RESUMEN
Covering: December 2005 to June 2016. Previous review: Nat. Prod. Rep., 2006, 23, 673-698Over the last decade, great efforts have been made to conduct phytochemistry research on the genus Isodon, which have led to the isolation and identification of a number of diterpenoids. At the same time, these newly reported diterpenoids with diverse structures have led to new findings on their biological functions and chemical synthesis research. In this update, we review more than 600 new diterpenoids, including their structures, classifications, biogenetic pathways, bioactivities, and chemical synthesis.
Asunto(s)
Diterpenos , Isodon/química , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Diterpenos/química , Diterpenos/aislamiento & purificación , Diterpenos/farmacología , Estructura Molecular , Resonancia Magnética Nuclear BiomolecularRESUMEN
Fourteen new diterpenoids (1-14) based on four skeletal types and two known analogues (15 and 16) were isolated from the aerial parts of Isodon scoparius. Compound 2 is the first ent-kaurane diterpenoid featuring a 1,11-ether bridge, and the structures of these new compounds were established mainly by NMR and MS methods. The absolute configurations of 1 and 5 and the relative configuration of 3 were determined using single-crystal X-ray diffraction. The absolute configuration of 14 was determined by comparison of the experimental and calculated electronic circular dichroism spectra. Compounds 1, 4, and 15 were active against five human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW-480), and they also inhibited NO production in LPS-stimulated RAW264.7 cells, with IC50 values of 1.0, 3.1, and 1.8 µM, respectively.
Asunto(s)
Antineoplásicos Fitogénicos , Diterpenos de Tipo Kaurano , Isodon/química , Componentes Aéreos de las Plantas/química , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Cristalografía por Rayos X , Diterpenos de Tipo Kaurano/química , Diterpenos de Tipo Kaurano/aislamiento & purificación , Diterpenos de Tipo Kaurano/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/aislamiento & purificación , Medicamentos Herbarios Chinos/farmacología , Células HL-60 , Humanos , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Estructura Molecular , Óxido Nítrico/biosíntesis , Resonancia Magnética Nuclear BiomolecularRESUMEN
Four new ent-abietane diterpenoids, along with four known ones were isolated from the aerial parts of Isodon serra, a traditional Chinese folk medicine. The new diterpenoids were named as serrin K (1), xerophilusin XVII (2), and enanderianins Q and R (3 and 4), while the known ones were identified as rubescansin J (5), (3α,14ß)-3,18-[(1-methylethane-1,1-diyl)dioxy]-ent-abieta-7,15(17)-diene-14,16-diol (6), xerophilusin XIV (7), and enanderianin P (8), respectively. Their structures were elucidated by extensive spectroscopic analysis and comparison with the literature. Compound 1 showed remarkable inhibitory activity towards NO production in LPS-stimulated RAW264.7 cells (IC50 = 1.8 µM) and weak cytotoxicity towards five human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7, SW480).
Asunto(s)
Abietanos/química , Abietanos/aislamiento & purificación , Isodon/química , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Abietanos/farmacología , Animales , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Línea Celular , Línea Celular Tumoral , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Espectroscopía de Resonancia Magnética , Ratones , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Óxido Nítrico/biosíntesis , Componentes Aéreos de las Plantas/química , Extractos Vegetales/farmacologíaRESUMEN
The phytochemical investigation on 1 g of materials from Gypsoplacamacrophylla (Zahlbr.) Timdal resulted in the discovery of gypmacrophin A, a rare pentacyclic sesterterpenoid; brialmontin III, a new polysubstituted depside and two known ones, brialmontins I and II. The structure and absolute configurations of gypmacrophin A were elucidated by spectroscopic analyses and computational methods. Gypmacrophin A showed weak inhibition of AchE with an IC50 value of 32.03 µM. The four compounds provided new chemical evidence for G. macrophylla identification.
