RESUMEN
Phytochemical investigation on the extract of the seeds of Thevetia peruviana resulted in the isolation of six new cardiac glycosides, namely theveperosides A-F (1-6), including a rare 19-nor-cardenolide (1), together with seven known analogues (7-13). The chemical structures of these compounds were determined based on detailed spectroscopic analysis. The cytotoxic activities of 1-13 were evaluated against MCF-7, HCT-116, HeLa, and HepG2 cancer cell lines, and their structure-activity relationships (SARs) were investigated. Compound 3 exhibited the significant cytotoxic effects with IC50 values ranging from 0.032 to 0.055 µΜ, which could induce HepG2 cells apoptosis in a dose-dependent manner.
Asunto(s)
Antineoplásicos Fitogénicos , Glicósidos Cardíacos , Fitoquímicos , Semillas , Thevetia , Humanos , Glicósidos Cardíacos/farmacología , Glicósidos Cardíacos/aislamiento & purificación , Glicósidos Cardíacos/química , Semillas/química , Estructura Molecular , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/aislamiento & purificación , Thevetia/química , Relación Estructura-Actividad , Fitoquímicos/farmacología , Fitoquímicos/aislamiento & purificación , Apoptosis/efectos de los fármacosRESUMEN
Background Numerous food wastes have been identified to possess potent bioactive compounds used for the treatment of several diseases. Therefore this study evaluated the potentials of cardiac and quercetin glycosides extracted from Dacryodes edulis seeds to reverse vascular and endothelial damage (VAED). Methods The glycoside composition of the seeds was extracted using standard methods and characterized by gas chromatography. We then recruited rats with L-NAME-induced VAED based on confirmatory biomarkers cardiac troponin (CnT), cellular adhesion molecule (VCAM-1), lipoprotein associated phospholipase A2 (Lp-PLA2), RAAS, VWF, endothelin, eNOx, and homocysteine. Only rats that showed total alterations of all biomarkers were recruited into the respective experimental groups and treated with either metaprolol succinate (met.su) + losartan or glycoside extracts of D. edulis seeds (NPSG). Results Chromatographic isolation of glycosides in the seed showed predominance of artemetin (1.59 mg/100 g), amygdalin (3.68 mg/100 g), digitoxin (19.21 mg/100 g), digoxin (27.23 mg/100 g), avicularin (133.59 mg/100 g), and hyperoside (481.76 mg/100 g). We observed decreased water intake and higher heart beats under vascular damage as the experiment progressed up to the fourth week. The met.su + losartan and H.D NPSG proved effective in restoring troponin, but both doses of NPSG normalized the VCAM-1 and RAAS activities excluding aldosterone and Lp-PLA2. Among the endothelial dysfunction biomarkers, H.D NPSG produced equivalent effects to met.su + losartan towards restoring the eNOx and VWF activities, but showed higher potency in normalizing the endothelin and Hcy levels. Conclusions We thus propose that the synergistic effect of the isolated glycosides from D. edulis shown in our study proved potent enough at high doses in treatment of vascular and endothelial dysfunction.
