RESUMO
Highly oxidized lignans produced during the cytochrome P-450 metabolism in the cells show biological activities significantly different from those of their parent natural compounds. Lignans precursors of mammalian enterolignans were treated with a methyltrioxorhenium/hydrogen peroxide catalytic system to afford new compounds oxidized at benzylic as well as in arylic positions. The evaluation of the antioxidant and apoptogenic activity by in vivo protocols of these compounds showed some interesting structure-activity relationships related to the oxidation degree of the molecules.
Assuntos
Antioxidantes/síntese química , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Lignanas/síntese química , Lignanas/farmacologia , Compostos Organometálicos , Antioxidantes/química , Catálise , Linhagem Celular Tumoral , Humanos , Peróxido de Hidrogênio , Lignanas/química , Linfoma de Células B/tratamento farmacológico , Oxirredução , Relação Estrutura-AtividadeRESUMO
Epstein-Barr Virus (EBV) is involved in the progression of lymphomas through still unknown mechanism involving increased resistance to induced apoptosis. We show here that in a set of apoptosis-resistant EBV-converted Burkitt's lymphoma clones, 5- and 12-lipoxygenases (LOXs) are over-expressed. Further investigations on 5-LOX showed that resistance to apoptosis increases parallely with the expression of 5-lipoxygenase (5-LOX). Inhibitors of 5-LOX: (a) decrease peroxides level, indicating that this enzyme promotes the generation of oxidative stress in EBV+ cells, and (b) potently induce apoptosis in the EBV resistant cell line E2R. 5- and 15-HETE, the products of the 5 and 15-LOXs, respectively, counteract 5-LOX inhibitor induced apoptosis, indicating that products of arachidonate metabolism, rather than peroxides, trigger a signal transduction that is required for survival of the EBV-converted cells. These findings suggest that 5- and, to a lesser extent, other LOXs, that are involved in tumor progression of several cell types, may also participate in lymphomagenesis, especially that EBV-mediated.
Assuntos
Araquidonato 5-Lipoxigenase/genética , Araquidonato 5-Lipoxigenase/metabolismo , Linfoma de Burkitt/enzimologia , Linfoma de Burkitt/virologia , Herpesvirus Humano 4/fisiologia , Apoptose , Araquidonato 12-Lipoxigenase/metabolismo , Linfoma de Burkitt/genética , Linfoma de Burkitt/patologia , Linhagem Celular Tumoral , Sobrevivência Celular , Progressão da Doença , Humanos , Peroxidação de Lipídeos , RNA Neoplásico/genética , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
A novel and efficient procedure to prepare highly oxidised aryltetralin lignans, such as isopodophyllotoxone and (-)-aristologone derivatives, by oxidation of podophyllotoxin and galbulin with methylrhenium trioxide (MTO) and novel MTO heterogeneous catalysts is reported. It is noteworthy that in the case of isopodophyllotoxone derivatives the functionalisation of the C-4 position of the C-ring and the ring-opening of the D-lactone moiety increased the activity against topoisomerase II while causing the undesired inhibition of tubulin polymerisation to disappear. The novel (-)-aristologone derivatives showed apoptogenic activity against resistant human lymphoma cell lines.