RESUMEN
Four previously unreported triterpenoid saponins named 3ß-hydroxy-23-oxours-12-en-28-oic acid 28-O-ß-D-glucopyranosyl ester (mannioside G) (1), 23-O-acetyl-3ß-hydroxyurs-12-en-28-oic acid 28-O-ß-D-glucopyranosyl ester (mannioside H) (2), ursolic acid 28-O-[α-L-rhamnopyranosyl-(1â4)-ß-D-glucopyranosyl-(1â6)-ß-D-glucopyranosyl] ester (mannioside I) (3), and 3ß-hydroxy-23-oxolup-20(29)-en-28-oic acid 28-O-ß-D-glucopyranosyl ester (mannioside J) (4) were isolated as minor constituents from the EtOAc soluble fraction of the MeOH extract of the leaves of Schefflera mannii along with the known compounds 23-hydroxyursolic acid 28-O-ß-D-glucopyranosyl ester (5), ursolic acid 28-O-ß-D-glucopyranosyl ester (6), pulsatimmoside B (7) betulinic acid 28-O-[α-L-rhamnopyranosyl-(1â4)-ß-D-glucopyranosyl-(1â6)-ß-D-glucopyranosyl] ester (8), 23-hydroxy-3-oxo-urs-12-en-28-oic acid (9), hederagenin (10), ursolic acid (11), betulinic acid (12), and lupeol (13). Their structures were elucidated by a combination of 1D and 2D NMR analysis and mass spectrometry. The MeOH extract, the EtOAc and n-BuOH fractions, and some of the isolated compounds were evaluated for their antibacterial activity against four bacteria: Staphylococcus aureus ATCC1026, Staphylococcus epidermidis ATCC 35984, Escherichia coli ATCC10536, and Klepsiella pnemoniae ATCC13882. They were also screened for their antioxidant properties, but no significant results were obtained.
Asunto(s)
Antibacterianos , Saponinas , Triterpenos , Triterpenos/química , Triterpenos/farmacología , Triterpenos/aislamiento & purificación , Saponinas/química , Saponinas/farmacología , Saponinas/aislamiento & purificación , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Pruebas de Sensibilidad Microbiana , Extractos Vegetales/química , Extractos Vegetales/farmacología , Estructura Molecular , Hojas de la Planta/química , Triterpenos Pentacíclicos/farmacología , Triterpenos Pentacíclicos/química , Triterpenos Pentacíclicos/aislamiento & purificación , Staphylococcus aureus/efectos de los fármacos , Araliaceae/químicaRESUMEN
The investigation of the leaves of Pittosporum elevaticostatum Chang et Yan led to the isolation of fifteen pentacyclic triterpenoids (1-15), including five previously undescribed ones (1-5), and nine others (16-24). The structures of compounds 1-5 were elucidated based on comprehensive spectroscopic techniques, including one dimension (1D) and 2D nuclear magnetic resonance (NMR), high resolution electrospray ionization mass spectroscopy (HR-ESI-MS), and other methods. Compounds 2 and 13 demonstrated significant inhibitory activity against Listeria monocytogenes (L. monocytogenes) with minimum inhibitory concentration (MIC) values of 32 µM. Scanning electron microscopy (SEM) observations revealed insights into the antibacterial mechanism, indicating that compounds 2 and 13 either prevent biofilm formation of dispersed the preformed cell membranes. Additionally, compounds 1, 5, 7, and 12 exhibited anti-inflammatory activity on lipopolysaccharide (LPS)-stimulated BV-2 microglial cells with IC50 values ranging from 11.27 to 17.80 µM.
Asunto(s)
Antibacterianos , Antiinflamatorios , Listeria monocytogenes , Pruebas de Sensibilidad Microbiana , Triterpenos Pentacíclicos , Hojas de la Planta , Hojas de la Planta/química , Antibacterianos/farmacología , Antibacterianos/aislamiento & purificación , Antiinflamatorios/farmacología , Antiinflamatorios/aislamiento & purificación , Estructura Molecular , Ratones , Animales , Listeria monocytogenes/efectos de los fármacos , Triterpenos Pentacíclicos/farmacología , Triterpenos Pentacíclicos/aislamiento & purificación , Fitoquímicos/farmacología , Fitoquímicos/aislamiento & purificación , Microglía/efectos de los fármacos , Línea Celular , ChinaRESUMEN
An extensive phytochemical investigation on the rare medicinal plant Semiliquidambar cathayensis (family: Hamamelidaceae) led to the isolation of four new (1-4, named semiliquidacids A-D, respectively) and 25 related known pentacyclic triterpenoids. The new structures with absolute configurations were elucidated by spectroscopic methods, electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction analysis. Compound 1 represents the first naturally occurring ursane-type triterpenoid featuring an uncommon C-25 formyl group. Compound 4 and oleanolic acid (13) exhibited remarkable inhibitory effects against the ATP-citrate lyase (ACL, an emerging drug target for hyperlipidemia and related metabolic disorders) with IC50 values of 6.5 and 11.9 µM, respectively. The molecular interaction and binding mode between the bioactive triterpenoids and ACL were elaborated by conducting a molecular docking study. Meanwhile, the chemotaxonomic significance of the isolated triterpenoids has been briefly discussed.
