Inhibitory effects of Ellipticine on inflammation in lipopolysaccharide-induced RAW264.7 cells / 中华危重病急救医学

Objective To determine the inhibitory effects of Ellipticine (ELL) on inflammation in lipopolysaccharide (LPS)-induced RAW264.7 cells of mouse and explore its molecular mechanism.Methods The RAW264.7 cells in log phase were challenged by LPS (10 mg/L) to induce inflammation and then treated with ELL (0.05, 0.5, 5μmol/L). At the same time the cells treated with ELL (5μmol/L) were considered as ELL control group while without any stimulation as control group. After 12 hours intervention, the content of inflammatory factors in cell supernatant was detected by enzyme linked immunosorbent assay (ELISA), and then confirmed the most suitable concentration for the next experiment. After LPS of 10 mg/L was used to challenged RAW264.7 cells to cause inflammation, 5μmol/L ELL was used for intervention, and the mRNA expressions of inflammatory cytokines were detected by reverse transcription-polymerase chain reaction (RT-PCR) after 2, 4, 6 and 12 hours; the nuclear translocation of nuclear factor-κB p65 (NF-κB p65) as well as the phosphorylation levels of extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinases (p38MAPK), c-Jun N-terminal kinase (JNK), c-jun, c-fos were detected by Western Blot after 15 minutes, 30 minutes, 1 hour and 2 hours.Results ① The different proliferative potential of RAW264.7 treated with LPS (10 mg/L) and ELL (0.05, 0.5, 5μmol/L) had no significant difference comparing with control group, which indicated that ELL had no cytotoxicity with experimental concentration and had no effect on the cell proliferative potential as the result of drug interaction. The levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in supernatant were significantly increased after induced by LPS comparing with control group. However, the different concentrations of ELL could dose-dependently reverse the production of inflammatory factors, and 5μmol/L was the optimum concentration of anti-inflammatory. ② Compared with control group, the mRNA expressions of TNF-α, IL-6 were significantly increased, the nuclear translocation level of NF-κB p65 increased as well as the phosphorylation levels of ERK, p38MAPK, JNK, c-fos, c-jun after stimulated by LPS. While, the different concentration of ELL could reverse the mRNA of TNF-α, IL-6 and phosphorylation levels of JNK, c-fos, c-jun [TNF-αmRNA (2-ΔCt): 2.45± 0.19 vs. 3.41±0.32 after 2 hours, 1.20±0.11 vs. 2.11±0.21 after 4 hours, 1.68±0.09 vs. 2.51±0.31 after 6 hours;IL-6 mRNA (2-ΔCt): 3.41±0.52 vs. 4.10±0.38 after 6 hours, 1.61±0.08 vs. 3.91±0.25 after 12 hours; p-JNK/GAPDH:0.557±0.034 vs. 1.049±0.056 after 1 hour, 0.439±0.040 vs. 0.855±0.038 after 2 hours; p-c-fos/GAPDH: 0.158± 0.030 vs. 0.741±0.035 after 1 hour, 0.156±0.015 vs. 0.932±0.030 after 2 hours; p-c-jun/GAPDH: 0.425±0.036 vs. 0.802±0.059 after 1 hour, 0.345±0.075 vs. 0.952±0.068 after 2 hours; allP < 0.05]. However, it had no significant effect on the nuclear translocation level of NF-κB p65 and the phosphorylation level of ERK and p38MAPK. Conclusion ELL inhibited the production of IL-6, TNF-α inflammatory factors in LPS-induced RAW264.7 cells through suppression the phosphorylation of JNK and activator protein-1 (AP-1).

Recent progress in synthesis and pharmacological effects of ellipticine and its derivatives / 药学学报

Ellipticine is an alkaloid isolated from natural product with cytotoxicity, which has antitumor and anti-aids activity. Since it was first identified in 1959, a great deal of effort has been devoted to the development of various approaches for synthesis of ellipticine. This review provides a summary for synthesis approaches of ellipticine from different starting materials. The antitumor mechanism and structure-activity relationship are also discussed.

