taxa de produção de matéria seca (TPMS) e maior eficiência de conversão da energia solar (Ec); e possui menor taxa de crescimento foliar relativo (TCRF) e menor razão de área foliar (RAF), que 'Monte Alegre',sendo que nao houve diferença entre o índice de área foliar (IAF) e relação parte aérea/sistema radicular (RPAR) entre os dois cultivares.

Alteration of brain glycogen turnover in the conscious rat after 5h of prolonged wakefulness.

Although glycogen (Glyc) is the main carbohydrate storage component, the role of Glyc in the brain during prolonged wakefulness is not clear. The aim of this study was to determine brain Glyc concentration ([]) and turnover time (tau) in euglycemic conscious and undisturbed rats, compared to rats maintained awake for 5h. To measure the metabolism of [1-(13)C]-labeled Glc into Glyc, 23 rats received a [1-(13)C]-labeled Glc solution as drink (10% weight per volume in tap water) ad libitum as their sole source of exogenous carbon for a "labeling period" of either 5h (n=13), 24h (n=5) or 48 h (n=5). Six of the rats labeled for 5h were continuously maintained awake by acoustic, tactile and olfactory stimuli during the labeling period, which resulted in slightly elevated corticosterone levels. Brain [Glyc] measured biochemically after focused microwave fixation in the rats maintained awake (3.9+/-0.2 micromol/g, n=6) was not significantly different from that of the control group (4.0+/-0.1 micromol/g, n=7; t-test, P>0.5). To account for potential variations in plasma Glc isotopic enrichment (IE), Glyc IE was normalized by N-acetyl-aspartate (NAA) IE. A simple mathematical model was developed to derive brain Glyc turnover time as 5.3h with a fit error of 3.2h and NAA turnover time as 15.6h with a fit error of 6.5h, in the control rats. A faster tau(Glyc) (2.9h with a fit error of 1.2h) was estimated in the rats maintained awake for 5h. In conclusion, 5h of prolonged wakefulness mainly activates glycogen metabolism, but has minimal effect on brain [Glyc].

Population pharmacokinetics in chronic myeloid leukaemia patients: observations under field-conditions

Introduction: Therapeutic drug monitoring (TDM) of imatinib has been increasingly proposed for chronic myeloid leukaemia (CML) patients, as several studies have found a correlation between trough concentrations (Cmin) >=1000ng/ml and improved response. The pharmacological monitoring project of EUTOS (European Treatment and Outcome Study) was launched to increase the availability of imatinib TDM, standardize labs, and validate proposed Cmin thresholds. Using the collected data, the objective of this analysis was to characterize imatinib Population pharmacokinetics (Pop-PK) in a large cohort of European patients, to quantify its variability and the influence of demographic factors and comedications, and to derive individual exposure variables suitable for further concentration-effect analyses.¦Methods: 4095 PK samples from 2478 adult patients were analyzed between 2006 and 2010 by LC-MS-MS and considered for Pop-PK analysis by NONMEM®. Model building used data from 973 patients with >=2 samples available (2590 samples). A sensitivity analysis was performed using all data. Available comedications (27%) were classified into inducers or inhibitors of P-glycoprotein, CYP3A4/5 and organic-cation-transporter-1 (hOCT-1).¦Results: A one-compartment model with linear elimination, zero-order absorption fitted the data best. Estimated Pop-PK parameters (interindividual variability, IIV %CV) for a 40-year old male patient were: clearance CL = 17.3 L/h (37.7%), volume V = 429L (51.1%), duration of absorption D1 = 3.2h. Outliers, reflecting potential compliance and time recording errors, were taken into account by estimating an IIV on the residual error (35.4%). Intra-individual residuals were 29.1% (proportional) plus ± 84.6 ng/mL (additive). Female patients had a 15.2% lower CL (14.6 L/h). A piece-wise linear effect of age estimated a CL of 18.7 L/h at 20 years, 17.3 L/h at 40 and 13.8 L/h at 60 years. These covariates explained 2% (CL) and 4.5% (V) of IIV variability. No effect of comedication was found. The sensitivity analysis expectedly estimated increased IIV, but similar fixed effect parameters.¦Conclusion: Imatinib PK was well described in a large cohort of CML patients under field conditions and results were concordant with previous studies. Patient characteristics explain only little IIV, confirming limited utility of prior dosage adjustment. As intra-variability is smaller than inter-patient variability, dose adjustment guided by TDM could however be beneficial in order to bring Cmin into a given therapeutic target.

