Síntese e avaliação da atividade fitotóxica de lactonas derivadas do 2,4-dimetil-8-oxabiciclo[3.2.1]-oct-6-en-3-ona

The alkene 2,4-dimethyl-8-oxabicyclo[3.2.1]-oct-6-en-3-one (3) was converted to 1,3,10-trimethyl-8-oxabicyclo[5.3.0]-dec-3-ene-2,9-dione (7) and 1,3-dimethyl-8-oxabicyclo[5.3.0]-dec-3-ene-2,9-dione (8) with a 55% overall yield in both cases. Lactones (7) and (8) were converted in two steps to 1,3,4-trimethyl-13-methylene-6-oxatricyclo[8.3.0.0(3,7)]-trideca-2,5,12-trione (12) (63%) and 1,3-dimethyl-13-methylene-6-oxatricycle[8.3.0.0(3,7)]-trideca-2,5,12-trione (13) (45% from 8). The effect of lactones (7), (8), (12), (13) and the intermediates (5) and (6), at the concentration of 250 mug mL-1, on the growth of Cucumis sativus L. and Sorghum bicolor L. was evaluated. The best results were observed for lactone (13) that caused 100% inhibition on the root growth of C. sativus and lactone (12) that inhibited 90% of the root growth for S. bicolor.

Ultrastructural alterations of intracellular stages and effects on blood forms of Trypanosoma cruzi induced in vivo by 2-amino-5-(1-methyil-5-nitro-2-imidazolyl)-1,3,4 - Thiadiazole

An electron microscopy study shows that the administration of a single dose (500 mg/kg, p.o.) of 2-amino-5-(1-methyl-5-nitro-2-imidazolyl)-1, 3, 4-thiadiazole induces in mice infected with Trypanosoma cruzi results in degenerative lesions of the intracellular stages. Ultrastructural alterations are detected as early as 6 hours after the drug administration and destruction of the parasites occurs within 18 - 36 hours. Trypomastigotes are cleared from the bloodstream 4 to 6 hours after treatment. The combined effect on both developmental stages is apparently responsible for the in vivo ejfects of this drug which is the most active drug ever tested in our laboratory in experimental Chagas' disease.

In Vitro and in Vivo Assays of 3,5-Disubstituted-Tetrahydro-2H-1,3,5-Thiadiazin-2-Thione Derivatives against Trypanosoma cruzi

Cytotoxicity assays of 24 new 3,5-disubstituted-tetrahydro-2H-1,3,5-thiadiazin-2-thione derivatives were performed. The 17 compounds with higher anti-epimastigote activity and lower cytotoxicity were, thereafter, screened against amastigote of Trypanosoma cruzi. Out of these 17 derivatives S-2d was selected to be assayed in vivo, because of its remarkable trypanocidal properties. To determine toxicity against J774 macrophages, a method based on quantification of cell damage, after 24 h, was used. Cell respiration, an indicator of cell viability, was assessed by the reduction of MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] to formazan. Anti-amastigote activity was estimated after 48 h by microscopic counts of May Grünwald-Giemsa-stained monolayers. Nifurtimox and benznidazole were used as reference drugs. For the in vivo experiences, mice were infected with 10(4) blood trypomastigotes and then treated during 15 days with S-2d or nifurtimox by oral route. All of the compounds were highly toxic at 100 µg/ml for macrophages and a few of them maintained this cytotoxicity even at 10 µg/ml. Of the derivatives assayed against amastigotes 3k and S-2d showed an interesting activity, that was held even at 1µg/ml. It is demonstrated that the high anti-epimastigote activity previously reported is mainly due to the non-specific toxicity of these compounds. In vivo assays assessed a reduction of parasitemia after administration of S-2d to infected mice.

