Apocinina e metóxi-catecóis correlatos: relação entre estrutura molecular e inibição da ativação do complexo NADPH oxidase
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Data
2009-11-19
Autores
Kanegae, Marília Pyles Patto [UNESP]
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
A apocinina, um métoxi-catecol (MC) extraído das raízes da planta Picrorhiza kurroa, é um eficiente inibidor do complexo NADPH oxidase (NOX) e seu mecanismo de ação está relacionado à inibição da agregação dos componentes enzimáticos e à oxidação catalisada por peroxidases. Estudamos a relação estrutura-atividade da apocinina e de metóxi-catecóis correlatos, na inibição da NOX. Com a função de alterar o potencial de redução das moléculas estudadas, escolhemos MC com grupos adicionais aceptores (MC-A) ou doadores de elétrons (MC-D) na posição para, em relação à hidroxila da molécula de apocinina. Os MC-D inibiram mais fracamente a ativação da NOX em neutrófilos ativados quando comparados aos MC-A. Acreditamos que isso se deva à fraca reatividade destes compostos com grupamentos sulfidrila de proteínas, assim, os MC-D são incapazes de oxidar grupos essenciais aos componentes citosólicos da enzima e desta forma, inibir sua ativação. A diapocinina, metabólito gerado após a oxidação da apocinina por peroxidases, foi sintetizada e avaliamos seus efeitos em neutrófilos e leucócitos mononucleares ativados quanto à inibição da ativação da NOX e em leucócitos mononucleares, em relação à liberação de citocinas e expressão do RNAm do componente de membrana gp91phox. Encontramos que a apocinina e a diapocinina inibiram os três fenômenos estudados, embora a diapocinina o tenha feito de modo mais eficiente. Acreditamos que isto possa estar relacionado ao efeito supressor da apocinina e diapocinina sobre a ativação da NADPH oxidase
Apocynin, a methoxy catechol (MC) extracted from the roots of Picrorhiza kurroa has been used as an efficient inhibitor of the NADPH oxidase (NOX) complex and its mechanism of action involves the impairment of the assemble process of the enzyme. Here, we studied the structure-activity relationship for apocynin and analogous ortho-methoxy-substituted catechols as inhibitors of the NADPH oxidase. Aiming to alter the reduction potential, the ortho-methoxy-catechol moiety was kept constant and the substituents at para position related to the hydroxyl group were varied. Two series of compounds were employed: methoxy-catechols bearing electron-withdrawing groups (MC-W) and methoxy-catechol bearing electron-donating groups (MC-D). We found that MC-D were weaker inhibitors of the NOX complex in stimulated neutrophils compared to MD-W. We suggest that there is a close relationship between the weak reactivity of MC-D compounds with sulfhydryl residues of proteins and there incapacity in inhibiting NOX activation. Diapocynin is a product generated by peroxidase oxidation of apocynin. Here we synthesized diapocynin and compared its efficacy as NOX inhibitor in peripheral blood mononuclear cells (PBMC) and neutrophils in relation to apocynin. Both drugs were also studied in cytokine release and its influence on gp91phox mRNA expression. We found that diapocynin was a more efficient inhibitor of NOX activation, gp91phox mRNA expression and cytokine release than apocynin. We suggest that these findings could be related to NOX inhibition process
Apocynin, a methoxy catechol (MC) extracted from the roots of Picrorhiza kurroa has been used as an efficient inhibitor of the NADPH oxidase (NOX) complex and its mechanism of action involves the impairment of the assemble process of the enzyme. Here, we studied the structure-activity relationship for apocynin and analogous ortho-methoxy-substituted catechols as inhibitors of the NADPH oxidase. Aiming to alter the reduction potential, the ortho-methoxy-catechol moiety was kept constant and the substituents at para position related to the hydroxyl group were varied. Two series of compounds were employed: methoxy-catechols bearing electron-withdrawing groups (MC-W) and methoxy-catechol bearing electron-donating groups (MC-D). We found that MC-D were weaker inhibitors of the NOX complex in stimulated neutrophils compared to MD-W. We suggest that there is a close relationship between the weak reactivity of MC-D compounds with sulfhydryl residues of proteins and there incapacity in inhibiting NOX activation. Diapocynin is a product generated by peroxidase oxidation of apocynin. Here we synthesized diapocynin and compared its efficacy as NOX inhibitor in peripheral blood mononuclear cells (PBMC) and neutrophils in relation to apocynin. Both drugs were also studied in cytokine release and its influence on gp91phox mRNA expression. We found that diapocynin was a more efficient inhibitor of NOX activation, gp91phox mRNA expression and cytokine release than apocynin. We suggest that these findings could be related to NOX inhibition process
Descrição
Palavras-chave
Estrutura molecular, Apocinina, Citocinas, Apocynin
Como citar
KANEGAE, Marília Pyles Patto. Apocinina e metóxi-catecóis correlatos: relação entre estrutura molecular e inibição da ativação do complexo NADPH oxidase. 2009. 78 f. Tese (doutorado) - Universidade Estadual Paulista, Faculdade de Ciências Farmacêuticas, 2009.