RESUMEN
The study of marine toxins in shellfish is of the utmost importance to ensure people's food safety. Marine toxins in shellfish and microalgae in the water column off the south-central coast of Chile (36°â43° S) were studied in a network of 64 stations over a 14-month period. The relative abundance of harmful species Alexandrium catenella, Alexandrium ostenfeldii, Protoceratium reticulatum, Dinophysis acuminata, Dinophysis acuta, Pseudo-nitzschia seriata group and P. delicatissima group was analyzed. The detection and quantification of lipophilic toxins and domoic acid (DA) in shellfish was determined by UHPLC-MS/MS, and for Paralytic Shellfish Toxins (PSTs) by HPLC-FD with post-column oxidation, while for a culture of A. ostenfeldii a Hylic-UHPLC-MS/MS was used. Results showed that DA, gonyautoxin (GTX)-2, GTX-3 and pectenotoxin (PTX)-2 were detected below the permitted limits, while Gymnodimine (GYM)-A and 13-desmethylespirolide C (SPX-1) were below the limit of quantitation. According to the distribution and abundance record of microalgae, DA would be associated to P. seriata and P. delicatissima-groups, PTX-2 to D. acuminata, and GTX-2, GTX-3, GYM-A, and SPX-1 to A. ostenfeldii. However, the toxin analysis of an A. ostenfeldii culture from the Biobío region only showed the presence of the paralytic toxins C2, GTX-2, GTX-3, GTX-5 and saxitoxin, therefore, the source of production of GYM and SPX is still undetermined.
Asunto(s)
Dinoflagelados , Compuestos Heterocíclicos con 3 Anillos , Hidrocarburos Cíclicos , Iminas , Microalgas , Humanos , Espectrometría de Masas en Tándem , Chile , Toxinas Marinas/análisis , Mariscos/análisis , Alimentos Marinos/análisisRESUMEN
Dapsone (DDS) is an antibacterial drug with well-known antioxidant properties. However, the antioxidant behavior of its derivatives has not been well explored. In the present work, the antioxidant activity of 10 dapsone derivatives 4-substituted was determined by an evaluation in two in vitro models (DPPH radical scavenging assay and ferric reducing antioxidant power). These imine derivatives 1-10 were obtained through condensation between DDS and the corresponding aromatic aldehydes 4-substuited. Three derivatives presented better results than DDS in the determination of DPPH (2, 9, and 10). Likewise, we have three compounds with better reducing activity than dapsone (4, 9, and 10). In order to be more insight, the redox process, a conceptual DFT analysis was carried out. Molecular descriptors such as electronic distribution, the total charge accepting/donating capacity (I/A), and the partial charge accepting/donating capacity (ω+/ω-) were calculated to analyze the relative donor-acceptor capacity through employing a donor acceptor map (DAM). The DFT calculation allowed us to establish a relationship between GAPHOMO-LUMO and DAM with the observed antioxidant effects. According to the results, we concluded that compounds 2 and 3 have the lowest Ra values, representing a good antioxidant behavior observed experimentally in DPPH radical capturing. On the other hand, derivatives 4, 9, and 10 display the best reducing capacity activity with the highest ω- and Rd values. Consequently, we propose these compounds as the best antireductants in our DDS imine derivative series.
Asunto(s)
Antioxidantes/síntesis química , Dapsona/química , Iminas/síntesis química , Antioxidantes/química , Antioxidantes/farmacología , Simulación por Computador , Teoría Funcional de la Densidad , Iminas/química , Iminas/farmacología , Estructura Molecular , Relación Estructura-ActividadRESUMEN
An efficient synthesis of ketimines was achieved through a regioselective Hg(I)-catalyzed hydroamination of terminal acetylenes in the presence of anilines. The Pd(II)-catalyzed cyclization of these imines into the 2-substituted indoles was satisfactorily carried out by a C-H activation. In a single-step approach, a variety of 2-substituted indoles were also generated via a Hg(I)/Pd(II)-catalyzed, one-pot, two-step process, starting from anilines and terminal acetylenes. The arylacetylenes proved to be more effective than the alkyl derivatives.