Asunto(s)
Ascomicetos/aislamiento & purificación , Depsidos/química , Sesterterpenos/química , Acetilcolinesterasa , Modelos Moleculares , Estructura Molecular , Fragmentos de Péptidos/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
Thirty-two enmein-type ent-kaurane diterpenoids, including 13 new compounds, were isolated from the aerial parts of Isodon phyllostachys. Compounds 1 and 2 are the first examples of 3,20:6,20-diepoxyenmein-type ent-kauranoids, and the structures of these new compounds were established mainly by analyzing NMR and HREIMS data. The absolute configurations of 1 and 8 and the relative configuration of 9 were determined using single-crystal X-ray diffraction. Compounds 11, 15, 20, and 21 were active against five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW-480), with IC50 values ranging from 1.2 to 5.0 µM. Compounds 3, 11, 15, 17, 20, 21, 25, and 29 strongly inhibited NO production in LPS-stimulated RAW264.7 cells, with IC50 values ranging from 0.74 to 4.93 µM.
Asunto(s)
Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Diterpenos de Tipo Kaurano/aislamiento & purificación , Diterpenos de Tipo Kaurano/farmacología , Medicamentos Herbarios Chinos/aislamiento & purificación , Medicamentos Herbarios Chinos/farmacología , Isodon/química , Animales , Antineoplásicos Fitogénicos/química , Cristalografía por Rayos X , Diterpenos , Diterpenos de Tipo Kaurano/química , Ensayos de Selección de Medicamentos Antitumorales , Medicamentos Herbarios Chinos/química , Células HL-60 , Humanos , Concentración 50 Inhibidora , Lipopolisacáridos/farmacología , Ratones , Conformación Molecular , Estructura Molecular , Óxido Nítrico/biosíntesis , Componentes Aéreos de las Plantas/químicaRESUMEN
Fourteen new rearranged 6/6/5/6-fused triterpenoid acids, namely, kadcoccine acids A-N (1-14), were isolated from an EtOAc-soluble extract of the stems of Kadsura coccinea. Their structures were characterized mainly by analyzing 1D and 2D NMR and HRESIMS data and were shown to feature a rare 14(13â12)-abeo-lanostane skeleton. Compounds 7 and 8 represented the first examples of a 5-substituted 2(5H)-furanone motif on the C-17 side chain of this skeleton. The absolute configurations of C-23 for compounds 1, 7, and 8 were determined by comparison of their experimental electronic circular dichroism spectra. All the isolates were screened for their in vitro cytotoxicity against six human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7, SW-480, and HeLa), and compounds 2 and 8 exhibited weak inhibitory effects with IC50 values ranging from 3.11 to 7.77 µM.
Asunto(s)
Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/aislamiento & purificación , Kadsura/química , Tallos de la Planta/química , Triterpenos/química , Triterpenos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Medicamentos Herbarios Chinos/farmacología , Femenino , Células HL-60 , Células HeLa , Humanos , Lanosterol/química , Células MCF-7 , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Relación Estructura-Actividad , Triterpenos/farmacologíaRESUMEN
Penicilfuranone A (1), a novel furancarboxylic acid, and its proposed biosynthetic precursor, gregatin A (2), were isolated from the cultures of the fungus Penicillium sp. sh18 endophytic to the stems of Isodon eriocalyx var. laxiflora guided by HPLC-MS. X-ray crystallography was applied to the structure determination of furancarboxylic acid for the first time, allowing unambiguous assignment of 1. Penicilfuranone A displays a significant antifibrotic effect in activated hepatic stellate cells via negative regulation of transforming growth factor-ß (TGF-ß)/Smad signaling.
Asunto(s)
Ácidos Carboxílicos/aislamiento & purificación , Ácidos Carboxílicos/farmacología , Furanos/aislamiento & purificación , Furanos/farmacología , Penicillium/química , Animales , Western Blotting , Ácidos Carboxílicos/química , Cristalografía por Rayos X , Furanos/química , Isodon/microbiología , Conformación Molecular , Estructura Molecular , Ratas , Factor de Crecimiento Transformador beta/efectos de los fármacosRESUMEN
Several significant advances in the field of phytochemistry were made between 2008 and 2014 because of the high level of interest in Schisandraceae triterpenoids. In addition to a dramatic increase in the number of newly identified triterpenoids, the first complete synthesis of a schinortriterpenoid was accomplished. There has also been substantial progress in investigations of biological activity and mechanism of action. In this update, we review more than 250 new triterpenoids and describe their structures, classifications, biogenetic pathways, syntheses, and bioactivities.
