RESUMO
The synthesis of inhibitors of SphK2 with novel structural scaffolds is reported. These compounds were designed from a molecular modeling study, in which the molecular interactions stabilizing the different complexes were taken into account. Particularly interesting is that 7-bromo-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1,4-epoxynaphtho[1,2-b]azepine, which is a selective inhibitor of SphK2, does not exert any cytotoxic effects and has a potent anti-inflammatory effect. It was found to inhibit mononuclear cell adhesion to the dysfunctional endothelium with minimal impact on neutrophil-endothelial cell interactions. The information obtained from our theoretical and experimental study can be useful in the search for inhibitors of SphK2 that play a prominent role in different diseases, especially in inflammatory and cardiovascular disorders.
Assuntos
Anti-Inflamatórios/síntese química , Azepinas/síntese química , Inibidores Enzimáticos/síntese química , Compostos de Epóxi/síntese química , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/toxicidade , Azepinas/química , Azepinas/farmacologia , Adesão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/imunologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/toxicidade , Compostos de Epóxi/química , Compostos de Epóxi/farmacologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Simulação de Acoplamento Molecular , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
Tibouchina pulchra saplings were exposed to carbon filtered air (CF), ambient non-filtered air (NF) and ambient non-filtered air+40 ppb ozone (NF+O3) 8 h per day during two months. The AOT40 values at the end of the experiment were 48, 910 and 12,895 ppb h(-1), respectively, for the three treatments. After 25 days of exposure (AOT40=3871 ppb h(-1)), interveinal red stippling appeared in plants in the NF+O3 chamber. In the NF chamber, symptoms were observed only after 60 days of exposure (AOT40=910 ppb h(-1)). After 60 days, injured leaves per plant corresponded to 19% in NF+O3 and 1% in the NF treatment; and the average leaf area injured was 7% within the NF+O3 and 0.2% within the NF treatment. The extent of leaf area injured (leaf injury index) was mostly explained by the accumulated exposure of ozone (r2=0.89; p<0.05).
Assuntos
Poluentes Atmosféricos/toxicidade , Melastomataceae/efeitos dos fármacos , Ozônio/toxicidade , Folhas de Planta/efeitos dos fármacos , Biomassa , Brasil , Exposição Ambiental , Monitoramento Ambiental/métodos , Plântula , Clima TropicalRESUMO
The effects induced by long-term (30 day) and short-term (6h) exposures to ozone on the physiological parameters in young plants of Caesalpinia echinata Lam., a Brazilian tree species, were determined. Potted plants were maintained in open-top chambers in Valencia, Spain, under charcoal filtered air (mean O3 level: 29 microg m3), nonfiltered air (NF; 43 microg m3), and nonfiltered air plus O3 (NF + O3; 68 microg m3), simulating prevailing concentrations observed in the city of São Paulo, Brazil, during spring months (50 microg m3 in 2002). In the plants kept in NF + O3 for 30 days, although no foliar visible injuries were observed, the net carbon assimilation rate was reduced to 50%, stomatal conductance 42%, and transpiration 40%, when compared to the results for the NF plants. No changes in antioxidants, in leaf, stem, and root biomass, and in the root/shoot ratio were observed. Significant reductions were observed in gas exchange and in PSII photochemical efficiency (Fv/Fm) after 6 h of exposure to an O3 peak. The species was shown to be sensitive to ambient O3 concentrations measured in São Paulo.