Asunto(s)
Burseraceae/química , Glicósidos Cardíacos/farmacología , Extractos Vegetales/farmacología , Quercetina/farmacología , Animales , Biomarcadores/metabolismo , Glicósidos Cardíacos/administración & dosificación , Glicósidos Cardíacos/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/patología , Losartán/farmacología , Masculino , Metoprolol/farmacología , Ratones , NG-Nitroarginina Metil Éster , Extractos Vegetales/administración & dosificación , Quercetina/administración & dosificación , Quercetina/aislamiento & purificación , Ratas , SemillasRESUMEN
A new non-cytotoxic [(+)-17ß-hydroxystrebloside (1)] and two known cytotoxic [(+)-3'-de-O-methylkamaloside (2) and (+)-strebloside (3)] cardiac glycosides were isolated and identified from the combined flowers, leaves, and twigs of Streblus asper collected in Vietnam, with the absolute configuration of 1 established from analysis of its ECD and NMR spectroscopic data and confirmed by computational ECD calculations. A new 14,21-epoxycardanolide (3a) was synthesized from 3 that was treated with base. A preliminary structure-activity relationship study indicated that the C-14 hydroxy group and the C-17 lactone unit and the established conformation are important for the mediation of the cytotoxicity of 3. Molecular docking profiles showed that the cytotoxic 3 and its non-cytotoxic analogue 1 bind differentially to Na+/K+-ATPase. Compound 3 docks deeply in the Na+/K+-ATPase pocket with a sole pose, and its C-10 formyl and C-5, C-14, and C-4' hydroxy groups may form hydrogen bonds with the side-chains of Glu111, Glu117, Thr797, and Arg880 of Na+/K+-ATPase, respectively. However, 1 fits the cation binding sites with at least three different poses, which all depotentiate the binding between 1 and Na+/K+-ATPase. Thus, 3 was found to inhibit Na+/K+-ATPase, but 1 did not. In addition, the cytotoxic and Na+/K+-ATPase inhibitory 3 did not affect glucose uptake in human lung cancer cells, against which it showed potent activity, indicating that this cardiac glycoside mediates its cytotoxicity by targeting Na+/K+-ATPase but not by interacting with glucose transporters.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Glicósidos Cardíacos/farmacología , Inhibidores Enzimáticos/farmacología , Moraceae/química , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidores , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Glicósidos Cardíacos/química , Glicósidos Cardíacos/aislamiento & purificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/aislamiento & purificación , Flores/química , Humanos , Conformación Molecular , Simulación del Acoplamiento Molecular , Hojas de la Planta/química , Tallos de la Planta/química , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Relación Estructura-ActividadRESUMEN
From ancient times, medicinal plants have been usually utilized to treat many disorders, but today, interest in these herbs is again aroused, because of their fewer side effects and low-cost. In traditional medicine, for many diseases, various medicinal herbs have been suggested so far. Drimia maritime, also named squill, is an important medicinal plant for the treatment of many diseases, especially respiratory diseases. In the current evidence-based study, we conducted a review of the general characteristics, ingredients, administration form, and side effects of squill in traditional medicine. For this purpose, traditional Persian medicine literatures and electronic databases were examined including PubMed, Scopus, and Google Scholar. Many compounds are isolated from D.maritima, including scillaren, scillirubroside, scillarenin, and bufadienolide glycosides. Oxymel is the most commonly used form of squill for various diseases, especially respiratory diseases. Besides, squill has been used in the treatment of cardiovascular, digestive, and dermatological disorders, it is also used against various cancer cells for its antioxidant and cytotoxic properties. Moreover, there is relatively reliable evidence of its benefits for bacterial and helminthic infections, rheumatism, edema, gout, abortion induction, healing of wounds and urine induction. It seems that supplementary studies are required to explore the bioactive agents and their effective mechanisms.
Asunto(s)
Drimia/química , Medicina Basada en la Evidencia/métodos , Fitoterapia/métodos , Preparaciones de Plantas/uso terapéutico , Bufanólidos/química , Bufanólidos/aislamiento & purificación , Bufanólidos/uso terapéutico , Glicósidos Cardíacos/química , Glicósidos Cardíacos/aislamiento & purificación , Glicósidos Cardíacos/uso terapéutico , Humanos , Preparaciones de Plantas/química , Preparaciones de Plantas/aislamiento & purificaciónRESUMEN
Streblus asper Lour. (Moraceae) is a medicinal plant in Asian countries including India and Thailand, possessing activities of anti-tumor, anti-allergy, anti-parasitic and anti-bacterial. In this paper, characterization, quantitation and similarity evaluation of cardiac glycosides in different parts of S. asper were investigated by HPLC-Q-TOF-MS and chemometric methods. Then, the inhibition of Na+,K+-ATPase activity by the compounds isolated from S. asper was measured. Meanwhile, enzyme kinetics and molecular docking were determined to exhibit the combination modes between cardiac glycosides and Na+,K+-ATPase. As a result, twenty peaks of cardiac glycosides were assigned. Strophanthidin-3-O-α-l-rhamnopyranosyl-(1â¯ââ¯4)-6-deoxy-ß-d-allopyranoside (1), glucostrebloside (2), strebloside (4) and mansonin (8) with a significant activity of inhibiting Na+,K+-ATPase (IC50 7.55-13.60⯵M) were chosen for the determination of enzyme kinetics, exhibiting anticompetitive inhibitory characteristics towards Na+,K+-ATPase. Compound 4 could reasonably bind to the active sites of Na+,K+-ATPase, proved by molecular docking. Furthermore, the contents of the major compounds in four different parts of S. asper were extremely different, analyzed by chemometric methods, similarity analysis and principle compounds analysis. All these findings indicated that the contents of major compounds in different parts of S. asper were extremely different with a significant activity of inhibiting Na+,K+-ATPase, providing a reference for determination of effective part and administered dosage. The combination modes between cardiac glycosides and Na+,K+-ATPase were also revealed by enzyme kinetics and molecular docking, which provided a basis for further study of pharmacological activity.
