RESUMEN
For a newly synthesized compound, identifying its target protein is a slow but pivotal step toward understand its pharmacologic mechanism. In this study, we systemically synthesized novel manzamine derivatives and chose 1-(9'-methyl-3'-carbazole)-3, 4-dihydro-ß-carboline (MCDC) as an example to identify its target protein and function. MCDC had potent toxicity against several cancer cells. To identify its target protein, we first used a docking screen to predict macrophage migration inhibitory factor (MIF) as the potential target. Biochemical experiments, including mutation analysis and hydrogen-deuterium exchange assays, validated the binding of MCDC to MIF. Furthermore, MCDC was shown by microarrays to interfere with the cell cycle of breast cancer MCF7 cells. The activated signaling pathways included AKT phosphorylation and S phase-related proteins. Our results showed MIF as a potential direct target of a newly synthesized manzamine derivative, MCDC, and its pharmacologic mechanisms.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Carbazoles/farmacología , Carbolinas/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Factores Inhibidores de la Migración de Macrófagos/antagonistas & inhibidores , Antineoplásicos/química , Apoptosis , Biomarcadores de Tumor , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Carbazoles/química , Carbolinas/química , Ciclo Celular , Proliferación Celular , Femenino , Perfilación de la Expresión Génica , Humanos , Oxidorreductasas Intramoleculares/metabolismo , Factores Inhibidores de la Migración de Macrófagos/metabolismo , Fosforilación , Células Tumorales CultivadasRESUMEN
Sapindus mukorossi is a deciduous plant and has recently been recognized to have anticancer property. In the present study, we discovered that S. mukorossi leaf and stem aqueous extract (SaM) contained two polysaccharides mainly made of myo-inositol, galactose, glucose, and fructose and the aim of this study was to investigate the antitumor property the aqueous extract SaM. In vitro treatment of SaM diminished proliferative potential of lung adenocarcinomic cells and induced intracellular oxidative stress, as well as necrotic cell death. Moreover, exposure to SaM attenuated cell migration, demonstrating the effectiveness at reducing invasive property of malignant lung cells. Gene and protein expression studies indicated that SaM treatment altered the expression of proliferation/survival modulator NF-κB, tumor growth modulator ERK2, metastasis-associated molecules MMP9/12, and tumor suppressor p53 in A549 cells. Using model animals bearing Lewis lung cancer cell LL/2, we demonstrated that SaM was antitumoral and did not induce any undesired organ damage, immunotoxicity, and off-target inflammation. This work, to our knowledge, is the first study documents the antitumor bioactivity of aqueous extract riched in polysaccharides from S. mukorossi and provides insights into the potential pharmacological application of SaM as antitumor agent against lung cancer.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Extractos Vegetales/farmacología , Sapindus/química , Agua/química , Células A549 , Animales , Antineoplásicos Fitogénicos/aislamiento & purificación , Muerte Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Humanos , Masculino , Ratones , Extractos Vegetales/aislamiento & purificación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Six new triterpenoids, euscaphic acids G-L (1-6), along with nine known triterpene acids, and two known lignans were isolated from the ethanolic extract of the twigs of Euscaphis japonica. This is the first report concerning 1α,3ß-dihydroxy-12-oleanen-28-oic acid isolated from a natural source. The structures of the new compounds were established by spectroscopic analysis. The cytotoxic and anti-NO production activities for the isolates are also evaluated and discussed; compound 1, hederagenin (11), and arjunic acid (12) showed significant cytotoxicity against NCI-H460 cells, HT-29 cells, and CEM cells (IC50 = 1.64 ± 0.87, 2.11 ± 1.54, 1.73 ± 0.64 µM, respectively). Some of the isolated triterpenoids showed marginal inhibitions on NO production induced by LPS.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Magnoliopsida/química , Ácido Oleanólico/análogos & derivados , Extractos Vegetales/farmacología , Triterpenos/farmacología , Animales , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Línea Celular Tumoral , Supervivencia Celular , Humanos , Concentración 50 Inhibidora , Lignanos/química , Lignanos/aislamiento & purificación , Lignanos/farmacología , Macrófagos/efectos de los fármacos , Ratones , Estructura Molecular , Óxido Nítrico/metabolismo , Ácido Oleanólico/química , Ácido Oleanólico/aislamiento & purificación , Ácido Oleanólico/farmacología , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Polisacáridos/efectos adversos , Triterpenos/química , Triterpenos/aislamiento & purificaciónRESUMEN
A new dimeric phenylpropanoid namely podonaka A (1), along with the 13 known compounds including diterpenes (2 and 3), norditerpenes (4 and 5), benzenoids (6-10), steroids (11 and 12), chalcone (13), and megastigmane (14), was isolated from the EtOH extract of Podocarpus nakaii Hayata. The structure of 1 was elucidated on the basis of spectroscopic analysis including 1D and 2D NMR and MS techniques. Biological evaluation showed that norditerpenes, inumakilactone B (4), and podolactone E (5) have potent cytotoxic activities against Daoy, WiDr, KB, and HeLa tumor cell lines. Moreover, low dosage of 5 may induce early apoptosis in KB cells before 12 h.