Síntese de novos herbicidas derivados do 1,2alfa,4alfa,5-tetrametil-8-oxabiciclo[3.2.1]oct-6-en-3-ona

In this paper we report the synthesis of biologically active compounds through a [3+4] cycloaddition reaction to produce the main frame structure, followed by several conventional transformations. The 1,2alpha,4alpha,5-tetramethyl-8-oxabicyclo[3.2.1]oct-6-en-3-one (11) obtained from a [3+4] cycloaddition reaction was converted into 1,2alpha,4alpha,5-tetramethyl-6,7-exo-isopropylidenedioxi-8 -oxabicyclo[3.2.1]octan-3-one (13) in 46% yield. This was further converted into the alcohols 1,2alpha,4alpha,5-tetramethyl-6,7-exo-isopropylidenedioxi-8-oxabicyclo[3.2.1]octan-3 alpha-ol (14), 1,2alpha,4alpha,5-tetramethyl-6,7-exo-isopropylidenedioxi-8 -oxabicyclo[3.2.1]octan-3beta-ol (15), 1,2alpha,4alpha,5-tetramethyl-3-butyl-6,7-exo-isopropylidenedioxi-8-oxabicyclo[3.2.1]octan-3 alpha-ol (17), 1,2alpha,4alpha,5-tetramethyl-3-hexyl-6,7-exo-isopropylidenedioxi-8-oxabicyclo[3.2.1]octan-3 alpha-ol (18) and 1,2alpha,4alpha,5-tetramethyl-3-decyl-6,7-exo-isopropylidenedioxi-8-oxabicyclo[3.2.1]octan-3 alpha-ol (19). Dehydration of 17, 18 and 19 with thionyl chloride in pyridine resulted in the alkenes 20, 21 and 22 in ca. 82% - 89% yields from starting alcohols. The herbicidal activity of the compounds synthesized was evaluated at a concentration of 100 µg g-1. The most active compound was 21 causing 42,7% inhibition against Cucumis sativus L.

Síntese de novas fitotoxinas derivadas do 8-oxabiciclo[3.2.1]oct-6-en-3-ona

The [4+3] cycloaddition was utilized in order to prepare 8-oxabicyclo[3.2.1]oct-6-en-3-one (1) derivatives. The correspondent acetonide 6 was converted into several alcohols (11-16). Addition of aryllithium reagents to 6 resulted in 3-(2-fluorophenyl)-6,7-exo-isopropylidenedioxy -8-oxabicyclo[3.2.1]octan-3alpha-ol (11, 72%) and 3-(2,4-dimethoxyphenyl)-6,7-exo-isopropylidenedioxy-8-oxabicyclo[3.2.1]octan -3alpha-ol (16, 20%). The 3-butyl-6,7-exo-isopropylidenedioxy-8-oxabicyclo[3.2.1]octan-3 alpha-ol (15, 56%) was obtained through a Grignard reaction. Reduction of 6 resulted in 6,7-exo-isopropylidenedioxy-8-oxabicyclo[3.2.1]octan-3 beta-ol (7, 62%) and 6,7-exo-isopropylidenedioxy-8-oxabicyclo[3.2.1]octan-3 alpha-ol (8, 20%). The alcohols were treated with thionyl chloride in pyridine, and the corresponding alkenes were obtained with 31-80% yield. The effect of these compounds on the development of radicle and aerial parts of Sorghum bicolor was evaluated.

Antifungal derivatives from Piper mollicomum and P. lhotzkyanum (Piperaceae)

Bioguided fractionation of the extracts from leaves of Piper mollicomum and Piper lhotzkyanum against the fungi Cladosporium cladosporioides and C. sphaerospermum afforded seven bioactive compounds, four being chromenes: methyl 2,2-dimethyl-2H-chromene-6-carboxylate, methyl 8-hydroxy-2,2-dimethyl-2H-chromene-6-carboxylate, 2-methyl-2-[4'-methyl-3'-pentenyl]-2H-1-benzopyran-6-carboxylic acid, 2,2-dimethyl-2H-chromene-6-carboxylic acid, one a dihydrochalcone: 2',6'-dihydroxy-4'-methoxydihydrochalcone, and two flavanones: 7-methoxy-5,4'-dihydroxy-flavanone and 7,4'-dimethoxy-5-hydroxy-flavanone. The structures of the bioactive isolated derivatives were elucidated by interpretation of their NMR data [¹H and 13C (BBD, DEPT 135º)], and mass spectral data as well as by comparison with data described in the literature.