Asunto(s)
ATP Citrato (pro-S)-Liasa , Simulación del Acoplamiento Molecular , Triterpenos Pentacíclicos , Plantas Medicinales , Estructura Molecular , Plantas Medicinales/química , Triterpenos Pentacíclicos/farmacología , Triterpenos Pentacíclicos/aislamiento & purificación , Triterpenos Pentacíclicos/química , ATP Citrato (pro-S)-Liasa/antagonistas & inhibidores , Fitoquímicos/farmacología , Fitoquímicos/aislamiento & purificación , Fitoquímicos/química , Ácido Oleanólico/aislamiento & purificación , Ácido Oleanólico/farmacología , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/química , China , Inhibidores Enzimáticos/aislamiento & purificación , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/químicaRESUMEN
Celastrus hindsii is a popular medicinal plant in Vietnam and Southeast Asian countries as well as in South America. In this study, an amount of 12.05 g of an α-amyrin and ß-amyrin mixture was isolated from C. hindsii (10.75 g/kg dry weight) by column chromatography applying different solvent systems to obtain maximum efficiency. α-Amyrin and ß-amyrin were then confirmed by gas chromatography-mass spectrometry (GC-MS), electrospray ionization-mass spectrometry (ESI-MS), and nuclear magnetic resonance (NMR). The antioxidant activities of the α-amyrin and ß-amyrin mixture were determined via 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,20-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays with IC50 of 125.55 and 155.28 µg/mL, respectively. The mixture exhibited a high potential for preventing gout by inhibiting a relevant key enzyme, xanthine oxidase (XO) (IC50 = 258.22 µg/mL). Additionally, an important enzyme in skin hyperpigmentation, tyrosinase, was suppressed by the α-amyrin and ß-amyrin mixture (IC50 = 178.85 µg/mL). This study showed that C. hindsii is an abundant source for the isolation of α-amyrin and ß-amyrin. Furthermore, this was the first study indicating that α-amyrin and ß-amyrin mixture are promising in future therapies for gout and skin hyperpigmentation.
Asunto(s)
Antioxidantes/farmacología , Celastrus/química , Inhibidores Enzimáticos/farmacología , Monofenol Monooxigenasa/antagonistas & inhibidores , Ácido Oleanólico/análogos & derivados , Triterpenos Pentacíclicos/aislamiento & purificación , Hojas de la Planta/química , Xantina Oxidasa/antagonistas & inhibidores , Espectroscopía de Resonancia Magnética con Carbono-13 , Cromatografía de Gases y Espectrometría de Masas , Monofenol Monooxigenasa/metabolismo , Ácido Oleanólico/química , Ácido Oleanólico/aislamiento & purificación , Triterpenos Pentacíclicos/química , Espectroscopía de Protones por Resonancia Magnética , Espectrometría de Masa por Ionización de Electrospray , Xantina Oxidasa/metabolismoRESUMEN
Pentacyclic triterpenes (PTs) are commonly found in medicinal plants with well-known antiparasitic effects. Previous research on C-3 and C-27 triterpenic esters showed effective and selective in vitro antiparasitic activities and in vivo effectiveness by parenteral routes. The aim of this study was to determine triterpenic esters' stability in different biological-like media and the main microsomal degradation products. An HPLC-PDA method was developed and validated to simultaneously analyze and quantify bioactive triterpenic esters in methanol (LOQ: 2.5 and 1.25-100 µg/mL) and plasma (LOQ: 5-125 µg/mL). Overall, both triterpenic esters showed a stable profile in aqueous and buffered solutions as well as in entire plasma, suggesting gaining access to the ester function is difficult for plasma enzymes. Conversely, after 1 h, 30% esters degradation in acidic media was observed with potential different hydrolysis mechanisms. C-3 (15 and 150 µM) and C-27 esters (150 µM) showed a relatively low hepatic microsomal metabolism (<23%) after 1 h, which was significantly higher in the lowest concentration of C-27 esters (15 µM) (>40% degradation). Metabolic HPLC-PDA-HRMS studies suggested hydrolysis, hydroxylation, dehydration, O-methylation, hydroxylation and/or the reduction of hydrolyzed derivatives, depending on the concentration and the position of the ester link. Further permeability and absorption studies are required to better define triterpenic esters pharmacokinetic and specific formulations designed to increase their oral bioavailability.