Asunto(s)
Schisandraceae/química , Triterpenos/aislamiento & purificación , Estructura Molecular , Triterpenos/química , Triterpenos/farmacologíaRESUMEN
BACKGROUND: Small-molecule compounds that inhibit human immunodeficiency virus type 1 (HIV-1) infection can be used not only as drug candidates, but also as reagents to dissect the life cycle of the virus. Thus, it is desirable to have an arsenal of such compounds that inhibit HIV-1 infection by various mechanisms. Until now, only a few small-molecule compounds that inhibit nuclear entry of viral DNA have been documented. RESULTS: We identified a novel, small-molecule compound, SJP-L-5, that inhibits HIV-1 infection. SJP-L-5 is a nitrogen-containing, biphenyl compound whose synthesis was based on the dibenzocyclooctadiene lignan gomisin M2, an anti-HIV bioactive compound isolated from Schisandra micrantha A. C. Smith. SJP-L-5 displayed relatively low cytotoxicity (50% cytoxicity concentrations were greater than 200 µg/ml) and high antiviral activity against a variety of HIV strains (50% effective concentrations (EC50)) of HIV-1 laboratory-adapted strains ranged from 0.16-0.97 µg/ml; EC50s of primary isolates ranged from 1.96-5.33 µg/ml). Analyses of the viral DNA synthesis indicated that SJP-L-5 specifically blocks the entry of the HIV-1 pre-integration complex (PIC) into the nucleus. Further results implicated that SJP-L-5 inhibits the disassembly of HIV-1 particulate capsid in the cytoplasm of the infected cells. CONCLUSIONS: SJP-L-5 is a novel small-molecule compound that inhibits HIV-1 nuclear entry by blocking the disassembly of the viral core.
Asunto(s)
Fármacos Anti-VIH/farmacología , ADN Viral/metabolismo , VIH-1/efectos de los fármacos , VIH-1/fisiología , Integración Viral/efectos de los fármacos , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/aislamiento & purificación , Fármacos Anti-VIH/toxicidad , Línea Celular , Supervivencia Celular/efectos de los fármacos , Humanos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Schisandra/químicaRESUMEN
Adenanthin, a diterpenoid isolated from the leaves of Isodon adenanthus, has been reported to possess antileukemic activity through targeting peroxiredoxin I/II. However, its other potential activities remain to be explored. Using myelin oligodendrocyte glycoprotein (MOG)35-55-induced experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, we report in this study that adenanthin exerts efficaciously preventive and therapeutic effects on EAE accompanied by significant restriction of infiltration of inflammatory cells and demyelination in CNS. Adenanthin-presented immunomodulatory effects on EAE are correlated with suppressed proliferation of MOG35-55-reactive T cells, decreased Th1 and Th17 cells, increased regulatory T cell populations, decreased production of serum proinflammatory cytokines, and reduced stimulatory capacity of APCs, which might be mediated by its inhibitory action on NF-κB signaling pathway. Our results propose that, as a novel NF-κB inhibitor, adenanthin has potent immunomodulatory activity for the treatment of multiple sclerosis and possibly other autoimmune disorders.
Asunto(s)
Diterpenos/farmacología , Encefalomielitis Autoinmune Experimental/metabolismo , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Western Blotting , Ensayo de Cambio de Movilidad Electroforética , Encefalomielitis Autoinmune Experimental/inmunología , Citometría de Flujo , Inmunohistoquímica , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
Two compounds belonging to a new group of diterpene alkaloids, kaurines A and B (1 and 2), and an alkaloid bearing a succinimide moiety (3) were obtained from Isodon rubescens. Their structures and absolute configurations were determined by spectroscopy and quantum-chemical computational (13)C NMR and ECD data analysis. These alkaloids differ from known diterpene alkaloids and diterpenoids and are presumably biosynthesized from ent-kaurane diterpenoids.