Fitotoxicidade de novos álcoois e alquenos derivados do 2alfa,4alfa-dimetil-8-oxabiciclo[3.2.1]oct-6-en-3-ona

A reação de cicloadição [4+3] entre o furano e o cátion oxialílico, gerado in situ a partir da 2,4-dibromopentan-3-ona, forneceu o 2alfa,4alfa-dimetil-8-oxabiciclo[3.2.1]oct-6-en-3-ona (1). A oxidação catalítica do oxabiciclo 1 com tetróxido de ósmio em presença de peróxido de hidrogênio em excesso levou à formação do acetonídeo 10, a partir do qual foram obtidos os álcoois 2, 11-15, com rendimentos de 23-86%. O tratamento dos álcoois 11-13 com cloreto de tionila, em presença de piridina, resultou nos respectivos alquenos 17 (94%), 18 (89%) e 19 (80%). A atividade herbicida dos compostos foi avaliada sobre o desenvolvimento do sistema radicular de Sorghum bicolor L. e Cucumis sativus L., nas concentrações de 100 e 250 ppm.

Antagonismo das associações de clodinafop-propargyl com metsulfuron-methyl e 2,4-D no controle de azevém (Lolium multiflorum)

Em geral, a eficiência de herbicidas inibidores da ACCase é reduzida quando da aplicação em conjunto com herbicidas latifolicidas. Dois experimentos - em casa de vegetação e campo - objetivaram determinar a existência de antagonismo nas associações de clodinafop-propargyl a metsulfuron-methyl ou 2,4-D, para controle de azevém anual. Em casa de vegetação, o delineamento foi o completamente casualizado, com 21 tratamentos compostos pela aplicação de clodinafop (0, 3, 6, 12, 24, 48 e 96 g ha-1) isolado ou em mistura com metsulfuron-methyl (2 e 4 g ha-1) ou 2,4-D (470 g ha-1). Em campo, o delineamento foi de blocos casualizados, com 12 tratamentos, arranjados em fatorial 6 x 2, composto pelos níveis de clodinafop-propargyl (0, 3, 6, 12, 24, 48 e 96 g ha¹) isolado ou em mistura com metsulfuron-methyl (2 g ha-1). A avaliação visual de controle, em casa de vegetação, revelou I50 das misturas de clodinafop-propargyl + metsulfuron-methyl (2 e 4 g ha-1) ou clodinafop-propargyl + 2,4-D (470 g ha-1), respectivamente, 33, 84 e 151% superiores ao de clodinafop-propargyl isolado. Já para matéria verde de azevém, o I50 das misturas supracitadas foi, respectivamente, 119, 244 e 72% superior ao de clodinafop-propargyl isolado. Em campo, ocorreu redução da matéria verde de azevém com a elevação dos níveis de clodinafop-propargyl isolado, mas não houve variação da matéria verde com a elevação dos níveis de clodinafop-propargyl, em associação a metsulfuron-methyl. Os resultados evidenciam a existência de antagonismo entre clodinafop-propargyl e os herbicidas metsulfuron-methyl e 2,4-D. São feitas considerações sobre as possíveis vantagens da aplicação dos herbicidas em mais de uma operação de controle, em comparação à associação entre graminicidas e latifolicidas.

Anxiolytic-like effects of 4-phenyl-2-trichloromethyl-3H-1,5-benzodiazepine hydrogen sulfate in mice

The pharmacological effects of 4-phenyl-2-trichloromethyl-3H-1,5-benzodiazepine hydrogen sulfate (PTMB), a novel synthetic benzodiazepine, were examined in mice. In the elevated plus-maze test of anxiety, 0.3-1 mg/kg diazepam ip (F(3,53) = 3.78; P<0.05) and 1-10 mg/kg PTMB ip increased (F(5,98) = 3.26; P<0.01), whereas 2 mg/kg picrotoxin ip decreased (F(3,59) = 8.32; P<0.001) the proportion of time spent in the open arms, consistent with an anxiolytic action of both benzodiazepines, and an anxiogenic role for picrotoxin. In the holeboard, 1.0 mg/kg diazepam ip increased (F(3,54) = 2.78; P<0.05) and 2 mg/kg picrotoxin ip decreased (F(3,59) = 4.69; P<0.01) locomotor activity. Rotarod assessment revealed that 1 mg/kg diazepam ip and 3, 10 and 30 mg/kg PTMB ip produced significant motor incoordination compared to vehicle control (F(4,70) = 7.6; P<0.001). These data suggest that the recently synthesized PTMB compound possesses anxiolytic activity and produces motor incoordination similar to those observed with diazepam.