Asunto(s)
Antiparasitarios/química , Triterpenos Pentacíclicos/química , Extractos Vegetales/farmacología , Plantas Medicinales/química , Antiparasitarios/farmacología , Cromatografía Líquida de Alta Presión , Ésteres/química , Ésteres/farmacología , Hidrólisis/efectos de los fármacos , Triterpenos Pentacíclicos/aislamiento & purificación , Extractos Vegetales/química , Plantas Medicinales/parasitologíaRESUMEN
In Sudanese traditional medicine, decoctions, macerations, and tonics of the stem and root of Combretum hartmannianum are used for the treatment of persistent cough, a symptom that could be related to tuberculosis (TB). To verify these traditional uses, extracts from the stem wood, stem bark, and roots of C. hartmannianum were screened for their growth inhibitory effects against Mycobacterium smegmatis ATCC 14468. Methanol Soxhlet and ethyl acetate extracts of the root gave the strongest effects (MIC 312.5 and 625 µg/ml, respectively). HPLC-UV/DAD and UHPLC/QTOF-MS analysis of the ethyl acetate extract of the root led to the detection of 54 compounds, of which most were polyphenols and many characterized for the first time in C. hartmannianum. Among the major compounds were terflavin B and its two isomers, castalagin, corilagin, tellimagrandin I and its derivative, (S)-flavogallonic acid dilactone, punicalagin, and methyl-ellagic acid xylopyranoside. In addition, di-, tri- and tetra-galloyl glucose, combregenin, terminolic acid, cordifoliside D, luteolin, and quercetin-3-O-galactoside-7-O-rhamnoside-(2â1)-O-ß-D-arabinopyranoside were characterized. Luteolin gave better growth inhibition against M. smegmatis (MIC 250 µg/ml) than corilagin, ellagic acid, and gallic acid (MIC 500-1000 µg/ml). Our study justifies the use of C. hartmannianum in Sudanese folk medicine against prolonged cough that could be related to TB infection. This study demonstrates that C. hartmannianum should be explored further for new anti-TB drug scaffolds and antibiotic adjuvants.
Asunto(s)
Antibacterianos/farmacología , Combretum , Flavonoides/farmacología , Glicósidos/farmacología , Taninos Hidrolizables/farmacología , Mycobacterium smegmatis/efectos de los fármacos , Triterpenos Pentacíclicos/farmacología , Fitoquímicos/farmacología , Extractos Vegetales/farmacología , Antibacterianos/aislamiento & purificación , Combretum/química , Etnofarmacología , Flavonoides/aislamiento & purificación , Glicósidos/aislamiento & purificación , Humanos , Taninos Hidrolizables/aislamiento & purificación , Pruebas de Sensibilidad Microbiana , Mycobacterium smegmatis/crecimiento & desarrollo , Triterpenos Pentacíclicos/aislamiento & purificación , Fitoquímicos/aislamiento & purificación , Extractos Vegetales/aislamiento & purificación , SudánRESUMEN
Betulinic acid (BA) is a pentacyclic triterpene compound that can be obtained by separation, chemical synthesis and biotransformation from birch. BA has antitumour activity, and its mechanisms of action mainly include the induction of mitochondrial oxidative stress; the regulation of specificity protein transcription factors, and the inhibition of signal transducer and activator of transcription 3 and nuclear factor-κB signalling pathways. In addition, BA can increase the sensitivity of cancer cells to other chemotherapy drugs. Recent studies have shown that BA plays an anticancer role in several kinds of tumour diseases. In this article, the anticancer mechanism of BA and its application in the treatment of tumour diseases are reviewed.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Neoplasias/tratamiento farmacológico , Triterpenos Pentacíclicos/farmacología , Animales , Antineoplásicos Fitogénicos/aislamiento & purificación , Betula/química , Humanos , Neoplasias/patología , Estrés Oxidativo/efectos de los fármacos , Triterpenos Pentacíclicos/aislamiento & purificación , Transducción de Señal/efectos de los fármacos , Ácido BetulínicoRESUMEN
Silver birch, Betula pendula Roth, is one of the most common trees in Europe. Due to its content of many biologically active substances, it has long been used in medicine and cosmetics, unlike the rare black birch, Betula obscura Kotula. The aim of the study was therefore to compare the antioxidant properties of extracts from the inner and outer bark layers of both birch trees towards the L929 line treated with acetaldehyde. Based on the lactate dehydrogenase test and the MTT test, 10 and 25% concentrations of extracts were selected for the antioxidant evaluation. All extracts at tested concentrations reduced the production of hydrogen peroxide, superoxide anion radical, and 25% extract decreased malonic aldehyde formation in acetaldehyde-treated cells. The chemical composition of bark extracts was accessed by IR and HPLC-PDA methods and surprisingly, revealed a high content of betulin and lupeol in the inner bark extract of B. obscura. Furthermore, IR analysis revealed differences in the chemical composition of the outer bark between black and silver birch extracts, indicating that black birch may be a valuable source of numerous biologically active substances. Further experiments are required to evaluate their potential against neuroinflammation, cancer, viral infections, as well as their usefulness in cosmetology.