Synthesis and antiproliferative evaluation of new isomeric ellipticine quinones / Síntesis y evaluación de la actividad antiproliferativa de nuevas elipticinquinonas isomericas

The synthesis of new isomeric ellipticine quinones 3a-c and their in vitro antiproliferative activities on cancer cell lines is reported. The designed N-heterocyclic quinones 3a-c were synthesized through a three step sequence which involves: a) one-pot preparation of 4-methoxycarbonyl-3,4-dimethylisoquinoline-5,8-quinone 1 from 2,5-dihydroxyacetophenone, methyl aminocrotonate and silver (II) oxide; b) regioselective amination of 1 with arylamines to give aminoquinones 2a-c and c) palladium-catalyzed intramolecular oxidative coupling of 7-aminoisoquinoline-5,8-quinones 2a-c. The in vitro antiproliferative activity of the new angular quinones was evaluated againts one normal cell line (lung fibroblasts) and gastric, lung and bladder cancer cell lines in 72-h drug exposure assays. The new compounds displayed similar or higher antiproliferative activity with respect to their quinone precursors 2a-c. The isomeric ellipticine quinone 2b appears as the more active member on bladder cancer cell line (IC50: 2.4 uM), comparable to etoposide used as anticancer reference drug...

Se describe la síntesis de las nuevas quinonas 3a-c, isoméricas de elipticina, y sus actividades antiproliferativas in vitro en líneas de células de cáncer. Las quinonas N-heterocíclicas 3a-c se sintetizaron a través de una secuencia que involucra: a) preparación de 4- metoxicarbonil-3,4-dimetlisoquinolin-5,8-quinone 1 a partir de 2,5-dihidroxiacetofenona, aminocrotonato de metilo y óxido de plata (I); b) aminación regioselectiva de 1 con arilaminas para producir las aminoquinonas 2a-c y c) acoplamiento oxidante intramolecular de 7- aminoisoquinolin-5,8-quinonas 2a-c catalizado con paladio. La actividad antiproliferative in vitro de los nuevos compuestos fue evaluada en una línea celular normal (fibroblastos de pulmón) y líneas de células de cáncer gástrico, pulmón y vejiga en ensayos de exposición de 72 horas a la droga. Las quinonas 3a-c exhiben interesantes propiedades antiproliferativas destacando la elipticinquinona isomérica 2b en células de cáncer de vejiga (IC50: 2.4 uM) comparado con etopósido usada como droga anticancer de referencia. Los nuevos compuestos mostraron actividades antiproliferativa similar o mayor respecto de las correspondientes quinonas precursoras 2a-c. La elipticin quinona isomérica 2b corresponde al miembro más activo en células de câncer de vejiga (IC50: 2.4 uM), comparable a la del etopósido, usada como droga anticáncer de referencia...

Aspidosperma subincanum I. characterisation, extraction of an uleine-enriched fraction and potential health hazard due to the contaminant ellipticine

The bark of the Brazilian tree Aspidosperma subincanum Mart. ex A. DC., Apocynaceae, has been characterised, and its constituents concentrated to obtain an uleine-enriched extract with the aim to produce food supplements. The concentration of the contaminant alkaloid ellipticine was assessed, and its potential to elicit toxic effects on consumers evaluated. It was found that this alkaloid posited no danger.

In vitro inhibition of Plasmodium falciparum by substances isolated from Amazonian antimalarial plants

In the present study, a quassinoid, neosergeolide, isolated from the roots and stems of Picrolemma sprucei (Simaroubaceae), the indole alkaloids ellipticine and aspidocarpine, isolated from the bark of Aspidosperma vargasii and A. desmanthum (Apocynaceae), respectively, and 4-nerolidylcatechol, isolated from the roots of Pothomorphe peltata (Piperaceae), all presented significant in vitro inhibition (more active than quinine and chloroquine) of the multi-drug resistant K1 strain of Plasmodium falciparum. Neosergeolide presented activity in the nanomolar range. This is the first report on the antimalarial activity of these known, natural compounds. This is also the first report on the isolation of aspidocarpine from A. desmanthum. These compounds are good candidates for pre-clinical tests as novel lead structures with the aim of finding new antimalarial prototypes and lend support to the traditional use of the plants from which these compounds are derived.