Asunto(s)
Glicósidos Cardíacos/farmacología , Inhibidores Enzimáticos/farmacología , Moraceae/química , Plantas Medicinales/química , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidores , Animales , Glicósidos Cardíacos/química , Glicósidos Cardíacos/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/aislamiento & purificación , Conformación Molecular , Simulación del Acoplamiento Molecular , ATPasa Intercambiadora de Sodio-Potasio/química , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Relación Estructura-Actividad , PorcinosRESUMEN
Cardiac glycosides are used for treatment of irregular heartbeats, cardiac arrhythmia and congestive heart failures. In this research, digitoxin as a cardiac glycoside was identified and isolated for the first time in the world from Adonis aestivalis and investigated for its cytotoxic activity against cervical cancer cell (HeLa) lines and human lymphocytes by MTT test. Digitoxin extracted from the aerial parts of the plant collected from west of Iran and purified by column and thin layer chromatographic techniques. The structure of isolated cardiac glycoside was identified by IR, 1H NMR and 13C NMR methods and so the presence of digitoxin was established. The half maximal inhibitory concentration values for cervical cancer and lymphocyte cells were obtained to be 5.62 and 412.94 µg/mL. The results of this study introduced the new resource of digitoxin which has considerable cytotoxic effects against HeLa cancer cells but did not damage normal human lymphocyte cells.
Asunto(s)
Adonis/química , Glicósidos Cardíacos/farmacología , Digitoxina/farmacología , Glicósidos Cardíacos/aislamiento & purificación , Cromatografía en Capa Delgada , Digitoxina/aislamiento & purificación , Células HeLa , Humanos , Irán , Estructura Molecular , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacología , Componentes Aéreos de las Plantas/químicaRESUMEN
Experiments have been undertaken and for the first time, we have identified that a new cardiac glycoside (CG) isolated from Helleborus thibetanus Franch. a plant endemic to China, bears potent anti-cancer activity. We have named it as HTF-1. By using in vitro cell models, we have found that HTF-1 induces apoptosis against several types of cancer cells in a concentration- and time-dependent manner. It is able to inhibit cancer cell in proliferation, migration and invasion. HTF-1 causes S cell cycle arrest. Further-on, we have identified that HTF-1 triggers caspase-9 dependent apoptosis pathway and double strand DNA breaks (DSBs). Additionally, HTF-1 activates JNK, but suppresses ERK and PI3K-Akt-mTOR pathways. Collectively, the above-mentioned mechanisms contribute to the anti-cancer activity of HTF-1. It is rare to discover novel anti-cancer CG during the past couple of decades. We believe that our work will enrich the understanding of CGs; also, pave the way for natural product-based anti-cancer drug development.
Asunto(s)
Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Glicósidos Cardíacos/química , Glicósidos Cardíacos/farmacología , Helleborus/química , Transducción de Señal/efectos de los fármacos , Antineoplásicos Fitogénicos/aislamiento & purificación , Apoptosis/fisiología , Glicósidos Cardíacos/aislamiento & purificación , Caspasa 9/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Células HeLa , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
The present study was designed to develop a practical strategy to tackle the problem of lacking standard compounds and limited references for identifying structure-related compounds in Streptocaulon griffithii Hook. f., especially those in trace concentrations, with a focus on antitumor activity. The cardiac glycosides (CGs)-enriched part was determined using in vitro bioactive assays in three cancer cell lines and then isolated using macroporous resins. The MS and MS/MS data were acquired using a high performance liquid chromatography coupled with hybrid quadrupole-time of flight (HPLC-Q-TOF-MS) system. To acquire data of trace compound in the extract, a multiple segment program was applied to modify the HPLC-Q-TOF-MS method. A mass defect filter (MDF) approach was employed to make a primary MS data filtration. Utilizing a MATLAB program, the redundant peaks obtained by imprecise MDF template calculated with limited references were excluded by fragment ion classification, which was based on the ion occurrence number in the MDF-filtered total ion chromatograms (TIC). Additionally, the complete cleavage pathways of CG aglycones were proposed to assist the structural identification of 29 common fragment ions (CFIs, ion occurrence number ≥ 5) and diagnostic fragment ions (DFIs, ion occurrence number < 5). As a result, 30 CGs were filtered out from the MDF results, among which 23 were identified. This newly developed strategy may provide a rapid and effective tool for identifying structure-related compounds in herbal medicines.