Asunto(s)
Antioxidantes/farmacología , Betula/química , Corteza de la Planta/química , Extractos Vegetales/farmacología , Acetaldehído/antagonistas & inhibidores , Acetaldehído/farmacología , Animales , Antioxidantes/química , Antioxidantes/aislamiento & purificación , Betula/clasificación , Línea Celular , Cromatografía Líquida de Alta Presión , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Humanos , Peróxido de Hidrógeno/antagonistas & inhibidores , Malondialdehído/antagonistas & inhibidores , Ratones , Oxidantes/antagonistas & inhibidores , Oxidantes/farmacología , Triterpenos Pentacíclicos/química , Triterpenos Pentacíclicos/aislamiento & purificación , Corteza de la Planta/clasificación , Extractos Vegetales/química , Polonia , Superóxidos/antagonistas & inhibidores , Triterpenos/química , Triterpenos/aislamiento & purificaciónRESUMEN
Pentacyclic triterpenes and cardenolides were isolated from Acokanthera oblongifolia leaves. Their chemical structures were determined based on comprehensive 1D and 2D NMR spectroscopy. Their MIC was determined against 12 microorganisms. Their exerted cytotoxicity on the immortalized normal cells, hTERT-RPE1 was assessed by the sulforhodamine-B assay. The viral inhibitory effects of compounds against Newcastle disease virus (NDV) and H5N1 influenza virus IV were evaluated. Four in vitro antioxidant assays were performed in comparison with BHT and trolox and a weak activity was exhibited. Acovenoside A was with potent against H5N1-IV and NDV with IC50 ≤ 3.2 and ≤ 2.1 µg/ml and SI values of 93.75 and 95.23%, respectively, in comparison to ribavirin. Its CC50 record on Vero cells was > 400 and 200 µg/ml, respectively. Acobioside A was the most active compound against a broad range of microbes while Pseudomonas aeruginosa was the most sensitive. Its MIC (0.07 µg/ml) was 1/100-fold of the recorded CC50 (7.1 µg/ml/72 h) against hTERT-RPE1. The molecular docking of compounds on human DNA topoisomerase I (Top1-DNA) and IV glycoprotein hemagglutinin were studied using MOE program. This study has introduced the cardenolides rather than triterpenoids with the best docking score and binding interaction with the active site of the studied proteins.
Asunto(s)
Antibacterianos/farmacología , Antivirales/farmacología , Apocynaceae/química , Cardenólidos/farmacología , Triterpenos Pentacíclicos/farmacología , Hojas de la Planta/química , Animales , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Antivirales/química , Antivirales/aislamiento & purificación , Cardenólidos/química , Cardenólidos/aislamiento & purificación , Línea Celular , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Células Epiteliales/efectos de los fármacos , Humanos , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Pruebas de Sensibilidad Microbiana/métodos , Simulación del Acoplamiento Molecular , Estructura Molecular , Triterpenos Pentacíclicos/química , Triterpenos Pentacíclicos/aislamiento & purificación , Epitelio Pigmentado de la Retina/citología , Células VeroRESUMEN
Medicinal plants are valuable sources of different active constituents that are known to have important pharmacological activities including anticancer effects. Lupeol, a pentacyclic triterpenoid, present in many medicinal plants, has a wide range of biological activities. Although the anticancer activity of lupeol was reported, the published data are inconsistent and the clear mechanism of action has never been assigned. The current study aims at investigating the anticancer specificity and mechanism of lupeol isolated from Avicennia marina, which grows in the desert of the United Arab Emirates. The compound was purified by chromatography and identified by spectroscopy. Compared with a negative control, lupeol caused significant (p < .001) growth inhibitory activity on MCF-7 and Hep3B parental and resistant cells by 45%, 46%, 72%, and 35%, respectively. The mechanism of action of lupeol was further explored by measuring its effect on key players in cancer development and progression, BCL-2 anti-apoptotic and BAX pro-apoptotic proteins. Lupeol significantly (p < .01) downregulated BCL-2 gene expression in parental and resistant Hep3B cells by 33 and 3.5 times, respectively, contributing to the induction of apoptosis in Hep3B cells, whereas it caused no effect on BAX. Furthermore, the immunoblotting analysis revealed that lupeol cleaved the executioner caspase-3 into its active form. Interestingly, lupeol showed no significant effect on the proliferation of monocytes, whereas it caused an increase in the sub-G1 population and a reduction in the apoptosis rates of monocytes at 48 and 72 h, indicative of no immuno-inflammatory responses. Collectively, lupeol can be considered as promising effective and safe anticancer agent, particularly against Hep3B cancer cells.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Avicennia/química , Triterpenos Pentacíclicos/farmacología , Antineoplásicos Fitogénicos/aislamiento & purificación , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Regulación hacia Abajo/efectos de los fármacos , Femenino , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Células MCF-7 , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Triterpenos Pentacíclicos/aislamiento & purificación , Proteínas Proto-Oncogénicas c-bcl-2/genética , Factores de TiempoRESUMEN
