The influence of structural modifications of dihydrophenazines on arachidonic acid mobilization and superoxide generation by human neutrophils

Abstract

Summary In this study the effects of nine dihydrophenazine derivatives, relative to clofazimine (B663), on the N-formyl-L-methionyl-L-Ieucyl-L-phenylalanine (FMLP) stimulated release of superoxide anion and on the spontaneous generation of arachidonic acid by human neutrophils were investigated. Previous findings that the pro-oxidative activity of the agents depended largely on the substituion in position 2 of the phenazine molecule and on chlorination in the paraposition of the phenyl and anilino rings were confirmed. Only riminophena zines, but not aposafranone derivatives or the imidazophenazine B621, could enhance superoxide release from activated neutrophils. The lack of chlorination of the phenyl and anilino rings could be compensated for by chlorine substitution in position 7 of the phenazine core.The priming effect of the agents on FMLP stimulated superoxide generation was completely prevented by the phospholipase A2 inhibitor 4-p-bromophenacyl bromide. Furthermore pro-oxidative activities correlated closely with a stimula tory effect of the agents on arachidonic acid release. It was therefore concluded that dihydrophenazine derivatives with pro-oxidative properties can prime neutrophils for FMLP-stimulated superoxide release by modulation of phospho lipase A 2 activity.