RESUMEN
BACKGROUND AND PURPOSE: Leishmaniasis is a globally prevalent vector-borne disease caused by parasites of the genus Leishmania. The available chemotherapeutic drugs present problems related to efficacy, emergence of parasite resistance, toxicity and high cost, justifying the search for new drugs. Several classes of compounds have demonstrated activity against Leishmania, including icetexane-type diterpenes, previously isolated from Salvia and other Lamiaceae genera. Thus, in this study, compounds of Salvia procurrens were investigated for their leishmanicidal and immunomodulatory activities. METHODS: The exudate of S. procurrens was obtained by rapidly dipping the aerial parts in dichloromethane. The compounds were isolated by column and centrifugal planar chromatography over silica gel. The effects on L. amazonensis growth, survival, membrane integrity, reactive oxygen species (ROS) generation, mitochondrial membrane potential and cytotoxicity of the compounds towards human erythrocytes, peripheral blood mononuclear cells and macrophages were evaluated. The effects on intracellular amastigote forms, nitric oxide (NO) and TNF-α production were also investigated. RESULTS: The exudate from the leaves afforded the novel icetexane 7-hydroxyfruticulin A (1) as well as the known demethylisofruticulin A (2), fruticulin A (3) and demethylfruticulin A (4). The compounds (1-4) were tested against promastigotes of L. amazonensis and showed an effective inhibition of the parasite survival (IC50 = 4.08-16.26 µM). In addition, they also induced mitochondrial ROS production, plasma membrane permeability and mitochondrial dysfunction in treated parasites, and presented low cytotoxicity against macrophages. Furthermore, all diterpenes tested reduced the number of parasites inside macrophages, by mechanisms involving TNF-α, NO and ROS. CONCLUSION: The results suggest the potential of 7-hydroxyfruticulin A (1) as well as the known demethylisofruticulin A (2),fruticulin A (3) and demethylfruticulin A (4) as candidates for use in further studies on the design of anti-leishmanial drugs.
Asunto(s)
Leishmania , Óxido Nítrico , Especies Reactivas de Oxígeno , Salvia , Factor de Necrosis Tumoral alfa , Salvia/química , Especies Reactivas de Oxígeno/metabolismo , Humanos , Leishmania/efectos de los fármacos , Animales , Factor de Necrosis Tumoral alfa/metabolismo , Óxido Nítrico/metabolismo , Ratones , Macrófagos/efectos de los fármacos , Antiprotozoarios/farmacología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Hojas de la Planta/química , Diterpenos/farmacología , Diterpenos/química , Leucocitos Mononucleares/efectos de los fármacos , Eritrocitos/efectos de los fármacos , Eritrocitos/parasitología , Extractos Vegetales/farmacología , Extractos Vegetales/química , Ratones Endogámicos BALB C , Células RAW 264.7RESUMEN
The interest in natural colorants derived from sustainable processes has prompted research into obtaining bixin from defatted annatto (Bixa orellana L.) seeds. Bixin is a compound that imparts yellow-orange-red coloration, known for its high biodegradability, low toxicity, and wide industrial applicability. Meanwhile, high-intensity ultrasound (HIUS) technology has emerged as a promising method for extracting natural colorants, offering higher yields through shorter processes and minimizing thermal degradation. Although some studies have demonstrated the efficiency of HIUS technology in bixin extraction, research on the effects of acoustic cavitation on the properties of the colorant remains limited. Therefore, this study aimed to investigate the influence of HIUS-specific energy levels (0.02, 0.04, 0.12, and 0.20 kJ/g) on the chemical, physical, and morphological characteristics of annatto extracts containing bixin and geranylgeraniol. Single-step extractions of bixin using ethanol as a solvent were evaluated at various acoustic powers (4.6, 8.5, 14.5, and 20 W) and extraction times (0.5, 1, 3, and 5 min) to determine their impact on the yield of natural colorant extraction. Increasing the acoustic power from 4.6 to 20 W and extending the extraction time from 0.5 to 5 min resulted in higher yields of natural colorant, likely due to the effects of acoustic cavitation and increased heat under more intense conditions. However, elevated levels of mechanical and thermal energy did not affect the chemical properties of the colorant, as indicated by UV-Vis and FTIR spectra. Conversely, higher specific energies yielded colorants with a more intense red hue, consistent with increased bixin content, and altered the microstructure and physical state, as observed in X-ray diffractograms. Nevertheless, these alterations did not impact the solubility of the colorant. Therefore, employing a cleaner extraction procedure aided by one-step ultrasound facilitated the recovery of natural colorants and contributed to the biorefining of annatto seeds, enabling the production of a rich geranylgeraniol colorant through a sustainable approach.
