RESUMO
Cytotoxicity-guided fractionation of the methanol soluble part of the dichloromethane extract of the leaves of Warionia saharae led to the isolation of the two new guaianolide-type sesquiterpene lactones, 5 alpha H-3 beta,4 beta-epoxy-14-oxo-guaia-1(10),11(13)-dien-6 alpha,12-olide (1), 5 alpha H-2 beta,4 beta-epoxy-3 alpha-hydroxy-guaia-1(10),11(13)-dien-6 alpha,12-olide (6), and the new eudesmane type sesquiterpene 1 beta,6 alpha-dihydroxycostic acid ( 4). In addition, the known sesquiterpene lactones 5 alpha H-2 beta-hydroxyguaia-3(4),10(14),11(13)-trien-6 alpha,12-olide (2), reynosin (3), 5 alpha H-1 alpha,10 alpha:3 alpha,4 alpha-diepoxyguaia-11(13)-en-6 alpha,12-olide (5), and dehydroleucodin (7) were isolated together with the known flavone hispidulin. Cytotoxicity testing of the sesquiterpene lactones against the KB cancer cell line (ATCC CCL17) revealed IC50 values of 3.5 (1), 2.6 ( 2), 2.7 ( 3), 4.3 ( 5), 3.6 ( 6), and 1.3 (7) microg/mL. Compound 4 was not active up to 20 microg/mL.
Assuntos
Antineoplásicos/farmacologia , Asteraceae , Lactonas/farmacologia , Fitoterapia , Extratos Vegetais/farmacologia , Sesquiterpenos/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Humanos , Concentração Inibidora 50 , Lactonas/administração & dosagem , Lactonas/química , Lactonas/uso terapêutico , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Folhas de Planta , Sesquiterpenos/administração & dosagem , Sesquiterpenos/química , Sesquiterpenos/uso terapêutico , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
Using cytotoxicity against the KB cancer cell line (ATCC CCL17) as a lead, bioactivity-guided fractionation of the MeOH-soluble part of the DCM extract of Warionia saharae leaves led to the isolation of six new cytotoxic guaianolide type sesquiterpene lactones (1-6). Besides two guaianolides showing the common 6,7-trans fused lactone ring (3 and 4), four compounds exhibiting the more rare 6,7-cis configuration (1,2 and 5,6) were also isolated. Compounds 1, 2, 5, and 6 showed an unprecedented ether bridge between C-2 and C-4. The structures were deduced from extensive 1D and 2D NMR spectroscopy ((1)H, (13)C, DQF-COSY, HSQC, HMBC, ROESY), as well as mass spectrometry (EI and HR-MALDI). Cytotoxicity testing against the KB cancer cell line revealed IC(50) values of 1.0 (1), 4.5 (2), 1.7 (3), 2.0 (4), 3.3 (5), and 5.5 (6) microg/mL.
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Asteraceae/química , Lactonas/isolamento & purificação , Plantas Medicinais/química , Sesquiterpenos/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Feminino , Células HeLa/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Células KB , Lactonas/química , Lactonas/farmacologia , Modelos Químicos , Conformação Molecular , Estrutura Molecular , Marrocos , Ressonância Magnética Nuclear Biomolecular , Folhas de Planta/química , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Estereoisomerismo , Células Tumorais Cultivadas/efeitos dos fármacos , Neoplasias do Colo do ÚteroRESUMO
Four guaianolide type sesquiterpene lactones (SL), namely the new 1,2-dihydro-3-oxo-costic acid guaianyl ester 3beta-O-(1,2-didehydro-3-oxo-costoyloxy)-4beta,10beta-dihydroxy-guaia-1(2)-en-6beta,12-olide (1) and 3beta-O-(1,2-didehydro-3-oxo-costoyloxy)-4beta,10beta-dihydroxy-guaia-1(2)-en-6alpha,12-olide (2), as well as the known moroccolide A [5alphaH-2beta,4-epoxy-3beta-hydroxy-guaia-1(10),11(13)-dien-6beta,12-olide, 3] and 3beta-O-(2-methylbutyryl)-moroccolide A [5alphaH-2beta,4-epoxy-3beta-(2-methylbutyryloxy)-guaia-1(10),11(13)-dien-6beta,12-olide, 4] were examined for their cytotoxic and anti-inflammatory effects in HeLa, Jurkat T and human peripheral blood mononuclear cells. Compounds 1, 2 and 4 were found to exert a strong cytotoxicity similar in potency in all investigated cell types, whereas 3 was significantly less active. Along with the cytotoxic effect compounds 1 and 4 showed a potent and comparable down-regulation of the mRNAs of the house-keeping genes beta-actin and GAP-DH in PBMCs after 20 h. In contrast, the down-regulation of the PMA-induced mRNA levels of the NF-kappaB-driven pro-inflammatory genes IL-2, IL-6, GM-CSF, TNF-alpha, and IL-1beta in PBMCs is significantly stronger with compound 4. Compound 3 did not significantly modulate cytokine mRNAs levels at biochemically relevant concentrations. The electromobility shift assay (EMSA), revealed a stronger inhibition of NF-kappaB for 1 (IC(50) 2.5 microM) than for 4 (IC(50) 5 microM). Both compounds were also subjected to an IL-6 luciferase reporter gene assay and showed IC(50) values of 1.0 (1) and 1.2 microM (4). Thus, the NF-kappaB inhibition measured by EMSA, as well as the IL-6 luciferase assay did not reflect the differential modulation of pro-inflammatory genes measured with RT-rt-PCR.