RESUMO
Inhibition of tumour promotion in multistage chemical carcinogenesis is considered a promising strategy for cancer chemoprevention. In an ongoing investigation of bioactive secondary metabolites from Celastraceae species, five new dihydro-ß-agarofuran sesquiterpenes (1-5), named Chiapens A-E, and seventeen known ones, were isolated from Maytenus chiapensis. Their structures were elucidated by extensive NMR spectroscopic and mass spectrometric techniques, and their absolute configurations were determined by circular dichroism studies, chemical correlations and biogenic means. The isolated compounds, along with twenty known sesquiterpenes, previously isolated from Zinowiewia costaricensis, have been tested for their inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorpol-13-acetate (TPA). Thirty three compounds from this series showed stronger effects than that of ß-carotene, the reference inhibitor. The structure-activity relationship (SAR) analysis revealed that the type of substituent, in particular at the C-1 position of the sesquiterpene scaffold, was able to modulate the anti-tumour promoting activity. Compounds 3, 6, and 33 showed significant effects in an in vivo two-stage mouse-skin carcinogenesis model.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Celastraceae/química , Papiloma/tratamento farmacológico , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Animais , Antígenos Virais/metabolismo , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Endogâmicos ICR , Modelos Moleculares , Estrutura Molecular , Papiloma/metabolismo , Papiloma/patologia , Sesquiterpenos/síntese química , Relação Estrutura-Atividade , Acetato de Tetradecanoilforbol/análogos & derivados , Acetato de Tetradecanoilforbol/antagonistas & inibidores , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
Multidrug resistance (MDR) is one of the main challenges in the chemotherapy of cancer, malaria, and other important diseases. Here, we report the inhibitory activity of a series of 76 dihydro-beta-agarofuran sesquiterpenes, tested on NIH-3T3 cells expressing the human P-glycoprotein (Pgp) multidrug transporter, to establish quantitative comparisons of their respective abilities to block the drug transport activity. The screening was performed on the basis of the ability of sesquiterpenes to modulate the intracellular accumulation of the classical Pgp substrate daunorubicin. To understand the structural basis for inhibitory activity and guide the design of more potent Pgp inhibitors, we have performed a three-dimensional quantitative structure-activity relationship model using the comparative molecular similarity indices analysis (CoMSIA). The most salient features of these requirements are in the region of the substituents at the C-2, C-3, and C-8 positions, which seem to be critical for determining the overall effectiveness of sesquiterpenes as Pgp inhibitors.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/biossíntese , Celastraceae/química , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Furanos/isolamento & purificação , Relação Quantitativa Estrutura-Atividade , Sesquiterpenos/isolamento & purificação , Animais , Antibióticos Antineoplásicos/metabolismo , Transporte Biológico , Daunorrubicina/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Furanos/química , Furanos/farmacologia , Humanos , Maytenus/química , Camundongos , Modelos Moleculares , Células NIH 3T3 , Folhas de Planta/química , Sesquiterpenos/química , Sesquiterpenos/farmacologia , TermodinâmicaRESUMO
In an intensive study of South American medicinal plants, herein we report the isolation, structure elucidation and biological activity of fourteen new and five known dihydro-beta-agarofuran sesquiterpenes from the leaves of Zinowiewia costaricensis (1-19). Their structures were determined by means of (1)H and (13)C NMR spectroscopic studies, including homonuclear and heteronuclear correlation experiments. The absolute configurations of the new compounds were determined by CD studies, chemical correlations or biogenetic grounds. All the natural compounds and derivative 20 have been tested on human MDR1-transfected NIH-3T3 cells, to determine their ability to revert the multidrug resistance phenotype due to P-glycoprotein overexpression. Six compounds from this series (1, 8, 11, 12, 13 and 14) showed similar effectiveness to the classical P-glycoprotein modulator verapamil when reversing resistance to daunorubicin, but it is up to sixteen times greater than that of verapamil when reversing resistance to vinblastine. The structure-activity relationships are discussed.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Plantas Medicinais , Rosaceae , Sesquiterpenos/farmacologia , Células 3T3 , Animais , Daunorrubicina/farmacologia , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Modelos Moleculares , Estrutura Molecular , Sesquiterpenos/síntese química , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificação , Relação Estrutura-Atividade , Transfecção , Verapamil/farmacologiaRESUMO
Seven new sesquiterpenes (1-7) with a 'dihydro-beta-agarofuran' (= 5,11-epoxy-5beta,10alpha-eudesmane) skeleton were isolated from Crossopetalum tonduzii. Their structures were elucidated spectroscopically, especially by means of homo- and heteronuclear NMR correlation (COSY, ROESY, HSQC, and HMBC). The absolute configurations of the new compounds were determined by circular dichroism (CD) studies and by chemical correlations via the derivatives 8-11. The new compounds showed moderate antitumor-promoting effects with respect to the activation of the Epstein-Barr virus early antigen (EBV-EA).