Asunto(s)
Bixaceae , Carotenoides , Semillas , Ondas Ultrasónicas , Semillas/química , Bixaceae/química , Carotenoides/química , Carotenoides/aislamiento & purificación , Fraccionamiento Químico/métodos , Diterpenos/química , Diterpenos/aislamiento & purificación , Color , Extractos VegetalesRESUMEN
Toxoplasmosis affects about one-third of the world's population. The disease treatment methods pose several side effects and do not efficiently eliminate the parasite, making the search for new therapeutic approaches necessary. We aimed to assess the anti-Toxoplasma gondii activity of four Copaifera oleoresins (ORs) and two isolated diterpene acids, named ent-kaurenoic and ent-polyalthic acid. We used HeLa cells as an experimental model of toxoplasmosis. Uninfected and infected HeLa cells were submitted to the treatments, and the parasite intracellular proliferation, cytokine levels and ROS production were measured. Also, tachyzoites were pre-treated and the parasite invasion was determined. Finally, an in silico analysis was performed to identify potential parasite targets. Our data show that the non-cytotoxic concentrations of ORs and diterpene acids controlled the invasion and proliferation of T. gondii in HeLa cells, thus highlighting the possible direct action on parasites. In addition, some compounds tested controlled parasite proliferation in an irreversible manner. An additional and non-exclusive mechanism of action involves the modulation of host cell components, by affecting the upregulation of the IL-6. Additionally, molecular docking suggested that ent-polyalthic acid has a high affinity for the active site of the TgCDPK1 protein. Copaifera ORs have great antiparasitic activity against T. gondii, and this effect can be partially explained by the presence of the isolated compounds ent-kaurenoic and ent-polyalthic acid.
Asunto(s)
Diterpenos , Fabaceae , Extractos Vegetales , Toxoplasma , Células HeLa , Humanos , Diterpenos/farmacología , Diterpenos/aislamiento & purificación , Diterpenos/química , Toxoplasma/efectos de los fármacos , Toxoplasma/crecimiento & desarrollo , Fabaceae/química , Extractos Vegetales/farmacología , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Especies Reactivas de Oxígeno/metabolismo , Citocinas/metabolismo , Interleucina-6/metabolismo , Simulación del Acoplamiento MolecularRESUMEN
Copaifera duckei oleoresin is a plant product extensively used by the Brazilian population for multiple purposes, such as medicinal and cosmetic. Despite its ethnopharmacological relevance, there is no pharmacokinetic data on this important medicinal plant. Due to this, we determined the pharmacokinetic profile of the major nonvolatile compounds of C. duckei oleoresin. The diterpenes ent-polyalthic acid and dihydro-ent-agathic acid correspond to approximately 40% of the total oleoresin. Quantification was performed using LC-MS/MS, and the validated analytical method showed to be precise, accurate, robust, reliable, and linear between 0.57 and 114.74 µg/mL plasma and 0.09 to 18.85 µg/mL plasma, respectively, for ent-polyalthic acid and dihydro-ent-agathic acid, making it suitable for application in preclinical pharmacokinetic studies. Wistar rats received a single 200 mg/kg oral dose (gavage) of C. duckei oleoresin, and blood was collected from their caudal vein through 48 h. Population pharmacokinetics analysis of ent-polyalthic and dihydro-ent-agathic acids in rats was evaluated using nonlinear mixed-effects modeling conducted in NONMEN software. The pharmacokinetic parameters of ent-polyalthic acid were absorption constant rate = 0.47 h-1, central and peripheral apparent volume of distribution = 0.04 L and 2.48 L, respectively, apparent clearance = 0.15 L/h, and elimination half-life = 11.60 h. For dihydro-ent-agathic acid, absorption constant rate = 0.28 h-1, central and peripheral apparent volume of distribution = 0.01 L and 0.18 L, respectively, apparent clearance = 0.04 L/h, and elimination half-life = 3.49 h. The apparent clearance, central apparent volume of distribution, and peripheral apparent volume of distribution of ent-polyalthic acid were approximately 3.75, 4.00-, and 13.78-folds higher than those of dihydro-ent-agathic.