Asunto(s)
Apocynaceae/química , Glicósidos Cardíacos/farmacología , Biología Computacional , Minería de Datos , Medicamentos Herbarios Chinos/farmacología , Espectrometría de Masas en Tándem , Células A549 , Animales , Glicósidos Cardíacos/química , Glicósidos Cardíacos/aislamiento & purificación , Glicósidos Cardíacos/toxicidad , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Medicamentos Herbarios Chinos/química , Humanos , Concentración 50 Inhibidora , Células MCF-7 , Ratones , Estructura Molecular , Raíces de Plantas/química , Plantas Medicinales/química , Flujo de TrabajoRESUMEN
Thirteen cardenolide glycosides (1-13) were isolated from the CH2Cl2 and MeOH extracts of Vallaris glabra leaves. The structures of the new compounds (2-13) were identified by spectroscopic methods, with the absolute configurations of the sugar moieties determined by acid hydrolysis. All compounds were evaluated for their cytotoxic activity against human cervix adenocarcinoma, lung carcinoma, and colorectal adenocarcinoma cell lines. The two most potent compounds [2'-O-acetylacoschimperoside P (1) and oleandrigenin-3-O-α-l-2'-O-acetylvallaropyranoside (2)] exhibited IC50 values in the range of 0.03-0.07 µM.
Asunto(s)
Glicósidos Cardíacos/aislamiento & purificación , Glicósidos Cardíacos/farmacología , Antineoplásicos Fitogénicos/química , Apocynaceae/química , Cardenólidos , Glicósidos Cardíacos/química , Femenino , Glicósidos/química , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Hojas de la Planta , Tailandia , Neoplasias del Cuello Uterino/tratamiento farmacológicoRESUMEN
Recent studies demonstrate that cardiac glycosides, known to inhibit Na+/K+-ATPase in humans, have increased susceptibility to cancer cells that can be used in tumor therapy. One of the most promising candidates identified so far is glucoevatromonoside, which can be isolated from the endangered species Digitalis mariana ssp. heywoodii. Due to its complex structure, glucoevatromonoside cannot be obtained economically by total chemical synthesis. Here we describe two methods for glucoevatromonoside production, both using evatromonoside obtained by chemical degradation of digitoxin as the precursor. 1) Catalyst-controlled, regioselective glycosylation of evatromonoside to glucoevatromonoside using 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide as the sugar donor and 2-aminoethyldiphenylborinate as the catalyst resulted in an overall 30â% yield. 2) Biotransformation of evatromonoside using Digitalis lanata plant cell suspension cultures was less efficient and resulted only in overall 18â% pure product. Structural proof of products has been provided by extensive NMR data. Glucoevatromonoside and its non-natural 1-3 linked isomer neo-glucoevatromonoside obtained by semisynthesis were evaluated against renal cell carcinoma and prostate cancer cell lines.