The bioassay-guided fractionation of a CHCl3-MeOH extract from the stems of Cissus trifoliata identified an active fraction against PC3 prostate cancer cells. The treatment for 24 h showed an 80% reduction in cell viability (p ≤ 0.05) by a WST-1 assay at a concentration of 100 µg/mL. The HPLC-QTOF-MS analysis of the fraction showed the presence of coumaric and isoferulic acids, apigenin, kaempferol, chrysoeriol, naringenin, ursolic and betulinic acids, hexadecadienoic and octadecadienoic fatty acids, and the stilbene resveratrol. The exposure of PC3 cells to resveratrol (IC25 = 23 µg/mL) for 24 h induced significant changes in 847 genes (Z-score ≥ ±2). The functional classification tool of the DAVID v6.8 platform indicates that the underlying molecular mechanisms against the proliferation of PC3 cells were associated (p ≤ 0.05) with the process of differentiation and metabolism. These findings provide experimental evidence suggesting the potential of C. trifoliata as a promising natural source of anticancer compounds.
Asunto(s)
Antineoplásicos Fitogénicos/química , Proliferación Celular/efectos de los fármacos , Cissus/química , Proteínas de Neoplasias/genética , Transcriptoma , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Apigenina/química , Apigenina/aislamiento & purificación , Apigenina/farmacología , Bioensayo , Supervivencia Celular/efectos de los fármacos , Flavanonas/química , Flavanonas/aislamiento & purificación , Flavanonas/farmacología , Flavonas/química , Flavonas/aislamiento & purificación , Flavonas/farmacología , Perfilación de la Expresión Génica , Humanos , Quempferoles/química , Quempferoles/aislamiento & purificación , Quempferoles/farmacología , Masculino , Análisis por Micromatrices , Proteínas de Neoplasias/clasificación , Proteínas de Neoplasias/metabolismo , Células PC-3 , Triterpenos Pentacíclicos/química , Triterpenos Pentacíclicos/aislamiento & purificación , Triterpenos Pentacíclicos/farmacología , Extractos Vegetales/química , Resveratrol/química , Resveratrol/aislamiento & purificación , Resveratrol/farmacología , Ácido BetulínicoRESUMEN
Maslinic acid and corosolic acid with high purity were successfully separated from Eriobotrya japonica (Thunb.) leaves by two-step countercurrent chromatographic separation. Two biphasic solvent systems composed of petroleum ether-ethyl acetate-ethanol-water (6:4:5:5, v/v) and petroleum ether-ethyl acetate-ethanol-0.10 mol/L of hydroxypropyl-ß-cyclodextrin with pH 7.0 (8:2:3.5:6.5, v/v) were selected according to the partition performance of the main structural isomeric pentacyclic triterpenes. The influences of pH value and concentration of hydroxypropyl-ß-cyclodextrin in separation of two isomers were investigated. In first step countercurrent chromatographic separation, a mixture of two target structural isomers (14.12 mg of sample I) was separated from 40.00 mg of a partially purified sample. In second step countercurrent chromatographic separation, maslinic acid and corosolic acid were completely isolated from 12.00 mg of sample I with hydroxypropyl-ß-cyclodextrin as aqueous phase additive. The recoveries of the two isomers were over 90%, yielding 5.18 mg of maslinic acid and 5.47 mg of corosolic acid, respectively.
Asunto(s)
2-Hidroxipropil-beta-Ciclodextrina/química , Distribución en Contracorriente/métodos , Eriobotrya/química , Triterpenos Pentacíclicos/aislamiento & purificación , Hojas de la Planta/química , Cromatografía Líquida de Alta Presión/métodos , Triterpenos Pentacíclicos/química , Espectrometría de Masa por Ionización de Electrospray/métodos , EstereoisomerismoRESUMEN
Three new ursane-type triterpenes (1-3) and twenty-one known triterpenoids (4-24) were isolated from the methanolic extract of the whole plants of Potentilla chinensis. Their structures were elucidated by extensive spectroscopic analysis of 1D and 2D NMR (HSQC, HMBC, COSY and ROESY) and HRESIMS data. The bioassay screening revealed the inhibitory effects on nitric oxide production of compounds 2, 5, 7, 9, 10, and 13-24 in LPS-induced RAW264.7 macrophages.