Asunto(s)
Diterpenos , Ratas Wistar , Animales , Diterpenos/farmacocinética , Diterpenos/sangre , Diterpenos/química , Ratas , Masculino , Resinas de Plantas/farmacocinética , Resinas de Plantas/química , Espectrometría de Masas en Tándem , Fabaceae/química , Extractos Vegetales/farmacocinética , Extractos Vegetales/química , Cromatografía LiquidaRESUMEN
Euphorbia is a large genus of the Euphorbiaceae family. Around 250 species of the Euphorbia genus have been studied chemically and pharmacologically; different compounds have been isolated from these species, especially diterpenes and triterpenes. Several reports show that several species have anti-inflammatory activity, which can be attributed to the presence of diterpenes, such as abietanes, ingenanes, and lathyranes. In addition, it was found that some diterpenes isolated from different Euphorbia species have anti-cancer activity. In this review, we included compounds isolated from species of the Euphorbia genus with anti-inflammatory or cytotoxic effects published from 2018 to September 2023. The databases used for this review were Science Direct, Scopus, PubMed, Springer, and Google Scholar, using the keywords Euphorbia with anti-inflammatory or cytotoxic activity. In this review, 68 studies were collected and analyzed regarding the anti-inflammatory and anti-cancer activities of 264 compounds obtained from 36 species of the Euphorbia genus. The compounds included in this review are terpenes (95%), of which 68% are diterpenes, especially of the types ingenanes, abietanes, and triterpenes (approximately 15%).
Asunto(s)
Antineoplásicos , Diterpenos , Euphorbia , Triterpenos , Euphorbia/química , Abietanos , Estructura Molecular , Diterpenos/química , Triterpenos/química , AntiinflamatoriosRESUMEN
From the aerial parts of Salvia carranzae Zamudio and Bedolla, three new icetexane-type diterpenoids were isolated. Their structures were established through spectroscopic methods and named the following: salvicarranzanolide (1), 19-deoxo-salvicarranzanolide (2) and 19-deoxo-20-deoxy-salvicarranzanolide (3). In addition, the known icetexane-type diterpenoids, 6,7,11,14-tetrahydro-7-oxo-icetexone (4), iso-icetexone (5), 19-deoxo-iso-icetexone (6), icetexone (7), 19-deoxo-icetexone (8) and 7α-acetoxy-6,7-dihydroicetexone (9), were also isolated, along with the abietanes sessein (10) and ferruginol (11). α-Tocopherol was also identified. Compounds 5, 6 and 8 were tested for their antiproliferative activity using the sulforhodamine B assay on six cancer and one normal human cell lines. Diterpenoids 5 and 6 showed noteworthy antiproliferative activity, exhibiting an IC50 (µM) = 0.43 ± 0.01 and 1.34 ± 0.04, respectively, for U251 (glioblastoma), an IC50 (µM) = 0.45 ± 0.01 and 1.29 ± 0.06 for K5621 (myelogenous leukemia), 0.84 ± 0.07 and 1.03 ± 0.10 for HCT-15 (colon cancer), and 0.73 ± 0.06 and 0.95 ± 0.09 for SKLU-1 (lung adenocarcinoma) cell lines. On the other hand, the phytotoxicity of compounds 5-7 and 9-10 was evaluated on seed germination and root growth in some weeds such as Medicago sativa, Panicum miliaceum, Amaranthus hypochondriacus and Trifolium pratense as models. While compounds 5 and 10 exhibited a moderate inhibitory effect on the root growth of A. hypochondriacus and T. pratense at 100 ppm, the diterpenoids 6, 7 and 9 were ineffective in all the plant models. Taxonomic positions based on the chemical profiles found are also discussed.