Asunto(s)
Antineoplásicos/metabolismo , Cardenólidos/metabolismo , Glicósidos Cardíacos/metabolismo , Digitalis/metabolismo , Digitoxina/química , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidores , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Biotransformación , Cardenólidos/síntesis química , Cardenólidos/aislamiento & purificación , Cardenólidos/farmacología , Glicósidos Cardíacos/síntesis química , Glicósidos Cardíacos/aislamiento & purificación , Glicósidos Cardíacos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Digitalis/química , Digitoxina/aislamiento & purificación , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/aislamiento & purificación , Inhibidores Enzimáticos/metabolismo , Glicosilación , Humanos , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , ATPasa Intercambiadora de Sodio-Potasio/metabolismoRESUMEN
(+)-Strebloside, a cardiac glycoside isolated from the stem bark of Streblus asper collected in Vietnam, has shown some potential for further investigation as an antineoplastic agent. A mechanistic study using an in vitro assay and molecular docking analysis indicated that (+)-strebloside binds and inhibits Na+/K+-ATPase in a similar manner to digitoxin. Inhibition of growth of different high-grade serous ovarian cancer cells including OVCAR3, OVSAHO, Kuramochi, OVCAR4, OVCAR5, and OVCAR8 resulted from treatment with (+)-strebloside. Furthermore, this compound blocked cell cycle progression at the G2 phase and induced PARP cleavage, indicating apoptosis activation in OVCAR3 cells. (+)-Strebloside potently inhibited mutant p53 expression through the induction of ERK pathways and inhibited NF-κB activity in human ovarian cancer cells. However, in spite of its antitumor potential, the overall biological activity of (+)-strebloside must be regarded as being typical of better-known cardiac glycosides such as digoxin and ouabain. Further chemical alteration of cardiac glycosides might help to reduce negative side effects while increasing cancer cell cytotoxicity.
Asunto(s)
Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Glicósidos Cardíacos/aislamiento & purificación , Glicósidos Cardíacos/farmacología , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidores , Antineoplásicos Fitogénicos/química , Apoptosis/efectos de los fármacos , Carcinoma Epitelial de Ovario , Glicósidos Cardíacos/química , Digoxina/farmacología , Femenino , Células HT29 , Humanos , Estructura Molecular , FN-kappa B/metabolismo , Neoplasias Glandulares y Epiteliales , Ouabaína/farmacología , Neoplasias Ováricas , Transducción de Señal/efectos de los fármacos , EstereoisomerismoRESUMEN
Phytochemical investigation of methanolic extract of Adenium obesum led to the isolation of 42 (1-42) compounds belongs to cardiac glycosides, triterpenoids and steroids. The chemical structures of isolated compounds were elucidated by spectral techniques UV, IR, NMR and FAB MS. The cardiac glycosides were tested against three human cell lines, 3T3 (normal cells), HeLa (Human cervical cancer cell lines) and PC-3 (Human prostate cancer cell lines). The cardiac glycoside, honghelin (4), obeside B (5) and obeside C (6) showed significant effects against cell lines Hela, 3T3 and PC-3 compared to standard drug doxorubicin. Compounds 4, 5 and 6 exhibited very low IC50 (µM) against the PC3 human cell line. 4 and 6 also showed least IC50 against the HeLa human cell lines as compared to the standard drug doxorubicin whereas these three compounds showed effect on 3T3 cell line with high IC50 values compared to drug cycloheximide.
Asunto(s)
Antineoplásicos Fitogénicos/aislamiento & purificación , Apocynaceae/química , Glicósidos Cardíacos/aislamiento & purificación , Glicósidos Cardíacos/química , Glicósidos Cardíacos/farmacología , Línea Celular Tumoral , Frutas/química , Humanos , Extractos Vegetales/análisisRESUMEN
Three new (1-3) and two known (4 and 5) cytotoxic cardiac glycosides were isolated and characterized from a medicinal plant, Streblus asper Lour. (Moraceae), collected in Vietnam, with six new analogues and one known derivative (5a-g) synthesized from (+)-strebloside (5). A preliminary structure-activity relationship study indicated that the C-10 formyl and C-5 and C-14 hydroxy groups and C-3 sugar unit play important roles in the mediation of the cytotoxicity of (+)-strebloside (5) against HT-29 human colon cancer cells. When evaluated in NCr nu/nu mice implanted intraperitoneally with hollow fibers facilitated with either MDA-MB-231 human breast or OVCAR3 human ovarian cancer cells, (+)-strebloside (5) showed significant cell growth inhibitory activity in both cases, in the dose range 5-30 mg/kg.
