RESUMO
In this study, we describe the hydrogenation of indolizines derived from Morita-Baylis-Hillman adducts. We demonstrate that functionalized tetrahydroindolizines and indolizidines can be prepared selectively, at low pressure, by simply adjusting the acidity of the medium. Using this simple and straightforward strategy, substituted tetrahydroindolizines and indolizidines were obtained diastereoselectively in high yield.
Assuntos
Indolizidinas/química , Indolizidinas/síntese química , Indolizinas/química , Indolizinas/síntese química , Catálise , Hidrogenação , Estrutura Molecular , EstereoisomerismoRESUMO
A variety of C-2 and C-5 difunctionalized indolizines have been prepared through the reaction of 1-ester-substituted indolizines with organometallic bases followed by a reaction with different electrophiles. Metalation takes place under mild conditions allowing the isolation of a number of difunctionalized indolizines in good yields. The regioselectivity of the reaction appears to be governed by the nature of the base and electrophile.
Assuntos
Indolizinas/química , Indolizinas/síntese química , Compostos Organometálicos/química , Paládio/química , Catálise , Ésteres , Estrutura Molecular , EstereoisomerismoRESUMO
Prosopis juliflora is a shrub largely used for animal and human consumption. However, ingestion has been shown to induce intoxication in animals, which is characterized by neuromuscular alterations induced by mechanisms that are not yet well understood. In this study, we investigated the cytotoxicity of a total alkaloid extract (TAE) and one alkaloid fraction (F32) obtained from P. juliflora leaves to rat cortical neurons and glial cells. Nuclear magnetic resonance characterization of F32 showed that this fraction is composed of a mixture of two piperidine alkaloids, juliprosopine (majority constituent) and juliprosine. TAE and F32 at concentrations between 0.3 and 45 µg/mL were tested for 24 h on neuron/glial cell primary cocultures. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test revealed that TAE and F32 were cytotoxic to cocultures, and their IC50 values were 31.07 and 7.362 µg/mL, respectively. Exposure to a subtoxic concentration of TAE or F32 (0.3-3 µg/mL) induced vacuolation and disruption of the astrocyte monolayer and neurite network, ultrastructural changes, characterized by formation of double-membrane vacuoles, and mitochondrial damage, associated with changes in ß-tubulin III and glial fibrillary acidic protein expression. Microglial proliferation was also observed in cultures exposed to TAE or F32, with increasing levels of OX-42-positive cells. Considering that F32 was more cytotoxic than TAE and that F32 reproduced in vitro the main morphologic and ultrastructural changes of "cara torta" disease, we can also suggest that piperidine alkaloids juliprosopine and juliprosine are primarily responsible for the neurotoxic damage observed in animals after they have consumed the plant.
Assuntos
Alcaloides/farmacologia , Citoplasma/efeitos dos fármacos , Indolizinas/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Neuroglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Prosopis/química , Alcaloides/química , Alcaloides/isolamento & purificação , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Citoplasma/patologia , Relação Dose-Resposta a Droga , Indolizinas/química , Indolizinas/isolamento & purificação , Estrutura Molecular , Neuroglia/patologia , Neurônios/patologia , Folhas de Planta/química , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
A versatile and concise approach for the stereoselective synthesis of mono-, di-, and trihydroxylated indolizidines is presented in four to six steps from Cbz-prolinal and a diazophosphonate. The key steps involved a Wolff rearrangement, followed by a stereoselective dihydroxylation/epoxidation reaction, from an α,ß-unsaturated diazoketone. The strategy also permits extension to the synthesis of many natural hydroxylated indolizidine alkaloids as demonstrated in the formal synthesis of pumiliotoxin 251D.
Assuntos
Alcaloides/química , Alcaloides/síntese química , Compostos de Diazônio/química , Indolizidinas/química , Indolizinas/química , Indolizinas/síntese química , Hidroxilação , Estrutura Molecular , EstereoisomerismoRESUMO
Toads belonging to the genus Melanophryniscus contain toxic alkaloids in their skin. From six locations in south-eastern Uruguay 81 specimens of Melanophryniscusmontevidensis were collected. In whole animal methanolic extracts of individual specimens, alkaloids of the pumiliotoxin (PTX) group and indolizidines were identified by gas chromatography/mass spectrometry; the predominant component PTX 251D was assayed quantitatively. The PTX-content of the various toad populations was found to be highly variable among individual specimens as well as among the populations. Very high levels of PTX 251D were detected in toads of the western part of the collection area, whereas very low levels of this alkaloid were assayed in toads near the Brazilian border. Remarkably high concentrations of the non-alkaloid hydroquinone were found to be present in all toads. The analysis of extracts from 125 arthropod samples (Arachnida and Insecta, including termites, ants and beetles), which may represent a potential food source, revealed no alkaloids of the PTX group.
Assuntos
Alcaloides/isolamento & purificação , Venenos de Anfíbios/isolamento & purificação , Secreções Corporais/química , Bufonidae , Indolizinas/isolamento & purificação , Pele/química , Alcaloides/química , Venenos de Anfíbios/química , Animais , Fezes/química , Cromatografia Gasosa-Espectrometria de Massas , Indolizinas/química , Insetos/química , Microscopia Eletrônica de Varredura , Pele/anatomia & histologia , UruguaiRESUMO
Free energy perturbation studies have been performed on Glucoamylase II (471) from Aspergillus awamori var. X100 complexed with three different inhibitors: (+)lentiginosine, (+)(1S,2S,7R,8aS) 1,2,7-trihydroxyindolizidine, (+)(1S,2S,7S,8aS) 1,2,7-trihydroxyindolizidine and the inactive compound (+)(1S,7R,8aS)-1,7-dihydroxyindolizidine. Molecular dynamic simulations were carried out using a recently developed procedure for fast Free Energy Perturbation calculations. In this procedure only a sphere of 1.8 nm around the central atom of the inhibitor is considered in the calculations. Crystallographic restraints are applied over this reduced system using a generated electron density map. The obtained values for the free energy differences agree with experimental data showing the importance of fast calculations in drug design even when the crystallographic structure of the complex is not available. As the method uses only the crystallographic structure of the receptor, it is possible to test the possible efficiency of even still not synthesised ligands, making the pre-selection of compounds much easy and faster.
Assuntos
Alcaloides/química , Inibidores Enzimáticos/química , Glucana 1,4-alfa-Glucosidase/química , Indolizinas/química , Termodinâmica , Alcaloides/farmacologia , Aspergillus/enzimologia , Cristalização , Inibidores Enzimáticos/farmacologia , Glucana 1,4-alfa-Glucosidase/antagonistas & inibidores , Indolizinas/farmacologia , Ligantes , Modelos Químicos , Modelos Moleculares , Conformação Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
The structure of alkaloid 223A (1), the first member of a new class of amphibian alkaloids, purified by HPLC from a skin extract of a Panamanian population of the frog Dendrobates pumilio Schmidt (Dendrobatidae) has been established as (5R,6S,8R,9S)- or (5S,6R,8S,9R)-6,8-diethyl-5-propylindolizidine, based on GC-MS, GC-FTIR, and 1H-NMR spectral studies. Three higher homologs of 223A, namely alkaloids 237L (2), 251M (3), and 267J (4), have been detected in other extracts, and tentative structures are proposed.