Asunto(s)
Alcaloides , Diterpenos , Neoplasias Pulmonares , Salvia , Humanos , Abietanos/farmacología , Abietanos/química , Salvia/química , Diterpenos/farmacología , Diterpenos/química , Línea Celular Tumoral , Estructura MolecularRESUMEN
Xylopia benthamii (Annonaceae) is a plant with limited phytochemical and pharmacological evidence. Thus, using LC-MS/MS, we performed exploratory analyses of the fruit extract of X. benthamii, resulting in the tentative identification of alkaloids (1-7) and diterpenes (8-13). Through the application of chromatography techniques with the extract of X. benthamii, two kaurane diterpenes were isolated, xylopinic acid (9) and ent-15-oxo-kaur-16-en-19-oic acid (11). Their structures were established using spectroscopy (NMR 1D/2D) and mass spectrometry. The isolated compounds were submitted to anti-biofilm analysis against Acinetobacter baumannii, anti-neuroinflammatory and cytotoxic activity in BV-2 cells. Compound 11 (201.75 µM) inhibited 35% of bacterial biofilm formation and high anti-inflammatory activity in BV-2 (IC50 = 0.78 µM). In conclusion, the results demonstrated that compound 11 was characterized for the first time with pharmacological potential in the development of new alternatives for studies with neuroinflammatory diseases.
Asunto(s)
Diterpenos , Xylopia , Xylopia/química , Frutas , Cromatografía Liquida , Espectrometría de Masas en Tándem , Diterpenos/química , Extractos Vegetales/farmacología , Extractos Vegetales/químicaRESUMEN
The biochemical profile of coffee beans translates directly into quality traits, nutraceutical and health promoting properties of the coffee beverage. Ent-kaurene is the ubiquitous precursor for gibberellin biosynthesis in plants, but it also serves as an intermediate in specialized (i.e., secondary) diterpenoid metabolism that leads to a diversity of more than 1,000 different metabolites. Nutraceutical effects on human health attributed to diterpenes include antioxidant, anticarcinogenic, and anti-inflammatory properties. Cafestol (CAF) and kahweol (KAH) are two diterpenes found exclusively in the Coffea genus. Our objective was to identify and functionally characterize genes involved in the central step of ent-kaurene production. We identified 17 putative terpene synthase genes in the transcriptome of Coffea arabica. Two ent-copalyl diphosphate synthase (CaCPS) and three kaurene synthase (CaKS) were selected and manually annotated. Transcript expression profiles of CaCPS1 and CaKS3 best matched the CAF and KAH metabolite profiles in different tissues. CaCPS1 and CaKS3 proteins were heterologously expressed and functionally characterized. CaCPS1 catalyzes the cyclization of geranylgeranyl diphosphate (GGPP) to ent-copalyl diphosphate (ent-CPP), which is converted to ent-kaurene by CaKS3. Knowledge about the central steps of diterpene formation in coffee provides a foundation for future characterization of the subsequent enzymes involved in CAF and KAH biosynthesis.