Fludarabine induces apoptosis in chronic lymphocytic leukemia - the role of P53, Bcl-2, Bax, Mcl-1, and Bag-1 proteins

The expression of P53, Bcl-2, Bax, Bag-1, and Mcl-1 proteins in CD5/CD20-positive B-chronic lymphocytic leukemia (B-CLL) cells from 30 typical CLL patients was evaluated before and after 48 h of incubation with 10-6 M fludarabine using multiparametric flow cytometric analysis. Protein expression was correlated with annexin V expression, Rai modified clinical staging, lymphocyte doubling time, and previous treatment. Our main goal was to determine the predictive value of these proteins in CLL cells in terms of disease evolution. Bcl-2 expression decreased from a median fluorescence index (MFI) of 331.71 ± 42.2 to 245.81 ± 52.2 (P < 0.001) after fludarabine treatment, but there was no difference between viable cells (331.57 ± 44.6 MFI) and apoptotic cells (331.71 ± 42.2 MFI) before incubation (P = 0.859). Bax expression was higher in viable cells (156.24 ± 32.2 MFI) than in apoptotic cells (133.56 ± 35.7 MFI) before incubation, probably reflecting defective apoptosis in CLL (P = 0.001). Mcl-1 expression was increased in fludarabine-resistant cells and seemed to be a remarkable protein for the inhibition of the apoptotic process in CLL (from 233.59 ± 29.8 to 252.04 ± 35.5; P = 0.033). After fludarabine treatment, Bag-1 expression was increased in fludarabine-resistant cells (from 425.55 ± 39.3 to 447.49 ± 34.5 MFI, P = 0.012), and interestingly, this higher expression occurred in patients who had a short lymphocyte doubling time (P = 0.022). Therefore, we could assume that Bag-1 expression in such situation might identify CLL patients who will need treatment earlier.

Prenylated flavonoids from maclura tinctoria fruits

A phytochemical investigation of Maclura tinctoria fruits yielded five flavonoids, including one prenylated flavonol (licoflavonol) and four prenylated isoflavones (wighteone, derrone, alpinum isoflavone, and 6-(2,2-dimethyl-2H-chromen-6-yl)-2-(1-hydroxy-1-methylethyl)-2,3-dihydro-5H-furo 1;3,2-g]chromen-5-one). The structures of the isolates were established by analyzing their spectroscopic data. Compound 6-(2,2-dimethyl-2H-chromen-6-yl)-2-(1-hydroxy-1-methylethyl)-2,3-dihydro-5H-furo 1;3,2-g]chromen-5-one is new and the other isolates are described for the first time in this species.

Perfil hematológico de cabras Saanen e mestiças (1/2 Saanen e 1/2 Anglo-nubiana) criadas em clima tropical do Ceará