RESUMEN
The synthesis of nitrogen-containing heterocycles, including natural alkaloids and other compounds presenting different types of biological activities have proved to be successful employing chiral sulfinyl imines derived from tert-butanesulfinamide. These imines are versatile chiral auxiliaries and have been extensively used as eletrophiles in a wide range of reactions. The electron-withdrawing sulfinyl group facilitates the nucleophilic addition of organometallic compounds to the iminic carbon with high diastereoisomeric excess and the free amines obtained after an easy removal of the tert-butanesulfinyl group can be transformed into enantioenriched nitrogen-containing heterocycles. The goal of this review is to the highlight enantioselective syntheses of heterocycles involving the use of chiral N-tert-butanesulfinyl imines as reaction intermediates, including the synthesis of several natural products. The synthesis of nitrogen-containing heterocycles in which the nitrogen atom is not provided by the chiral imine will not be considered in this review. The sections are organized according to the size of the heterocycles. The present work will comprehensively cover the most pertinent contributions to this research area from 2012 to 2020. We regret in advance that some contributions are excluded in order to maintain a concise format.
RESUMEN
Most of the shellfish fisheries of Mexico occur in the Gulf of California. In this region, known for its high primary productivity, blooms of diatoms and dinoflagellates are common, occurring mainly during upwelling events. Dinoflagellates that produce lipophilic toxins are present, where some outbreaks related to okadaic acid and dinophisystoxins have been recorded. From January 2015 to November 2017 samples of three species of wild bivalve mollusks were collected monthly in five sites in the southern region of Bahía de La Paz. Pooled tissue extracts were analyzed using LC-MS/MS to detect lipophilic toxins. Eighteen analogs of seven toxin groups, including cyclic imines were identified, fortunately individual toxins did not exceed regulatory levels and also the total toxin concentration for each bivalve species was lower than the maximum permitted level for human consumption. Interspecific differences in toxin number and concentration were observed in three species of bivalves even when the samples were collected at the same site. Okadaic acid was detected in low concentrations, while yessotoxins and gymnodimines had the highest concentrations in bivalve tissues. Although in low quantities, the presence of cyclic imines and other lipophilic toxins in bivalves from the southern Gulf of California was constant.
Asunto(s)
Bivalvos/metabolismo , Toxinas Marinas/análisis , Animales , Compuestos Heterocíclicos con 3 Anillos/análisis , Hidrocarburos Cíclicos/análisis , Iminas/análisis , Toxinas Marinas/química , Venenos de Moluscos , Ácido Ocadaico/análisis , Oxocinas/análisis , SolubilidadRESUMEN
Imine functionality is found in many compounds with important biological activity. Thus, the development of novel synthetic approaches for imines is important. In this work, it is propose an easy, eco-friendly and straightforward synthesis pathway of aryl imines under microwave irradiation catalyzed by Alumina-sulfuric acid. In addition, the in vitro enzymatic inhibition, antioxidant activity and molecular docking studies were performed. The aryl imines were isolated with yields in the range of 37-94%. All aryl imines synthesized were evaluated for in vitro inhibitory potential against α-glucosidase and α-amylase enzymes and the results exhibited that the most of the compounds displayed inhibitory activity against both enzymes. The (E)-1-(4-nitrophenyl)-N-(pyridin-2-yl)methanimine (3d) was 1.15-fold more active than acarbose against α-amylase whilst the (E)-1-phenyl-N-(pyridin-2-yl)methanimine (3c) displayed similar activity that acarbose against α-glucosidase. The molecular docking studies in α-glucosidase and α-amylase reveal that aryl imines mainly establish an H-bond with the R2-subtituent and hydrophobic interactions with the R1-subtituent. The docking analysis reveals these synthetic aryl imines 3d-i interact in same active site than acarbose drug in both enzymes.
Asunto(s)
Inhibidores de Glicósido Hidrolasas/farmacología , Iminas/farmacología , Simulación del Acoplamiento Molecular , alfa-Amilasas/antagonistas & inhibidores , alfa-Glucosidasas/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Inhibidores de Glicósido Hidrolasas/síntesis química , Inhibidores de Glicósido Hidrolasas/química , Humanos , Iminas/síntesis química , Iminas/química , Estructura Molecular , Relación Estructura-Actividad , Porcinos , alfa-Amilasas/metabolismoRESUMEN
OBJECTIVES: The in vitro antileishmanial effect of analogues of resveratrol (AR) present in the N-aryl imines and N-aryl hydrazones series was investigated. In addition, possible parasite targets were evaluated. METHODS: Antipromastigote activity of Leishmania amazonensis, L. braziliensis and L. infantum, as well as the cytotoxicity on macrophages was determined by MTT assay and L. braziliensis-infected macrophages effect by Giemsa stain. After staining, effects on the parasite targets were analysed by flow cytometry or by fluorescence microscopy. KEY-FINDINGS: Among the tested compounds, the derivative AR26 showed the best effect against promastigotes of all Leishmania species (IC50 < 3.0 µg/ml), being more active than miltefosine, the control drug. AR26 was also effective against amastigotes of L. braziliensis (IC50 = 15.9 µg/ml), with low toxicity to mammalian cells. The evaluation of mechanism of action of AR26 on L. braziliensis promastigotes indicates mitochondrial potential depolarization, plasma membrane permeabilization, interference in the progression of the cell cycle and accumulation of autophagic vacuoles. In addition, any increase of the reactive oxygen species levels was detected in the treated L. braziliensis-macrophages. CONCLUSIONS: Data indicate that the antileishmanial activity of AR26 is related to multitarget action, and the resveratrol analogues could be used in future studies as antileishmanial agent.