Influência de fitorreguladores de crescimentona produção de estolhosde morangueiro (Fragaria spp.)

O presente trabalho, conduzido no campo experimental do Setor de Horticultura da Escola Superior de Agricultura "Luiz de Queiroz", em Piracicaba (SP), teve como finalidade estudar a influência de diferentes fitorreguladores de crescimento na formação de estolhos em morangueiro (Fragaria spp.), cultivares Campinas e Monte Alegre. Foram aplicados os fitorreguladores: ácidoindolil- 3-acético (IAA), 30 ppm; ácido 2-(3-clorofenoxi) propiônico (CPA), 75 ppm; ácido giberélico (GA3), 30 ppm; cloreto de (2-cloroetil) trimetilamônio (CCC), 1500 ppm; sal potássico de 6-hidroxi-3-(2H) piridazinone (MH), 900 ppm; e ácido succinioo-2,2 dimetilhidrazida (SADH), 900 ppm; sendo que essas doses foram subdivididas, e aplicadas em três vezes, com intervalo de uma semana, iniciando-se a três semanas após o transplante das plantas do morangueiro para o local definitivo. Concluiu-se que, a cultivar Monte Alegre iniciou antes a emissão de estolhos e emitiu maior número deles em comparação com a 'Campinas'. Houve maior emissão de estolhos nas parcelas tratadas com GA3, CPA e IAA, e as que menos produziram estolhos foram as tratadas com MH.

Análise dos compostos voláteis da aguardente de cana por concentração dinâmica do "headspace" e cromatografia gasosa-espectrometria de massas

Os compostos voláteis da aguardente de cana foram extraídos por meio da concentração dinâmica do "headspace" em armadilhas contendo Tenax-TA e analisados por cromatografia gasosa-espectrometria de massas. Cerca de 100 compostos voláteis, com número de carbonos que variavam de 5 a 18, foram detectados. Destes, 22 foram selecionados, sendo 18 ésteres, com base nas suas quantidades no extrato ou nas suas características sensoriais obtidas na literatura. Os compostos presentes em maiores quantidades foram o 3-metil-1-butanol (álcool isoamílico), 1,1-dietoxi-etano (acetaldeído dietil acetal) e os ésteres acetato de 3-metilbutila, hexanoato de etila, octanoato de etila, decanoato de etila e dodecanoato de etila. Dentre os compostos identificados em menor quantidade, destacou-se, devido a sua natureza química, o composto sulfurado 4,5-de-hidro-2-metil-3(2H)-tiofenona. Esta é a primeira vez que este e outros compostos voláteis são reportados em aguardente de cana. Conclui-se que a metodologia empregada neste trabalho permitiu a identificação de compostos voláteis da fração C5-C18, que potencialmente contribuem para o aroma da aguardente de cana.

Bending, twisting, and breaking CuCN chains to produce framework materials: the reactions of CuCN with alkali-metal halides

