RESUMO
The synthesis of a series of novel 3,4-cis- and 3,4-trans-substituted carbocyclic nucleoside analogs from protected uracil and thymine is described. The key reaction in the followed synthetic protocols utilized the Mitsunobu reaction to couple 3,4-substituted cyclopentanols to (3)N-benzoyl uracil or (3)N-benzoyl thymine. These molecules were evaluated with regard to their ability to treat diabetic nephropathy. Our results show that two analogs significantly reduced high-glucose induced glomerular mesangial cells proliferation and matrix protein accumulation in vitro and, more interestingly, exhibited an anti-oxidative effect suggesting that the activity may be mediated through ROS-dependent mechanism.
Assuntos
Proteínas da Matriz Extracelular/metabolismo , Nucleosídeos/química , Espécies Reativas de Oxigênio/metabolismo , Actinas/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Neuropatias Diabéticas/metabolismo , Neuropatias Diabéticas/patologia , Fibronectinas/metabolismo , Mesângio Glomerular/citologia , Mesângio Glomerular/metabolismo , Glucose/farmacologia , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , RatosRESUMO
Four sesquiterpene lactones were isolated from Achillea falcata, through bioassay-guided fractionation, based on their differential ability to affect HaCaT cell growth. Identified seco-tanapartholides: 3-beta-methoxy-iso-seco-tanapartholide (1), tanaphillin (2), iso-seco-tanapartholide (3), and 8-hydroxy-3-methoxy-iso-seco-tanaparatholide (4) were found to differentially decrease keratinocyte cell viability. In addition, the stereoselectivity, lipophilicity, and number and position of hydroxyl groups present in these compounds were correlated with their biological activities for HaCaT cell growth inhibition. Statistical analyses confirmed an enhanced potency of the beta-OH iso-seco-tanapartholide over the alpha:beta-OH diastereoisomeric mixture. The highest potency, however, was mainly the function of the enhanced lipophilicity of the molecule.