Asunto(s)
Alcaloides/química , Alcaloides/aislamiento & purificación , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Diterpenos de Tipo Kaurano/química , Diterpenos de Tipo Kaurano/aislamiento & purificación , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/aislamiento & purificación , Isodon/química , Alcaloides/farmacología , Antineoplásicos Fitogénicos/farmacología , Diterpenos de Tipo Kaurano/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Medicamentos Herbarios Chinos/farmacología , Células HL-60 , Humanos , Células MCF-7 , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Componentes Aéreos de las Plantas/químicaRESUMEN
Eleven triterpene acids including 10 new compounds (kadcoccinic acids A-J, 1-10) were isolated from the stems of Kadsura coccinea. Except for 10, these compounds feature a rearranged lanostane skeleton with a 6/6/5/6 tetracyclic ring system, and compounds 1 and 2 are the first examples of 2,3-seco-6/6/5/6-fused tetracyclic triterpenoids. Their structures were established primarily by spectroscopic and spectrometric methods. Additionally, the absolute configuration of 3 was determined by single-crystal X-ray diffraction. Several of the compounds isolated were tested for their anti-HIV-1 and cytotoxic activities.
Asunto(s)
Fármacos Anti-VIH/aislamiento & purificación , Antineoplásicos Fitogénicos/aislamiento & purificación , Medicamentos Herbarios Chinos/aislamiento & purificación , Kadsura/química , Triterpenos/aislamiento & purificación , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Femenino , VIH-1/efectos de los fármacos , Células HL-60 , Humanos , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Tallos de la Planta/química , Triterpenos/química , Triterpenos/farmacologíaRESUMEN
Coleifolides A and B (1 and 2), two new sesterterpenoids with a ß-methyl-α,ß-unsaturated-γ-lactone moiety, were isolated from the aerial parts of Scutellaria coleifolia H.Lév. (Lamiaceae), together with three known compounds. Their structures were elucidated by NMR and MS examinations. Coleifolides A and B were concluded to be partially racemic compounds by the HPLC analysis using a chiral column or introduction of chiral derivatizing agents. The absolute configuration of the major isomer was determined by analyses of the CD spectrum as well as NMR data of (R)- and (S)-2-NMA derivatives. Coleifolides A and B are structurally similar to manoalide derivatives, previously isolated from marine sponges, and appear to be the first examples of this type of compounds being isolated from higher plants.
Asunto(s)
Lactonas/análisis , Componentes Aéreos de las Plantas/química , Scutellaria/química , Sesterterpenos/análisis , Cromatografía Líquida de Alta Presión , Lactonas/aislamiento & purificación , Espectroscopía de Resonancia Magnética , Conformación Molecular , Extractos Vegetales/química , Sesterterpenos/aislamiento & purificaciónRESUMEN
INTRODUCTION: Peroxiredoxin-1 (PRDX1) is a multifunctional protein, acting as a hydrogen peroxide (H2O2) scavenger, molecular chaperone and immune modulator. Although differential PRDX1 expression has been described in many tumors, the potential role of PRDX1 in breast cancer remains highly ambiguous. Using a comprehensive antibody-based proteomics approach, we interrogated PRDX1 protein as a putative biomarker in estrogen receptor (ER)-positive breast cancer. METHODS: An anti-PRDX1 antibody was validated in breast cancer cell lines using immunoblotting, immunohistochemistry and reverse phase protein array (RPPA) technology. PRDX1 protein expression was evaluated in two independent breast cancer cohorts, represented on a screening RPPA (n = 712) and a validation tissue microarray (n = 498). In vitro assays were performed exploring the functional contribution of PRDX1, with oxidative stress conditions mimicked via treatment with H2O2, peroxynitrite, or adenanthin, a PRDX1/2 inhibitor. RESULTS: In ER-positive cases, high PRDX1 protein expression is a biomarker of improved prognosis across both cohorts. In the validation cohort, high PRDX1 expression was an independent predictor of improved relapse-free survival (hazard ratio (HR) = 0.62, 95% confidence interval (CI) = 0.40 to 0.96, P = 0.032), breast cancer-specific survival (HR = 0.44, 95% CI = 0.24 to 0.79, P = 0.006) and overall survival (HR = 0.61, 95% CI = 0.44 to 0.85, P = 0.004). RPPA screening of cancer signaling proteins showed that ERα protein was upregulated in PRDX1 high tumors. Exogenous H2O2 treatment decreased ERα protein levels in ER-positive cells. PRDX1 knockdown further sensitized cells to H2O2- and peroxynitrite-mediated effects, whilst PRDX1 overexpression protected against this response. Inhibition of PRDX1/2 antioxidant activity with adenanthin dramatically reduced ERα levels in breast cancer cells. CONCLUSIONS: PRDX1 is shown to be an independent predictor of improved outcomes in ER-positive breast cancer. Through its antioxidant function, PRDX1 may prevent oxidative stress-mediated ERα loss, thereby potentially contributing to maintenance of an ER-positive phenotype in mammary tumors. These results for the first time imply a close connection between biological activity of PRDX1 and regulation of estrogen-mediated signaling in breast cancer.