Asunto(s)
Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Diterpenos/aislamiento & purificación , Diterpenos/farmacología , Fenilpropionatos/aislamiento & purificación , Fenilpropionatos/farmacología , Plantas Medicinales/química , Tracheophyta/química , Antineoplásicos Fitogénicos/química , Diterpenos/química , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Células KB , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Fenilpropionatos/química , Corteza de la Planta/química , Tallos de la Planta/química , TaiwánRESUMEN
A new diterpene, 16-hydroxy communic acid (1), along with thirty one known compounds including five norditerpenes (2-6), twenty two flavonoids containing four biflavonoids (7-10), nine monoflavonoids (11-19) and nine flavanoid glycosides (20-28), as well as four phenolic constituents (29-32) were isolated from the 95% ethanolic extract of Podocarpus fasciculus. The structure of 1 was elucidated using spectral methods. Of these isolates, nagilactone C (2) showed the most significant inhibitory effects against DLD cells (human colon carcinoma) (ED(50)=2.57 microg/ml) and compounds 7, 8, 10, 11, and 12 had moderate cytotoxic activity against human KB (human oral epithelium carcinoma), Hela (human cervical carcinoma), Hepa (human hepatoma), DLD (colon carcinoma), and A-549 (human lung carcinoma) tumor cell lines. Preliminary structure-activity relationship studies of the isolated diterpenoids and biflavonoids are discussed.
Asunto(s)
Antineoplásicos Fitogénicos/química , Diterpenos/química , Tracheophyta/química , Antineoplásicos Fitogénicos/farmacología , Conformación de Carbohidratos , Línea Celular Tumoral , Cromatografía Líquida de Alta Presión , Diterpenos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Indicadores y Reactivos , Espectrometría de Masa por Ionización de Electrospray , Espectrofotometría Infrarroja , Espectrofotometría Ultravioleta , Relación Estructura-Actividad , Sales de Tetrazolio , TiazolesRESUMEN
From the ethanolic extract of Smilax bracteata, six phenylpropanoid glycosides, smilasides G-L (1-6), along with four known phenylpropanoid compounds, helonioside A, helonioside B, smilaside E, and (1-p-O-coumaroyl-6-O-feruroyl)-beta-d-fructofuranosyl-alpha-d-glucopyranoside, and fourteen known phenolic compounds were isolated. Their structures were elucidated on the basis of spectroscopic analyses. Moreover, 1-6 exhibited moderate scavenging activities against DPPH radicals.
Asunto(s)
Glicósidos/química , Smilax/química , Compuestos de Bifenilo , Depuradores de Radicales Libres/química , Hidrazinas , Estructura Molecular , Picratos , Componentes Aéreos de las PlantasRESUMEN
[structure: see text]. Two novel triterpene dilactones, kadsuphilactones A (1) and B (2), were isolated from the Taiwanese medicinal plant Kadsura philippinensis. The structures of 1 and 2 were elucidated on the basis of extensive spectroscopic methods, including two-dimensional NMR techniques, and confirmed by X-ray crystallographic analysis. Kadsuphilactone B (2) exhibited in vitro anti-HBV activity with IC(50) values of 6 microg/mL by HBsAg enzyme immunoassay.