Asunto(s)
Óxido Nítrico/antagonistas & inhibidores , Triterpenos Pentacíclicos/farmacología , Potentilla/química , Animales , Relación Dosis-Respuesta a Droga , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Estructura Molecular , Óxido Nítrico/biosíntesis , Triterpenos Pentacíclicos/química , Triterpenos Pentacíclicos/aislamiento & purificación , Células RAW 264.7 , Relación Estructura-ActividadRESUMEN
ACT's low levels of Plasmodium parasitemia clearance are worrisome since it is the last treatment option against P. falciparum. This scenario has led to investigations of compounds with different mechanisms of action for malaria treatment. Natural compounds like ursolic acid (UA) and betulinic acid (BA), distinguished by their activity against numerous microorganisms, including P. falciparum, have become relevant. This study evaluated the antiplasmodial activity of imidazole derivatives of UA and BA against P. falciparum in vitro. Eight molecules were obtained by semisynthesis and tested against P. falciparum strains (NF54 and CQ-resistant 106/cand isolated in Porto Velho, Brazil); 2a and 2b showed activity against NF54 and 106/cand strains with IC50 < 10 µM. They presented high selectivity indexes (SI > 25) and showed synergism when combined with artemisinin. 2b inhibited the parasite's ring and schizont forms regardless of when the treatment began. In silico analysis presented a tight bind of 2b in the topoisomerase II-DNA complex. This study demonstrates the importance of natural derivate compounds as new candidates for malarial treatment with new mechanisms of action. Semisynthesis led to new triterpenes that are active against P. falciparum and may represent new alternatives for malaria drug development.
Asunto(s)
Antimaláricos/farmacología , Resistencia a Medicamentos/efectos de los fármacos , Triterpenos Pentacíclicos/química , Plasmodium falciparum/efectos de los fármacos , Triterpenos/química , Antimaláricos/química , Antimaláricos/aislamiento & purificación , Antimaláricos/metabolismo , Sitios de Unión , Brasil , Cloroquina/farmacología , ADN-Topoisomerasas de Tipo II/química , ADN-Topoisomerasas de Tipo II/metabolismo , Estadios del Ciclo de Vida/efectos de los fármacos , Simulación del Acoplamiento Molecular , Triterpenos Pentacíclicos/aislamiento & purificación , Triterpenos Pentacíclicos/farmacología , Plasmodium falciparum/metabolismo , Proteínas Protozoarias/química , Proteínas Protozoarias/metabolismo , Relación Estructura-Actividad , Triterpenos/aislamiento & purificación , Triterpenos/farmacología , Ácido Betulínico , Ácido UrsólicoRESUMEN
Previous studies have demonstrated the potential antiophidic activity of Zanthoxylum monogynum A.St.-Hil. a tree from the Rutaceae family native to South America. In this present contribution, we demonstrate the activity of the metabolite lupeol, a triterpenoid isolated from the stem bark of Z. monogynum against the harmful effects of the Bothrops alternatus venom. We investigated the antiophidic properties of lupeol, for this purpose, and use crude venom (Pb) incubated with lupeol in different concentrations, testing in vitro experiments and inoculated in mice for inhibitory evaluations in vivo. Besides, we tried to elucidate through the molecular dynamics the mechanism of action of lupeol with the bothropic thrombin-like toxin Jararacussin-I; the acidic phospholipase A2 toxin BthA-I from Bothrops jararacussu and the metalloproteinase toxin BmooMP-I from Bothrops moojeni. In our results, we demonstrated the potential inhibitory effect upon coagulant, phospholipasic and myotoxic activities of the bothropic venom, previously incubated with lupeol. We found that lupeol triterpenoid was able to partially inhibit local and systemic damage caused by snake venom toxins. Our in silico results demonstrate that lupeol is capable of interacting and altering the activity of the thrombin-like toxin Jararacussin-I, and capable of interacting with the BthA-I acidic PLA2, both toxins present in Bothrops snakes venom, thus demonstrating the pharmacological potential of this compound for the treatment of bothropic accidents.
Asunto(s)
Triterpenos Pentacíclicos/aislamiento & purificación , Zanthoxylum , Animales , Bothrops , Venenos de Crotálidos/toxicidad , Ratones , América del SurRESUMEN
Three new triterpene saponins including two lupane-types and an ursane-type were isolated from the leaves of Trevesia palmata. Their structures were determined as 2α,3ß,23-trihydroxylup-20(29)-en-28-oic acid 3-O-α-L-arabinopyranoside (1), 2α,3ß,23-trihydroxylup-20(29)-en-28-oic acid 3-O-[α-L-arabinopyranoside]-28-O-[ß-D-glucopyranosyl] ester (2), and 2α,3ß,23-trihydroxyurs-12-en-28-oic acid 3-O-[α-L-arabinopyranoside]-28-O-[ß-D-glucopyranosyl(1â2)-ß-D-glucopyranosyl] ester (3) by analysis of their HR-ESI-MS, 1D and 2D NMR spectra. The 2α,3ß,23-trioxygenated pentacyclic triterpenes were uncommonly found in the nature. At concentration of 100 µM, compounds 1-3 inhibited NO production in LPS activated BV2 cells with inhibitory rates of 17.4 ± 1.8%, 33.1 ± 1.2%, and 11.7 ± 2.2%, respectively. But, they did not significantly inhibit yeast α-glucosidase activity.