Asunto(s)
Biomarcadores de Tumor , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Receptor alfa de Estrógeno/metabolismo , Estrés Oxidativo , Peroxirredoxinas/metabolismo , Línea Celular Tumoral , Estudios de Cohortes , Femenino , Humanos , Inmunohistoquímica , Pronóstico , Transducción de SeñalRESUMEN
Peroxiredoxins (Prxs) are potential therapeutic targets for major diseases such as cancers. However, isotype-specific inhibitors remain to be developed. We report that adenanthin, a diterpenoid isolated from the leaves of Rabdosia adenantha, induces differentiation of acute promyelocytic leukemia (APL) cells. We show that adenanthin directly targets the conserved resolving cysteines of Prx I and Prx II and inhibits their peroxidase activities. Consequently, cellular H(2)O(2) is elevated, leading to the activation of extracellular signal-regulated kinases and increased transcription of CCAAT/enhancer-binding protein ß, which contributes to adenanthin-induced differentiation. Adenanthin induces APL-like cell differentiation, represses tumor growth in vivo and prolongs the survival of mouse APL models that are sensitive and resistant to retinoic acid. Thus, adenanthin can serve as what is to our knowledge the first lead natural compound for the development of Prx I- and Prx II-targeted therapeutic agents, which may represent a promising approach to inducing differentiation of APL cells.
Asunto(s)
Antineoplásicos/farmacología , Diferenciación Celular/efectos de los fármacos , Diterpenos de Tipo Kaurano/farmacología , Diterpenos/farmacología , Leucemia Promielocítica Aguda/tratamiento farmacológico , Peroxirredoxinas/antagonistas & inhibidores , Animales , Antineoplásicos/química , Proteína beta Potenciadora de Unión a CCAAT/biosíntesis , Cisteína/química , Diterpenos/química , Diterpenos de Tipo Kaurano/química , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Peróxido de Hidrógeno/análisis , Ratones , Peroxirredoxinas/química , Tretinoina/farmacología , Células Tumorales CultivadasRESUMEN
Thirteen new heterodimeric ent-kauranoids, bistenuifolins A-M (1-13), were isolated from the aerial parts of Isodon tenuifolius. The constituent units of compounds 1-6 were linked by a six-membered dihydropyran ring, while those of compounds 7-11 were joined by a rare single carbon-carbon bond (C-16âC-17'). The constituent units of 12 and 13 were linked via an unusual cyclobutane moiety. The structures of these metabolites were established via spectrometric analyses, and the absolute configurations of 1 and 4 were defined by single-crystal X-ray diffraction. Selected compounds were evaluated for their cytotoxicity against a small panel of human tumor cell lines; bistenuifolin B (2) exhibited weak inhibitory effects.
Asunto(s)
Antineoplásicos Fitogénicos/aislamiento & purificación , Diterpenos de Tipo Kaurano/aislamiento & purificación , Medicamentos Herbarios Chinos/aislamiento & purificación , Isodon/química , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Cristalografía por Rayos X , Diterpenos de Tipo Kaurano/química , Diterpenos de Tipo Kaurano/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Humanos , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Componentes Aéreos de las Plantas/químicaRESUMEN
Phytochemical investigation of EtOAc extracts of the aerial parts of Isodon wikstroemioides afforded 18 new ent-kaurane diterpenoids (wikstroemioidins E-V, 1-18), along with 17 known analogues (19-35). The absolute configurations of 1 and 16 were confirmed by single-crystal X-ray diffraction analysis. The isolates were screened against five human tumor cell lines; compounds 3, 4, 9, 11-13, 23, 25-28, and 33 exhibited significant cytotoxic activity against all five, with IC50 values ranging from 0.4 to 5.1 µM. In addition, 17 of the isolates strongly inhibited nitric oxide production in LPS-activated RAW264.7 macrophages.