Asunto(s)
Transferasas Alquil y Aril , Coffea , Diterpenos de Tipo Kaurano , Diterpenos , Humanos , Coffea/genética , Coffea/metabolismo , Diterpenos/química , Diterpenos de Tipo Kaurano/metabolismo , Transferasas Alquil y Aril/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMEN
Plants of Hyptidinae subtribe (Lamiaceae - family), as Mesosphaerum sidifolium, are a source of bioactive molecules. In the search for new drug candidates, we perform chemical characterization of diterpenes isolated from the aerial parts of M. sidifolium was carried out with uni- and bidimensional NMR spectral data, and evaluate in silico through the construction of a predictive model followed by in vitro testing Mycobacterium tuberculosis and Mycobacterium smegmatis. Resulted in the isolation of four components: Pomiferin D (1), Salviol (2), Pomiferin E (3) and 2α-hydroxysugiol (4), as well as two phenolic compounds, rosmarinic and caffeic acids. In silico model identified 48 diterpenes likely to have biological activity against M. tuberculosis. The diterpenes isolated were tested in vitro against M. tuberculosis demonstrating MIC = 125 µM for 4 and 1, while 2 and 3 -MIC = 250 µM. These compounds did not show biological activity at these concentrations for M. smegmatis.
Asunto(s)
Diterpenos , Lamiaceae , Mycobacterium tuberculosis , Tuberculosis , Pruebas de Sensibilidad Microbiana , Diterpenos/química , Lamiaceae/química , Antituberculosos/químicaRESUMEN
A new nor-ent-kaurene diterpene and ten other compounds were isolated from Annona vepretorum stems, including four kaurene diterpenes, three alkamides, one sesquiterpene and two steroids. Their chemical structures were elucidated using spectroscopic methods, including 1D-, 2D-NMR, and HRESIMS. The absolute configuration of compounds 1, 5, 8, 9 and 10 was confirmed by CD experiments. Compounds 1-5 and 8-10 were evaluated for cytotoxic activity using (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) MTT method, against three human carcinoma cell lines: human colon (HCT-116), glioblastoma (SF295) and prostate (PC3). However, all isolated compounds exhibited low cytotoxic activity.
Asunto(s)
Annona , Annonaceae , Diterpenos de Tipo Kaurano , Diterpenos , Masculino , Humanos , Annona/química , Diterpenos de Tipo Kaurano/química , Diterpenos/química , Extractos Vegetales/químicaRESUMEN
The chemical composition and the antioxidant potential of Ecuadorian propolis samples (n = 19) collected in different provinces were investigated. HPLC-DAD-ESI/MSn and GC-EI-MS analysis of the methanol extracts enabled us to define six types of Ecuadorian propolis based on their secondary metabolite composition. 68 compounds were identified, 59 of which are reported for the first time in Ecuadorian propolis. The detected compounds include flavonoids, diterpenes, triterpenes, organic acid derivatives, alkylresorcinol derivatives and nemorosone. Plants belonging to genera Populus, Mangifera and Clusia seemed to be vegetable sources employed by bees to produce Ecuadorian propolis. Total phenolic content and antioxidant activity of propolis extracts were determined by the Folin-Ciocalteu assay and 2,2-diphenyl-1-picrylhydrazyl and ferric reducing/antioxidant potential assays, respectively. As expected, the variable chemical composition affected the differences in terms of antioxidant potential.
Asunto(s)
Diterpenos , Própolis , Triterpenos , Antioxidantes/química , Antioxidantes/farmacología , Cromatografía Líquida de Alta Presión , Diterpenos/química , Ecuador , Flavonoides/química , Metanol , Própolis/química , Triterpenos/análisisRESUMEN
The deficit of effective treatments for Chagas disease has led to searching for new substances with therapeutic potential. Natural products possess a wide variety of chemical structural motifs and are thus a valuable source of diverse lead compounds for the development of new drugs. Castanedia santamartensis is endemic to Colombia, and local indigenous communities often use it to treat skin sores from leishmaniasis; however, its mechanism of action against the infective form of Trypanosoma cruzi has not been determined. Thus, we performed chemical and biological studies of two alcoholic leaf extracts of C. santamartensis to identify their active fractions and relate them to a trypanocidal effect and evaluate their mechanism of action. Alcoholic extracts were obtained through cold maceration at room temperature and fractionated using classical column chromatography. Both ethanolic and methanolic extracts displayed activity against T. cruzi. Chemical studies revealed that kaurenoic acid was the major component of one fraction of the methanolic extract and two fractions of the ethanolic extract of C. santamartensis leaves. Moreover, caryophyllene oxide, kaurenol, taraxasterol acetate, pentadecanone, and methyl and ethyl esters of palmitate, as well as a group of phenolic compounds, including ferulic acid, caffeic acid, chlorogenic acid, myricetin, quercitrin, and cryptochlorogenic acid were identified in the most active fractions. Kaurenoic acid and the most active fractions CS400 and CS402 collapsed the mitochondrial membrane potential in trypomastigotes, demonstrating for the first time the likely mechanism against T. cruzi, probably due to interactions with other components of the fractions.