The reactions of the low-temperature polymorph of copper(I) cyanide (LT-CuCN) with concentrated aqueous alkali-metal halide solutions have been investigated. At room temperature, KX (X = Br and I) and CsX (X = Cl, Br, and I) produce the addition products K[Cu-2(CN)(2)Br](H2O)-H-. (I), K-3[Cu-6(CN)(6)I-3](.)2H(2)O (II), Cs[Cu-3(CN)(3)Cl] (III), Cs[Cu-3(CN)(3)Br] (IV), and Cs-2[Cu-4(CN)(4)I-2](H2O)-H-. (V), with 3-D frameworks in which the -(CuCN)- chains present in CuCN persist. No reaction occurs, however, with NaX (X = Cl, Br, I) or KCl. The addition compounds, I-V, reconvert to CuCN when washed. Both low- and high-temperature polymorphs of CuCN (LT- and HT-CuCN) are produced, except in the case of Cs[Cu-3(CN)(3)Cl] (III), which converts only to LT-CuCN. Heating similar AX-CuCN reaction mixtures under hydrothermal conditions at 453 K for 1 day produces single crystals of I-V suitable for structure determination. Under these more forcing conditions, reactions also occur with NaX (X = Cl, Br, I) and KCl. NaBr and KCl cause some conversion of LT-CuCN into HT-CuCN, while NaCl and NaI, respectively, react to form the mixed-valence Cu(I)/Cu(II) compounds [Cu-II(OH2)(4)][Cu-4(I)(CN)(6)], a known phase, and [Cu-II(OH2)(4)][Cu-4(I)(CN)(4)I-2] (VI), a 3-D framework, which contains infinite -(CuCN)- chains. After 3 days of heating under hydrothermal conditions, the reaction between KI and CuCN produces [Cu-II(OH2)(4)][Cu-2(I)(CN)I-2](2) (VII), in which the CuCN chains are broken into single Cu-CN-Cu units, which in turn are linked into chains via iodine atoms and then into layers via long Cu-C and Cu-Cu interactions.

Síntese do Poli (ácido láctico) por policondensação direta utilizando um planejamento fatorial

The environmental impact caused by the disposal of non-biodegradable polymer packaging on the environment, as well as the high price and scarcity of oil, caused increase of searches in the area of biodegradable polymers from renewable resources were developed. The poly (lactic acid) (PLA) is a promising polymer in the market, with a large availability of raw material for the production of its monomer, as well as good processability. The aimed of this study was synthesis PLA by direct polycondesation of lactic acid, using the tool of experimental design (DOE) (central composite rotatable design (CCRD)) to optimize the conditions of synthesis. The polymer obtained was characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), viscosimetric analysis, differential scanning calorimeter (DSC) and size exclusion chromatography (SEC). The results confirmed the formation of a poly (lactic acid) semicrystalline in the syntheses performed. Through the central composite rotatable design was possible to optimize the crystallization temperature (Tc) and crystallinity degree (Xc). The crystallization temperature maximum was found for percentage of catalyst around the central point (0,3 (%W)) and values of time ranging from the central point (6h) to the upper level (+1) (8h). The crystallization temperature maximum was found for the total synthesis time of 4h (-1) and percentage of catalyst 0,1(W%) (-1). The results of size exclusion chromatography (SEC) showed higher molecular weights to 0,3 (W%) percent of catalyst and total time synthesis of 3,2h

Thermal studies of solid 4-chlorobenzylidenepyruvates of heavy lanthanides(III) and yttrium(III)

Solid-state compounds of general formula LnL(3).2H(2)O, where Ln is heavier trivalent lanthanides and yttrium, L is 4-chlorobenzylidenepyruvate have been synthetised.On heating these compounds decompose in steps. They lose the hydration water in the first step and the thermal decomposition of the anhydrous compounds occurs with the formation of oxochloride (Eu, Gd); mixture of oxide and oxochloride that decrease with increasing of atomic number of metal (Tb-Tm); or oxide (Yb, Lu, Y) as final residue, up to 900degreesC. The dehydration enthalpies found for terbium, holmium, ytterbium and yttrium compounds were: 34.93, 42.40, 57.39 and 62.24 kJ mol(-1), respectively.