Asunto(s)
Araliaceae/química , Triterpenos Pentacíclicos/farmacología , Saponinas , Triterpenos , Animales , Línea Celular , Ratones , Triterpenos Pentacíclicos/aislamiento & purificación , Hojas de la Planta/química , Saponinas/aislamiento & purificación , Saponinas/farmacología , Triterpenos/aislamiento & purificación , Triterpenos/farmacologíaRESUMEN
Ten pentacyclic triterpenes (1-10) were isolated from Lavandula coronopifolia. We evaluated their α-glucosidase inhibitory activity, and found that the aglycones, 1, 2, 3, 4, 7 and 10 showed superior IC50 values to the positive control. In order to explain the structural requirements for α-glucosidase inhibitory activity, eleven derivatives were prepared, including one new compound, 2-formyl-(A)1-19α-hydroxy-1-norursane-2, 12-dien-28-oic acid 10c. The results demonstrated that a free hydroxyl at ring-A and a free carboxylic group at position 28 are key structural features for the α-glucosidase inhibitory activity, also that an ursane skeleton is optimum for the activity. Additionally, enzyme kinetic analysis of pomolic acid 2, the most potent compound, revealed that it inhibited α-glucosidase in a mixed-type manner. The molecular docking simulation validated this type of inhibition and highlighted the role of the C-3 hydroxyl and C-28 carboxylic groups in interaction with the enzyme in silico.
Asunto(s)
Inhibidores de Glicósido Hidrolasas/química , Inhibidores de Glicósido Hidrolasas/farmacología , Lavandula/química , Triterpenos Pentacíclicos/química , Triterpenos Pentacíclicos/aislamiento & purificación , Espectroscopía de Resonancia Magnética con Carbono-13 , Pruebas de Enzimas , Concentración 50 Inhibidora , Cinética , Simulación del Acoplamiento Molecular , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/química , Ácido Oleanólico/farmacología , Triterpenos Pentacíclicos/farmacología , Espectroscopía de Protones por Resonancia Magnética , Relación Estructura-Actividad , alfa-Glucosidasas/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Uapaca species including Uapacastaudtii Pax (Phyllanthaceae) are used in West Africa ethnomedicine to treat diverse ailments including pile, rheumatism, oedema and wound healing. However, the anti-inflammatory and analgesic potential as well as constituents of the Uapacastaudtii stem bark has not been investigated. AIM OF THE STUDY: The study was designed to evaluate the anti-inflammatory, analgesic, and antioxidant activities of extract and fractions ofU. staudtii stem bark, and to isolate the bioactive constituents. MATERIALS AND METHODS: The anti-inflammatory, analgesic and antioxidant activities of the ethanol extract, dichloromethane, ethyl acetate, butanol, and aqueous fractions of U. staudtii stem bark, as well as protocatechuic acid and betulinic acid isolated from the bioactive ethyl acetate fraction were evaluated in different mice models of inflammation and pain; furthermore, antioxidant assays were carried out. Chemical structures of isolated compounds were established based on spectroscopic studies and comparison with literature data. RESULTS: The ethanol extract and ethyl acetate fraction exhibited good anti-inflammatory, analgesic, and antioxidant capacity in all studied models, comparable with those of the standard drugs used. Protocatechuic acid also gave significant (p < 0.05) anti-inflammatory (83%and 88% inhibition for egg-albumin induced and xylene induced oedema, respectively), analgesic (56% inhibition and 22 s of pain suppression for acetic acid-induced and hot plate-induced pain, respectively), and antioxidant effects (97% inhibition and absorbance of 2.516 at 100 µg/mL for DPPH and FRAP assay, respectively) in all the models, whereas betulinic acid only exhibited significant (p < 0.05) anti-inflammatory and antioxidant activity. CONCLUSIONS: The result supports the medicinal uses of the U. staudtii stem bark in the management of pain and inflammatory disease. This is the first report on the biological activities and characterization of compounds inU. staudtii, and presence of protocatechuic acid in Uapaca genus.