Asunto(s)
Asteraceae , Extractos Vegetales/farmacología , Tripanocidas/química , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Diterpenos/química , Mitocondrias/efectos de los fármacos , Extractos Vegetales/química , Hojas de la PlantaRESUMEN
A phytochemical investigation of cytotoxic extract and fractions of Cnidoscolus quercifolius Pohl led to isolation of five terpenoids, including three lupane-type triterpenes (1-3) and two bis-nor-diterpenes (4-5). Compounds 4 (phyllacanthone) and 5 (favelanone) are commonly found in this species and have unique chemical structure. Although their cytotoxic activity against cancer cells has been previously reported, the anticancer potential of these molecules remains poorly explored. In this paper, the antimelanoma potential of phyllacanthone (PHY) was described for the first time. Cell viability assay showed a promising cytotoxic activity (IC50 = 40.9 µM) against chemoresistant human melanoma cells expressing the BRAF oncogenic mutation (A2058 cell line). After 72 h of treatment, PHY inhibited cell migration and induced apoptosis and cell cycle arrest (p < 0.05). Immunofluorescence assay showed that the pro-apoptotic effect of PHY is probably associated with tubulin depolymerization, resulting in cytoskeleton disruption of melanoma cells. Molecular docking investigation confirmed this hypothesis given that satisfactory interaction between PHY and tubulin was observed, particularly at the colchicine binding site. These results suggest PHY from C. quercifolius could be potential leader for the design of new antimelanoma drugs.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Diterpenos/química , Euphorbiaceae/química , Proteínas Proto-Oncogénicas B-raf/genética , Tubulina (Proteína)/metabolismo , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/metabolismo , Sitios de Unión , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular , Colchicina/química , Colchicina/metabolismo , Diterpenos/metabolismo , Diterpenos/farmacología , Euphorbiaceae/metabolismo , Humanos , Melanoma/metabolismo , Melanoma/patología , Simulación del Acoplamiento Molecular , Mutación , Corteza de la Planta/química , Corteza de la Planta/metabolismo , Extractos Vegetales/química , Proteínas Proto-Oncogénicas B-raf/metabolismo , Tubulina (Proteína)/químicaRESUMEN
HIV is a public health problem, which makes necessary the development of new drugs. Natural products are known for their anti-HIV potential and a good strategy to suggest its mechanism of action is using in silico tools. Herein, diterpenes 1-3 had the binding mode evaluated in the HIV-1 glycoprotein; and properties ADMET in silico performed. In molecular docking important interactions between the hydrophobic cavity, and 1 and 2 were observed. In the molecular dynamics, 1 remained stable covering the entire hydrophobic cavity and performed hydrogen bond during all simulation. ADMET evaluation showed good properties for the diterpenes. Based on these findings, it was possible to suggest the potential from natural products as entry inhibitor and HIV-1 treatment.
Asunto(s)
Productos Biológicos , Diterpenos , VIH-1 , Phaeophyceae , Simulación del Acoplamiento Molecular , Phaeophyceae/química , Diterpenos/químicaRESUMEN
Nowadays, new leishmanicidal drugs are needed and natural products arise as a promising alternative source. Therefore, bioguided fractionation of a hydroethanolic extract from the stem bark of Croton echioides Baill. were conducted based on its antileishmanial activity. Two novel neo-clerodane diterpenoids methyl-15,16-epoxy-3,13(16),14-neo-clerodatrien-17,18-dicarboxylate (1) and dimethyl-3-oxo-15,16-epoxy-13(16),14-neo-clerodadien-17,18-dicarboxylate (2) were isolated, as well as four known compounds (3-6) and lupeol, from the hexane fraction. Their structures were established by NMR analysis. The crude extract, fractions and the compounds (1 and 3-6) were evaluated for their in vitro antileishmanial activity and cytotoxicity against macrophages J774A.1. The selectivity index (SI) were calculated. The most active compound against promastigote forms of L. amazonensis was the clerodane diterpene 4, with IC50 values of 8.3 µM and SI value of 80.9. Our results highlighted stem bark of Croton echioides Baill. as a promising source for the development of a new chemotherapeutic agent to combat leishmaniasis.