Ebselen and cytokine-induced nitric oxide synthase expression in insulin-producing cells

Interleukin-1 (IL-1) may be a mediator of β-cell damage in insulin-dependent diabetes mellitus (IDDM). The IL-1 mechanism of action on insulin-producing cells probably includes activation of the transcription nuclear factor κB (NF-κB), increased transcription of the inducible form of nitric oxide synthase (iNOS) and the subsequent production of nitric oxide (NO). Reactive oxygen intermediates, particularly H2O2, have been proposed as second messengers for NF-κB activation. In the present study, we tested whether ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one), a glutathione peroxidase mimicking compound, could counteract the effects of IL-1β, H2O2 and alloxan in rat pancreatic islets and in the rat insulinoma cell line RINm5F (RIN cells). Some of these experiments were also reproduced in human pancreatic islets. Ebselen (20 μM) prevented the increase in nitrite production by rat islets exposed to IL-1β for 6 hr and induced significant protection against the acute inhibitory effects of alloxan or H2O2 exposure, as judged by the preserved glucose oxidation rates. However, ebselen failed to prevent the increase in nitrite production and the decrease in glucose oxidation and insulin release by rat islets exposed to IL-1β for 24 hr. Ebselen prevented the increase in nitrite production by human islets exposed for 14 hr to a combination of cytokines (IL-1β, tumor necrosis factor-α and interferon-γ). In RIN cells, ebselen counteracted both the expression of iNOS mRNA and the increase in nitrite production induced by 6 hr exposure to IL-β but failed to block IL-1β-induced iNOS expression following 24 hr exposure to the cytokine. Moreover, ebselen did not prevent IL-1β-induced NF-κB activation. As a whole, these data indicate that ebselen partially counteracts cytokine-induced NOS activation in pancreatic β-cells, an effect not associated with inhibition of NF-κB activation.

Chorismate synthase: An attractive target for drug development against orphan diseases

The increase in incidence of infectious diseases worldwide, particularly in developing countries, is worrying. Each year, 14 million people are killed by infectious diseases, mainly HIV/AIDS, respiratory infections, malaria and tuberculosis. Despite the great burden in the poor countries, drug discovery to treat tropical diseases has come to a standstill. There is no interest by the pharmaceutical industry in drug development against the major diseases of the poor countries, since the financial return cannot be guaranteed. This has created an urgent need for new therapeutics to neglected diseases. A possible approach has been the exploitation of the inhibition of unique targets, vital to the pathogen such as the shikimate pathway enzymes, which are present in bacteria, fungi and apicomplexan parasites but are absent in mammals. The chorismate synthase (CS) catalyses the seventh step in this pathway, the conversion of 5-enolpyruvylshikimate-3-phosphate to chorismate. The strict requirement for a reduced flavin mononucleotide and the anti 1,4 elimination are both unusual aspects which make CS reaction unique among flavin-dependent enzymes, representing an important target for the chemotherapeutic agents development. In this review we present the main biochemical features of CS from bacterial and fungal sources and their difference from the apicomplexan CS. The CS mechanisms proposed are discussed and compared with structural data. The CS structures of some organisms are compared and their distinct features analyzed. Some known CS inhibitors are presented and the main characteristics are discussed. The structural and kinetics data reviewed here can be useful for the design of inhibitors. © 2007 Bentham Science Publishers Ltd.

Structure of the HIV-1 integrase catalytic domain complexed with an inhibitor: A platform for antiviral drug design

HIV integrase, the enzyme that inserts the viral DNA into the host chromosome, has no mammalian counterpart, making it an attractive target for antiviral drug design. As one of the three enzymes produced by HIV, it can be expected that inhibitors of this enzyme will complement the therapeutic use of HIV protease and reverse transcriptase inhibitors. We have determined the structure of a complex of the HIV-1 integrase core domain with a novel inhibitor, 5ClTEP, 1-(5-chloroindol-3-yl)-3-hydroxy-3-(2H-tetrazol-5-yl)-propenone, to 2.1-Å resolution. The inhibitor binds centrally in the active site of the integrase and makes a number of close contacts with the protein. Only minor changes in the protein accompany inhibitor binding. This inhibitor complex will provide a platform for structure-based design of an additional class of inhibitors for antiviral therapy.