Asunto(s)
Analgésicos/farmacología , Antiinflamatorios/farmacología , Inflamación/tratamiento farmacológico , Dolor/tratamiento farmacológico , Phyllanthus/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , África Occidental , Analgésicos/química , Analgésicos/aislamiento & purificación , Analgésicos/uso terapéutico , Animales , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/uso terapéutico , Antioxidantes/química , Antioxidantes/aislamiento & purificación , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Edema/inducido químicamente , Edema/tratamiento farmacológico , Femenino , Depuradores de Radicales Libres/farmacología , Hidroxibenzoatos/aislamiento & purificación , Hidroxibenzoatos/farmacología , Hidroxibenzoatos/uso terapéutico , Inflamación/etiología , Masculino , Ratones , Dolor/etiología , Triterpenos Pentacíclicos/aislamiento & purificación , Triterpenos Pentacíclicos/farmacología , Triterpenos Pentacíclicos/uso terapéutico , Fenol/análisis , Fenol/química , Corteza de la Planta/química , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/uso terapéutico , Ácido BetulínicoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Ocimum gratissimum is a plant spice widely used in African traditional medicine to treat pain-related conditions. However, the anti-inflammatory mechanisms underlying this activity and the main active ingredients in O. gratissimum have not yet been fully characterized. AIM OF THE STUDY: To isolate and identify the main anti-inflammatory active constituents of Ocimum gratissimum extract and their underlying mechanisms in murine macrophages. MATERIAL AND METHODS: Chromatographic techniques and spectroscopic data were used for compounds isolation and identification. Inflammatory conditions were produced in cultured RAW 264.7 macrophage cells by the application of lipopolysaccharide (LPS). The WST-1 assay was used to evaluate the cell viability, and the nitric oxide production was quantified by the Griess reagent method. The fluorometric cyclooxygenase (COX) activity assay kit was used to assess the activity of COX-1 and COX-2 enzymes. The levels of IFN-γ, TNF-α, IL-2, IL-4, IL-6, and IL-10 cytokines and the apoptosis-inducing effect were measured by flow cytometer using the cytometric Bead Array (CBA) Human Th1/Th2 Cytokine Kit II and FITC Annexin V Apoptosis Detection kit, respectively. RESULTS: The results showed that the extract and fractions of Ocimum gratissimum inhibit nitric oxide production and the proliferation of Raw 264.7 macrophage cells. The bioguided fractionation led to the identification of pentacyclic triterpenes as anti-inflammatory bioactive compounds. Pomolic and tormentic acids being the most active, inhibiting the secretion of IFN-γ cytokine, COX enzyme, and inducing apoptosis in activated Raw 264.7 macrophage cells. CONCLUSIONS: This study revealed that pomolic and tormentic acids are the main active principles responsible at least in part for the anti-inflammatory effect of the extract of Ocimum gratissimum. Besides of providing more evidence for the traditional use of Ocimum gratissimum against inflammatory disorders, this study reveals the multitarget potential of pomolic and tormentic acids as promising future drugs against inflammatory diseases.
Asunto(s)
Antiinflamatorios/aislamiento & purificación , Mediadores de Inflamación/antagonistas & inhibidores , Ocimum , Triterpenos Pentacíclicos/aislamiento & purificación , Fitoquímicos/aislamiento & purificación , Extractos Vegetales/aislamiento & purificación , Animales , Antiinflamatorios/farmacología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Relación Dosis-Respuesta a Droga , Humanos , Mediadores de Inflamación/metabolismo , Ratones , Triterpenos Pentacíclicos/farmacología , Fitoquímicos/farmacología , Extractos Vegetales/farmacología , Células RAW 264.7RESUMEN
Fibroproliferative diseases are characterized by excessive accumulation of extracellular matrix (ECM) components leading to organ dysfunction. This process is characterized by an increase in myofibroblast content and enzyme activity of xylosyltransferase-I (XT-I), the initial enzyme in proteoglycan (PG) biosynthesis. Therefore, the inhibition of XT-I could be a promising treatment for fibrosis. We used a natural product-inspired compound library to identify non-substrate-based inhibitors of human XT-I by UPLC-MS/MS. We combined this cell-free approach with virtual and molecular biological analyses to confirm and prioritize the inhibitory potential of the compounds identified. The characterization for compound potency in TGF-ß1-driven XYLT1 transcription regulation in primary dermal human fibroblasts (key cells in ECM remodeling) was addressed by gene expression analysis. Consequently, we identified amphotericin B and celastrol as new non-substrate-based XT-I protein inhibitors. Their XT-I inhibitory effects were mediated by an uncompetitive or a competitive inhibition mode, respectively. Both compounds reduced the cellular XYLT1 expression level and XT-I activity. We showed that these cellular inhibitor-mediated changes involve the TGF-ß and microRNA-21 signaling pathway. The results of our study provide a strong rationale for the further optimization and future usage of the XT-I inhibitors identified as promising therapeutic agents of fibroproliferative diseases.