Asunto(s)
Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Glicósidos Cardíacos/aislamiento & purificación , Glicósidos Cardíacos/farmacología , Moraceae/química , Animales , Antineoplásicos Fitogénicos/química , Glicósidos Cardíacos/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HT29 , Humanos , Ratones , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Plantas Medicinales , Relación Estructura-Actividad , VietnamRESUMEN
Phytochemical investigation of the seeds of Thevetia peruviana resulted in the isolation of seven cardiac glycosides (1-7), including two new compounds (1 and 2). Cytotoxicity of them toward cancer cell lines P15 (human lung cancer cell), MGC-803 (human gastric cancer cells), SW1990 (human pancreatic cancer cells), and normal hepatocyte cell LO2 suggested that compound 1 could selectively inhibit the proliferation of cancer cell lines with IC50 from 0.05 to 0.15 µM. Pro-apoptotic activity revealed that it induced the apoptosis of MGC-803 cancer cells in a dose-dependent manner. Meanwhile, treatment of MGC-803 cancer cells with 1 resulted in diminution of pro-caspases 3 and 9 and activation of caspases 3 and 9, while it increased the Bax/Bcl-2 ratio in a dose-dependent manner. These meant that 1 induced the apoptosis of cancer cells by involving the intrinsic apoptotic pathway. In addition, the cell cycle distribution of MGC-803 cancer cells treated by 1 revealed that it could lead to cell cycle arrest at the G2/M phase. Altogether, this study suggested that compound 1 may exhibit anticancer activity by its capability of induction of intrinsic apoptosis and cell cycle arrest at G2/M phase.
Asunto(s)
Glicósidos Cardíacos/aislamiento & purificación , Glicósidos Cardíacos/farmacología , Medicamentos Herbarios Chinos/aislamiento & purificación , Medicamentos Herbarios Chinos/farmacología , Semillas/química , Thevetia/química , Glicósidos Cardíacos/química , Caspasa 3/metabolismo , Caspasas/metabolismo , Ciclo Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Medicamentos Herbarios Chinos/química , Humanos , Estructura Molecular , Resonancia Magnética Nuclear BiomolecularRESUMEN
An aqueous extract from the roots of Kalanchoe daigremontiana turned out to be a rich source of bufadienolides. The existing literature data relate mainly to the aerial parts of Kalanchoe but there is no information about the metabolic profile of the roots, which are also used in traditional medicine. Our investigation concerning the roots of K. daigremontiana led to the isolation and characterization of eight new bufadienolides, namely 1ß,3ß,5ß,14ß,19-pentahydroxybufa-20,22-dienolide (1), 19-(acetyloxy)-1ß,3ß,5ß,14ß-tetrahydroxybufa-20,22-dienolide (2), 3ß-O-α-l-rhamno-pyranosyl-5ß,11α,14ß,19-tetrahydroxybufa-20,22-dienolide (3), 19-(acetyloxy)-3ß,5ß,11α,14ß-tetrahydroxybufa-20,22-dienolide (4), 3ß,5ß,11α,14ß,19-pentahydroxy-12-oxo-bufa-20,22-dienolide (5), 19-(acetyloxy)-3ß,5ß,11α,14ß-tetrahydroxy-12-oxo-bufa-20,22-dienolide (6), 19-(acetyloxy)-1ß,3ß,5ß,11α,14ß-pentahydroxy-12-oxo-bufa-20,22-dienolide (7) and 1ß-(acetyloxy)-3ß,5ß,11α,14ß,19-pentahydroxy-12-oxo-bufa-20,22-dienolide (8), together with seven known compounds: 11α,19-dihydroxytelocinobufagin (9), bersaldegenin-1-acetate (10), daigredorigenin-3-acetate (11), bersaldegenin-1,3,5-orthoacetate (12), bryotoxin B (13), bryophyllin B (14) and bersaldegenin (15). The structures were established applying extensive 1D- and 2D-NMR and MS spectroscopic analyses.
Asunto(s)
Bufanólidos/química , Glicósidos Cardíacos/química , Cardiotónicos/química , Kalanchoe/química , Raíces de Plantas/química , Bufanólidos/aislamiento & purificación , Glicósidos Cardíacos/aislamiento & purificación , Cardiotónicos/aislamiento & purificación , Humanos , Espectroscopía de Resonancia Magnética , Estructura Molecular , Extractos Vegetales/química , Solventes , AguaRESUMEN
Investigation of the seeds of Thevetia peruviana resulted in the isolation of 15 new (2-16) and 18 known (1 and 17-33) cardiac glycosides. Eight 19-nor-cardenolides (1-8), including two rare 19-nor-10-hydroperoxycardenolides, were obtained from T. peruviana for the first time. All the structures were characterized by NMR spectroscopy and chemical derivatization. The inhibitory effects of cardiac glycosides 1-33 against three cancer cell lines (human lung cancer cells, P15; human gastric cancer cells, MGC-803; and human pancreatic cancer cells, SW1990) and one normal hepatocyte cell line, LO2, were evaluated, and a preliminary structure-activity relationship is discussed. In addition, cardiac glycosides 1, 22, 26, and 28 were evaluated for their apoptosis-inducing activities in MGC-803 cells, showing IC50 values in the range 0.02-0.53 µM.