Asunto(s)
Antiprotozoarios/farmacología , Leishmania/efectos de los fármacos , Leishmaniasis/tratamiento farmacológico , Resveratrol/farmacología , Animales , Antiprotozoarios/administración & dosificación , Antiprotozoarios/química , Modelos Animales de Enfermedad , Femenino , Hidrazonas/administración & dosificación , Hidrazonas/química , Hidrazonas/farmacología , Iminas/administración & dosificación , Iminas/química , Iminas/farmacología , Concentración 50 Inhibidora , Leishmaniasis/parasitología , Macrófagos/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacología , Especies Reactivas de Oxígeno/metabolismo , Resveratrol/administración & dosificación , Resveratrol/análogos & derivadosRESUMEN
Neste trabalho foram sintetizados complexos de cobre(II) com derivados imínicos da isatina, incluindo isatinas bromadas semelhantes a compostos encontrados em gastrópodes, a fim de compará-los com o composto já produzido e investigado [Cu(isaepy)], complexo de cobre(II) com base de Schiff feita a partir da isatina e 2-aminoetilpiridina. A isatina é um oxindol produzido em algumas plantas, também encontrado no tecido de mamíferos, com propriedades antitumorais naturais. Isatinas bromadas foram previamente constatadas como mais citotóxicas frente a células tumorais do que a isatina sem substituições. O objetivo principal foi verificar se a presença de bromo nos compostos análogos ao [Cu(isaepy)] levaria a um aumento da atividade antitumoral, assim como maior interação com DNA, alvo usual de metalofármacos. Depois de sintetizados, os compostos foram caracterizados por análise elementar (CHN), espectroscopia no infravermelho, espectroscopia UV/Vis e EPR. Foram feitos testes de citotoxicidade pelo método MTT com células de sarcoma uterino (MES-SA e MES-AS/Dx5, esta última resistente a doxorrubicina), adenocarcinoma cervical (HeLa) e células não cancerosas de fibroblasto humano P4. Adicionalmente, foram feitos testes de interação com DNA por UV/Vis e dicroísmo circular, além de testes de clivagem de DNA plasmidial. De modo geral, foi demonstrado que a simetria tetragonal em torno do cobre, determinada pelo EPR, é importante para a citotoxicidade dos complexos, que dessa forma podem se intercalar ao DNA e impedir sua replicação, por acabar distorcendo a hélice, e pela habilidade de realizarem clivagem oxidativa das fitas. [Cu(isaepy)] e seus análogos bromados demonstraram uma atividade citotóxica muito parecida, assim como grau de interação e clivagem com DNA. Conclui-se que, embora a presença de bromo nos análogos de [Cu(isaepy)] não levem a um aumento de atividade antitumoral, como observado em ligantes correlatos livres, nossos estudos apontam para diferentes fontes naturais (animal ou vegetal) para obtenção de precursores de novos compostos antitumorais
In the present work, copper(II) complexes were synthesized with isatin derived imine ligands, including brominated oxindoles similar to compounds found in gastropods, in order to compare their reactivity with that of [Cu(isaepy)], a Schiff base-copper(II) complex already investigated, obtained with the precursors isatin and 2-aminoethylpyridine. Isatin is a natural oxindole extracted from plants, and also found in mammal tissue, with antitumor properties. Brominated isatins were previously described as much more cytotoxic, towards tumor cells, than unsubstituted isatin. The aim of this work was to verify if the presence of brome in analogue [Cu(isaepy)] compounds would increase their antitumor activity, along with higher DNA interaction, an usual target for metallodrugs. The copper(II) complexes were synthesized and then characterized through elemental analyses (CHN), infrared, UV/Vis and EPR spectroscopies. Cytotoxicity tests were carried out using MTT assay with cells lines MES-SA e MES-SA/Dx5 (uterine sarcome, sensitive and resistent to doxorubicin), HeLa (cervical adenocarcinoma) and non-tumor cells, human fibroblast P4. Additionally, DNA interaction experiments were carried out through UV/Vis spectroscopy and circular dichroism, and at last, DNA cleavage experiments with the studied complexes. In general, it was shown that a tetragonal symmetry around copper, shown by EPR, is very important to the complexes toxicity, since in that way they are able to intercalate DNA, and prevent its replication, as a consequence of double helix distortion, and eventual oxidative cleavage. [Cu(isaepy)] and its brominated analogues demonstrated a very similar cytotoxicity towards cancer cells, as well as quite same level of DNA interaction and cleavage. Although the presence of brome did not increase significantly their antitumor activity, as verified with the free isatin derivatives, our studies pointed to different natural sources to obtain precursors for such new antitumor compounds