Asunto(s)
Antiprotozoarios , Croton , Diterpenos de Tipo Clerodano , Diterpenos , Antiprotozoarios/farmacología , Croton/química , Diterpenos/química , Diterpenos/farmacología , Diterpenos de Tipo Clerodano/química , Diterpenos de Tipo Clerodano/farmacología , Espectroscopía de Resonancia Magnética , Estructura MolecularRESUMEN
In this paper, a complete 1 H and 13 C NMR data assignment of ent-polyalthic acid, a biologically active labdane-type diterpene, is presented. The assignments were carried on the basis of spectroscopic data from 1 H NMR, 13 C{1 H} NMR, gCOSY, gHMQC, and gHMBC experiments. Furthermore, a software-assisted methodology, using FOMSC3_rm_NB and NMR_MultSim programs, supported the detailed and unequivocal assignment of 1 H and 13 C signals, allowing all hydrogen coupling constants to be determined and thus clarifying all hydrogen signal multiplicities.
Asunto(s)
Diterpenos , Protones , Isótopos de Carbono/química , Diterpenos/química , Espectroscopía de Resonancia Magnética/métodosRESUMEN
Coffee is one of the most consumed beverages worldwide. Cafestol is an endogenous coffee diterpene present in raw coffee beans and also found in hot beverages, with several biological activities. However, there is still little information on this molecule after ingestion of coffee infusion. Zebrafish (Danio rerio) is a promising in vivo model for metabolic studies due to the annotation of mammalian orthologs to encode enzymes related to drug metabolism. Experiments using Zebrafish Water Tank (ZWT) model produce more significant number of metabolites for molecular investigation in a cleaner matrix than other classical models, such as purified hepatocytes. This work aimed to investigate the biotransformation of cafestol by the ZWT model using ultra-performance liquid chromatography coupled to hybrid quadrupole-orbitrap high-resolution mass spectrometry equipped with electrospray ionization (UPLC-HRMS) supported by in silico approach using SMARTCyp, Way2Drug and XenoSite Softwares. Twenty-five metabolites of cafestol were proposed by in silico analysis, in which 5 phase I metabolites were confirmed in the ZWT by UPLC and MS/HRMS investigation: 6-hydroxy-cafestol, 6,12-dihydroxy-cafestol, 2-oxo-cafestol, 6-oxo-cafestol and one isomer whose position in the carboxyl group was not determined. These metabolites were observed during 9 h of the experiment, whose contents were associated with the behavioral responses of the fish.
Asunto(s)
Diterpenos/química , Diterpenos/metabolismo , Pez Cebra/metabolismo , Animales , Biotransformación , Cromatografía Líquida de Alta Presión , Cromatografía Liquida , Café/química , Café/metabolismo , Simulación por Computador , Espectrometría de Masas , Modelos Animales , Estructura MolecularRESUMEN
Even today, weeds continue to be a considerable problem for agriculture. The application of synthetic herbicides produces serious environmental consequences, and crops suffer loss of their activity due to the appearance of new resistant weed biotypes. Our aim is to develop new effective natural herbicides that improve the problem of resistance and do not harm the environment. This work is focused on a bioassay-guided isolation and the characterization of natural products present in Moquiniastrum pulchrum leaves with phytotoxic activity and its preliminary application in weeds. Moquiniastrum pulchrum was selected for two reasons: it is an abundant species in the Cerrado region (the second most important ecosystem in Brazil, after the Amazon)-the explanation behind its being a dominant species is a major focus of interest-and it has traditional employment in folk medicine. Six major compounds were isolated in this plant: one flavone and five diterpenes, two of which are described for the first time in the literature. Four of the six compounds exhibited phytotoxic activity in the bioassays performed. The results confirmed the phytotoxic potential of this plant, which had not been investigated until now.
