RESUMO
Bioactivity-guided fractionation of the stem bark of Mitrephora glabra yielded nine compounds, comprising three ent-kaurenoids (1-3), five polyacetylenic acids/esters (4-8), and one aporphine alkaloid, liriodenine (9). The structures of the six new compounds (1-3, 5, 7, and 8) were determined by spectroscopic data interpretation. All compounds were evaluated for their inhibitory activities against a panel of cancer cell lines and a battery of microorganisms.
Assuntos
Annonaceae/química , Anti-Infecciosos/isolamento & purificação , Antineoplásicos Fitogênicos/isolamento & purificação , Diterpenos/isolamento & purificação , Plantas Medicinais/química , Poli-Inos/isolamento & purificação , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Aporfinas/isolamento & purificação , Aspergillus niger/efeitos dos fármacos , Diterpenos/química , Diterpenos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Indonésia , Testes de Sensibilidade Microbiana , Micrococcus luteus/efeitos dos fármacos , Estrutura Molecular , Mycobacterium/efeitos dos fármacos , Ressonância Magnética Nuclear Biomolecular , Casca de Planta/química , Poli-Inos/química , Poli-Inos/farmacologia , Saccharomyces cerevisiae/efeitos dos fármacosRESUMO
[chemical reaction: see text]. Three new ent-trachylobane diterpenoids (1-3) were isolated and structures elucidated from Mitrephora glabra Scheff. (Annonaceae). Mitrephorone A (1) possesses a hexacyclic ring system with adjacent ketone moieties and an oxetane ring, both of which are unprecedented among trachylobanes. All compounds were evaluated for cytotoxicity against a panel of cancer cells, where 1 displayed the most potent and broadest activity, and against a battery of antimicrobial assays, where all compounds were approximately equipotent.
Assuntos
Annonaceae/química , Antineoplásicos Fitogênicos/isolamento & purificação , Diterpenos/isolamento & purificação , Plantas Medicinais/química , Anfotericina B/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Bactérias/efeitos dos fármacos , Diterpenos/química , Diterpenos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Saccharomyces cerevisiae/efeitos dos fármacos , Células Tumorais CultivadasRESUMO
Two anthracenone C-glycosides, alvaradoins E and F, isolated from the leaves of Alvaradoa haitiensis Urb. (Simaroubaceae), were found to have potent inhibitory activities with cultured cancer cells. Using the in vivo hollow fiber model, these compounds demonstrated significant growth inhibition at the i.p. site when tested with KB, LNCaP, and Col2 cells. To determine if these anthracenone C-glycosides mediated anticancer activity through an apoptotic pathway, a series of assays were performed with the 10S isomeric compound, alvaradoin E. With a DAPI assay, treatment of LNCaP cells with alvaradoin E at concentrations of 0.4, 2, 10, or 50 microM for 24 or 48 h showed chromatin condensation, a morphological characteristic of apoptosis. Mitochondrial membrane potential, analyzed with a DiOC6 uptake assay, showed that treatment of LNCaP cells with 0.07, 0.14, 0.28, 0.56, 0.86, and 1.12 microM alvaradoin E for 12 h caused dose-dependent membrane depolarization, another indication of early apoptosis. Also, with an annexin V-FITC assay system, treatment of HL-60 cells with 0.07 microM alvaradoin E for 24 h increased annexin V-FITC binding from 3 to 25.9% (8.6-fold). Finally, with the TUNEL assay system, treatment of HL-60 cells with 1.12 microM alvaradoin E for 32 h increased FITC-dUTP binding from 1.2 to 12.1% (10-fold). These data suggest alvaradoin E is an effective anticancer agent that induces apoptosis. Additional studies to establish clinical utility should be of interest.
Assuntos
Antracenos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Monossacarídeos/farmacologia , Simaroubaceae/química , Anexina A5 , Antracenos/isolamento & purificação , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Citometria de Fluxo , Fluoresceína-5-Isotiocianato , Glicosídeos/isolamento & purificação , Glicosídeos/farmacologia , Células HL-60 , Humanos , Marcação In Situ das Extremidades Cortadas , Indóis , Membranas Intracelulares/efeitos dos fármacos , Membranas Intracelulares/fisiologia , Células KB , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/fisiologia , Monossacarídeos/isolamento & purificação , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Coloração e Rotulagem/métodosRESUMO
Bioactivity-directed fractionation of an extract of the leaves of Alvaradoa haitiensis, using the KB (human oral epidermoid carcinoma) cell line, led to the isolation and identification of 10 new anthracenone C-glycosides, alvaradoins E-N (1-10), along with the known compound chrysophanol (11). The cytotoxicity of all compounds was evaluated, and preliminary structure-activity relationships are suggested. The most potent compounds in the in vitro assays (1 and 2) were evaluated in vivo versus the P388 (murine lymphocytic leukemia) model, and alvaradoin E (1) showed antileukemic activity (125% T/C) at a dose of 0.2 mg kg-1 per injection when administered intraperitoneally.