Asunto(s)
Antineoplásicos Fitogénicos , Diterpenos de Tipo Kaurano , Medicamentos Herbarios Chinos , Isodon/química , Animales , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Cristalografía por Rayos X , Diterpenos de Tipo Kaurano/química , Diterpenos de Tipo Kaurano/aislamiento & purificación , Diterpenos de Tipo Kaurano/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/aislamiento & purificación , Medicamentos Herbarios Chinos/farmacología , Células HL-60 , Humanos , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Ratones , Óxido Nítrico/biosíntesis , Resonancia Magnética Nuclear BiomolecularRESUMEN
BACKGROUND: Longikaurin A is a natural ent-kaurene diterpenoid isolated from Isodon genus. The ent-kaurene diterpenoids isolated from medicinal plants have been shown to have anti-disease effects. The present study was designed to examine the anti-tumour effects of longikaurin A (LK-A) in nasopharyngeal carcinoma in vitro and in vivo. METHODS: Apoptosis and cell cycle arrest were determined by flow cytometry analysis of the cells treated with Longikaurin A. The proteins of apoptosis signaling pathway were detected by western blotting analysis. Finally, we examined whether LK-A exhibits anti-tumour activity in xenograft models. RESULTS: Longikaurin A inhibited the cell growth by inducing apoptosis and cell cycle arrest. At low concentrations, longikaurin A induced S phase arrest and at higher concentrations, longikaurin A induced caspase-dependent apoptosis by regulating apoptotic molecules. Finally, longikaurin A significantly inhibited the tumour growth of CNE2 xenografts in vivo and showed no obvious effect on the body weights of the mice. CONCLUSION: Our results suggest that Longikaurin A exhibited anti-tumour activity in nasopharyngeal carcinoma in vitro and in vivo.
Asunto(s)
Antineoplásicos/uso terapéutico , Diterpenos de Tipo Kaurano/uso terapéutico , Neoplasias Nasofaríngeas/tratamiento farmacológico , Clorometilcetonas de Aminoácidos/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/metabolismo , Carcinoma , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Diterpenos de Tipo Kaurano/química , Diterpenos de Tipo Kaurano/farmacología , Ratones , Ratones Desnudos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/enzimología , Neoplasias Nasofaríngeas/patología , Poli(ADP-Ribosa) Polimerasas/metabolismo , Fase S/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Ensayo de Tumor de Célula Madre , Regulación hacia Arriba/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Three new abietane diterpenoids, isoabietenins A-C (1-3), and 13 new ent-kauranoids, tenuifolins A-M (4-16), along with four known compounds (17-20), were isolated from the aerial parts of Isodon tenuifolius. The structures of the new metabolites were established on the basis of detailed spectroscopic analysis. The absolute configurations of 1, 15, and 16 were confirmed by single-crystal X-ray diffraction. Selected compounds were evaluated for their cytotoxicity against a small panel of human tumor cell lines, and some compounds showed inhibitory effects. Furthermore, several isolates exhibited inhibitory activity against nitric oxide production in LPS-activated RAW264.7 macrophages.
Asunto(s)
Abietanos/aislamiento & purificación , Abietanos/farmacología , Diterpenos de Tipo Kaurano/aislamiento & purificación , Diterpenos de Tipo Kaurano/farmacología , Isodon/química , Abietanos/química , Animales , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Cristalografía por Rayos X , Diterpenos de Tipo Kaurano/química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Ratones , Estructura Molecular , Óxido Nítrico/biosíntesis , Resonancia Magnética Nuclear BiomolecularRESUMEN
Isorosthin A (1), the first 20-nor-enmein-type diterpenoid, and 15 new ent-kauranoids, isorosthins B-P (2-16), along with 22 known analogues were isolated from the aerial parts of Isodon rosthornii. The structures of 1-16 were elucidated by means of spectroscopic analysis. The relative configuration of 2 and the absolute configuration of 3 were determined by single-crystal X-ray diffraction. Cytotoxicity evaluation against five human tumor lines showed inhibitory effects by several of the compounds tested. Furthermore, 12 of the isolates exhibited inhibitory activity against nitric oxide production in LPS-activated RAW264.7 macrophages.