Asunto(s)
Asteraceae/química , Agentes de Control Biológico/toxicidad , Diterpenos/toxicidad , Flavonas/toxicidad , Herbicidas/toxicidad , Malezas/efectos de los fármacos , Control de Malezas/métodos , Bioensayo , Agentes de Control Biológico/química , Agentes de Control Biológico/aislamiento & purificación , Productos Agrícolas/crecimiento & desarrollo , Diterpenos/química , Diterpenos/aislamiento & purificación , Flavonas/química , Flavonas/aislamiento & purificación , Herbicidas/química , Herbicidas/aislamiento & purificación , Humanos , Estructura Molecular , Extractos Vegetales/química , Hojas de la Planta/química , Malezas/crecimiento & desarrolloRESUMEN
Among the compounds of natural origin, diterpenes have proved useful as drugs for the treatment of cancer. Marine organisms, such as soft corals and algae, are a promising source of diterpenes, being a rich and unexplored source of cytotoxic agents. This study evaluated a library of 32 natural and semisynthetic marine diterpenes, including briarane, cembrane, and dolabellane nuclei, with the aim of determining their cytotoxicity against three human cancer cell lines (A549, MCF7, and PC3). The three most active compounds were submitted to a flow cytometry analysis in order to determine induction of apoptosis against the A549 cell line. An NMR analysis was conducted to determine and evaluate the interactions between active diterpenes and tubulin. These interactions were characterized by a computational study using molecular docking and MD simulations. With these results, two cembrane and one chlorinated briarane diterpenes were active against the three human cancer cell lines, induced apoptosis in the A549 cell line, and showed interactions with tubulin preferably at the taxane-binding site. This study is a starting point for the identification and optimization of the marine diterpenes selected for better antitumor activities. It also highlights the power of integrating NMR studies, computational predictions, and in vitro assays in the search for compounds with antitumor activity.
Asunto(s)
Antozoos/química , Antineoplásicos/química , Productos Biológicos/química , Mezclas Complejas/química , Diterpenos/química , Bibliotecas de Moléculas Pequeñas/química , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Productos Biológicos/farmacología , Línea Celular Tumoral , Mezclas Complejas/farmacología , Biología Computacional , Diterpenos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Halogenación , Humanos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-ActividadRESUMEN
Nonsteroidal anti-inflammatory drugs (NSAIDs) are very commonly used, but their adverse effects warrant investigating new therapeutic alternatives. Polyalthic acid, a labdane-type diterpenoid, is known to produce gastroprotection, tracheal smooth muscle relaxation, and antitumoral, antiparasitic and antibacterial activity. This study aimed to evaluate the antinociceptive, antiallodynic, antihyperalgesic and anti-inflammatory effect of polyalthic acid on rats. Moreover, the effectiveness of treating hyperalgesia with a combination of polyalthic acid and naproxen was analyzed, as well as the type of drug-drug interaction involved. Nociception was examined by injecting 1% formalin into the right hind paw and thermal hyperalgesia and inflammation by injecting a 1% carrageenan solution into the left hind paw of rats. Allodynia was assessed on an L5/L6 spinal nerve ligation model. Polyalthic acid generated significant antinociceptive (56-320 mg/kg), antiallodynic (100-562 mg/kg), and antihyperalgesic and anti-inflammatory (10-178 mg/kg) effects. Antinociception mechanisms were explored by pretreating the rats with naltrexone, ODQ and methiothepin, finding the effect blocked by the former two compounds, which indicates the participation of opioid receptors and guanylate cyclase. An isobolographic analysis suggests synergism between polyalthic acid and naproxen in the combined treatment of hyperalgesia.