Asunto(s)
Antineoplásicos Fitogénicos/aislamiento & purificación , Cardenólidos/aislamiento & purificación , Glicósidos Cardíacos/aislamiento & purificación , Medicamentos Herbarios Chinos/aislamiento & purificación , Semillas/química , Thevetia/química , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Cardenólidos/química , Cardenólidos/farmacología , Glicósidos Cardíacos/química , Glicósidos Cardíacos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Relación Estructura-ActividadRESUMEN
Topic applications of Calendula officinalis L. lipophilic extracts are used in phytotherapy to relieve skin inflammatory conditions whereas infusions are used as a remedy for gastric complaints. Such a different usage might be explained by some cytotoxicity of lipophilic extracts at gastric level but little is known about this. Therefore, we screened the CH2Cl2 extract from the flowers of C. officinalis by MTT and LDH assays in human epithelial gastric cells AGS. This bioassay-oriented approach led to the isolation of several sesquiterpene glycosides which were structurally characterized by spectroscopic measurements, chemical reactions and MM calculations. The conformational preferences of viridiflorol fucoside were established and a previously assigned stereochemistry was revised. The compounds 1a, 2a and 3f showed comparably high cytotoxicity in the MTT assays, whereas the effect on LDH release was lower. Our study provides new insights on the composition of C. officinalis extracts of medium polarity and identifies the main compounds that could be responsible for cytotoxic effects at gastric level.
Asunto(s)
Calendula/química , Glicósidos Cardíacos/aislamiento & purificación , Glicósidos Cardíacos/farmacología , Glicósidos/aislamiento & purificación , Glicósidos/farmacología , L-Lactato Deshidrogenasa/metabolismo , Sesquiterpenos/aislamiento & purificación , Sesquiterpenos/farmacología , Terpenos/química , Glicósidos Cardíacos/química , Ésteres , Flores/química , Glicósidos/química , Humanos , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Fitoterapia , Extractos Vegetales/química , Extractos Vegetales/farmacología , Sesquiterpenos/química , EstereoisomerismoRESUMEN
Five new cardiac glycosides (1-5, namely antiaroside Y-ZC) together with 19 known compounds were obtained from the bark of Antiaris toxicaria. Their chemical structures were determined by IR, HR-ESI-MS, 1D and 2D NMR (HSQC, (1)H-(1)H COSY, HMBC, ROESY). The absolute configuration of sugar unit was defined by acid hydrolysis and appropriate derivatization. Compound 1 was rare 5ß-H-10ß-H-19-nor-cardenolide, which might derive from decarboxylative derivative of 19-COOH cardenolide. The inhibitory effects of cardiac glycosides 1-11 on the viability of NIH-H460 lung cancer cells and their induction of Nur77 expression were evaluated and preliminary structure-activity relationship (SAR) was also discussed.
Asunto(s)
Antiaris/química , Glicósidos Cardíacos/aislamiento & purificación , Neoplasias Pulmonares/tratamiento farmacológico , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Glicósidos Cardíacos/química , Glicósidos Cardíacos/uso terapéutico , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Neoplasias Pulmonares/metabolismo , Corteza de la Planta/química , Relación Estructura-ActividadRESUMEN
We have studied the ethyl acetate fraction of the methanolic extract of the root barks of Calotropis procera (Asclepiadaceae) from Egypt. Bioassay-directed fractionation and final purification of the extract resulted in the identification of a new cardenolide glycoside named proceraside A (1) together with two known compounds, frugoside (2) and calotropin (3). Their structures were elucidated by extensive NMR studies and mass spectrometric data. The in vitro cytotoxicity of the isolated compounds was evaluated against A549 non-small cell lung cancer, U373 glioblastoma and PC-3 prostate cancer cell lines. They showed potent activity against the tested cancer cell lines with IC50 ranging from 0.005 to 0.3 µg/mL. Cisplatin was used as positive control.