Asunto(s)
ADN , Cobre/efectos adversos , Isatina/análisis , Productos Biológicos/uso terapéutico , Oxindoles/clasificaciónRESUMEN
An efficent access to a series of N-(pyrrol-2-yl)amines, namely (E)-1-tert-butyl-5-[(4-chlorobenzylidene)amino]-1H-pyrrole-3-carbonitrile, C16H16ClN3, (7a), (E)-1-tert-butyl-5-[(2,4-dichlorobenzylidene)amino]-1H-pyrrole-3-carbonitrile, C16H15Cl2N3, (7b), (E)-1-tert-butyl-5-[(pyridin-4-ylmethylene)amino]-1H-pyrrole-3-carbonitrile, C15H16N4, (7c), 1-tert-butyl-5-[(4-chlorobenzyl)amino]-1H-pyrrole-3-carbonitrile, C16H18ClN3, (8a), and 1-tert-butyl-5-[(2,4-dichlorobenzyl)amino]-1H-pyrrole-3-carbonitrile, C16H17Cl2N3, (8b), by a two-step synthesis sequence (solvent-free condensation and reduction) starting from 5-amino-1-tert-butyl-1H-pyrrole-3-carbonitrile is described. The syntheses proceed via isolated N-(pyrrol-2-yl)imines, which are also key synthetic intermediates of other valuable compounds. The crystal structures of the reduced compounds showed a reduction in the symmetry compared with the corresponding precursors, viz. Pbcm to P-1 from compound (7a) to (8a) and P21/c to P-1 from compound (7b) to (8b), probably due to a severe change in the molecular conformations, resulting in the loss of planarity observed in the nonreduced compounds. In all of the crystals, the supramolecular assembly is controlled mainly by strong (N,C)-H...N hydrogen bonds. However, in the case of (7a)-(7c), C-H...Cl interactions are strong enough to help in the three-dimensional architecture, as observed in Hirshfeld surface maps.
RESUMEN
Both sonochemical and classical methodologies have been employed to convert camphor, 1,7,7-trimethylbicyclo[2.2.1]heptan-2-one, C9H16C=O, into a number of derivatives including hydrazones, C9H16C=N-NHAr 3, imines, C9H16C=N-R 7, and the key intermediate nitroimine, C9H16C=N-NO2 6. Reactions of nitroamine 6 with nucleophiles by classical methods provided the desired compounds in a range of yields. In evaluations of activity against Mycobacterium tuberculosis, compound 7j exhibited the best activity (minimal inhibitory concentration (MIC) = 3.12 µg/mL), comparable to that of the antitubercular drug ethambutol. The other derivatives displayed modest antimycobacterial activities at 25-50 µg/mL. In in vitro tests against cancer cell lines, none of the synthesized camphor compounds exhibited cytotoxic activities.
RESUMEN
Here, we report different lipophilic toxins (LTs) detected by LC-MS/MS in Mediterranean mussels (Mytilus galloprovincialis) collected through 2012 in Todos Santos Bay, northwest Baja California, Mexico. The concentration of okadaic acid (OA), dinophysistoxin 2 (DTX2), and pectenotoxin 2 (PTX2) reached 500 µg kg(-1) during July and increased to 1647 µg kg(-1) in October. These toxins were associated with the presence of Dinophysis fortii and Dinophysis acuminata and a strong stratification of the water column. Other LTs present were yessotoxins, with a maximum concentration of 1080 µg kg(-1) in June. Cyclic imines (13-desmethyl spirolide and gymnodimine) and azaspiracid 1 were also detected in the mussels but at low concentrations. Diarrhetic toxins concentrations evaluated by LC-MS/MS were compared with the results of two mouse bioassay protocols. Positive results were obtained with both MBA protocols in several samples that presented toxicities below 160 µg OA-eq kg(-1), as estimated by LC-MS/MS results whereas other samples returned negative MBA results in samples with concentrations above this level. Therefore, analytical methods need to be applied to confirm the presence of regulated LTs. This is the first report of LTs in mussels cultivated in Mexico. The occurrence of these toxins represents an emerging problem in the region.