Objetivou-se verificar a influência das condi1;ões climáticas sobre o perfil hematológico de cabras Saanen e mesti1;a (1/2 Saanen x 1/2 Anglo-nubiana), bem como determinar valores de referência para esses animais criados no Ceará. Foram utilizadas 30 cabras que tiveram o sangue coletado mensalmente durante a época chuvosa (fevereiro a maio) e seca (agosto a novembro) para realiza1;ão do eritrograma e leucograma. As médias foram comparadas pelo teste t-Student e Mann Whitney, quando constatada distribui1;ão paramétrica e não paramétrica dos dados, respectivamente, com signific6;ncia quando p<0,05. Procedeu-se ainda um estudo de correla1;ões simples de Pearson dos par6;metros hematológicos com variáveis ambientais e fisiológicas. O número de hemácias foi maior em cabras Saanen e na época chuvosa, enquanto que o hematócrito foi maior na época seca (p<0,05). Os leucócitos e linfócitos foram maiores em cabras mesti1;as nas duas épocas (p<0,05). Nos dois genótipos, os leucócitos e linfócitos foram maiores na época seca e os neutrófilos segmentados maiores na época chuvosa (p<0,05). Os demais par6;metros não diferiram (p>0,05). As hemácias e neutrófilos segmentados apresentaram uma correla1;ão negativa com a temperatura ambiente, porém positiva com a umidade do ar e a temperatura retal (p<0,05). O hematócrito correlacionou-se positivamente com a temperatura ambiente e frequência respiratória (p<0,05). Os leucócitos e linfócitos mostraram uma correla1;ão negativa com a temperatura retal (p<0,05). Conclui-se, portanto, que fêmeas Saanen sofrem mais influência das varia1;ões climáticas e a época chuvosa tem maior impacto negativo sobre os par6;metros hematológicos. Os valores obtidos poderão servir como referência para esses genótipos no Ceará.

Metabólitos secundários de Esenbeckia almawillia Kaastra (Rutaceae)

The phytochemical investigation of the roots of E. almawillia is reported for the first time. Chromatographic fractionation of the methanol extract allowed the isolation of the alkaloids 3,3-diisopentenyl-N-methyl-2,4-quinoldione (1), maculine (2) and 3'-methoxygraveoline (3), (E)-N-isobutyl-3-methoxy-4,5-methylenedioxicinnamoyl amide (4), the flavones gardenine B (5) and nevadensin (6), and the sesquiterpene intermediol (7). Structure elucidation was based on the analysis of their spectrometric data (uni- and bidimensional ¹H and 13C NMR, MS and IR) and comparison with literature data. Compounds 3-7 are being reported as constituents of Esenbeckia species for the first time.

Condiciones sociodemograficas y estado nutricional de niños menores de un año en areas periféricas de Guadalajara, México

Se objetivó determinar la proporción de niños menores de un año con peso inferior al mínimo adecuado para su edad, identificar factores de índole sociodemográfica que pudieran estar asociados a tal problemática, y estudiar la importancia sociosanitaria de los mismos, en áreas periféricas de la zona metropolitana de Guadalajara (ZMG), México. Se estudió una muestra probabilística, y representativa de niños menores de un año, nacidos entre el 1.5.1990 y 30.4.1991, e hijos de madres derechohabientes del Instituto Mexicano del Seguro Social, en Tlaquepaque y Tonalá, municipios conurbados con Guadalajara, segunda ciudad en importancia de México. La evaluación ponderal de los infantes se realizó a partir de las tablas que con tal fin ha elaborado el Centro Latinoamericano de Perinatología. Mediante el empleo de la regresión logística se estimaron Odds Ratios (OD), con intervalos de confianza (IC) del 90%. El modelo hallado fue ajustado mediante el estadístico H*. Se calculó el riesgo atribuíble poblacional (RAP), y la probabilidad de que un niño no alcanzara el peso mínimo adecuado (PMA) para su edad en presencia o ausencia de los factores de riesgo identificados. Los resultados muestran que casi la quinta parte de los lactantes estudiados no alcanzan el PMA. Se evidenció la asociación existente entre la edad de la madre menor de 20 años (OR= 2,53, IC 1,03-6,22) y la pertenencia materna al grupo social "obrero" (OR= 2,28,IC 1,01-5,21) con que el infante no alcance el PMA y la transcendencia social de tales factores (RAP= 26,4% y 36,7%, respectivamente). En presencia de todos los factores analizados, la probabilidad de que un infante no alcance el PMA, es 0,85, y en particular, en presencia solo de los factores de riesgo identificados, esta probabilidad es de 0,41. Esta información brinda pautas a los servicios de salud para diseñar acciones apropriadas dirigidas a grupos de población específicos con vistas a mejorar el estado nutricional de la población infantil.