Investigation of the structural properties of dihydrophenazines which contribute to their pro-oxidative interactions with human phagocytes.
Twenty-six dihydrophenazine compounds, including clofazimine, were investigated, at a fixed concentration of 1 mg/l, for their effects on spontaneous and stimulus-activated generation of superoxide by human neutrophils in vitro. The synthetic chemotactic tripeptide N-formyl-L-methionyl-L-leucyl-L phenyl-alanine (FMLP) (0.1 microM) was used as a stimulant of membrane-associated oxidative metabolism. None of the agents tested influenced basal levels of superoxide generation by neutrophils. However sixteen of these compounds, all rimino phenazines, significantly increased the production of superoxide by FMLP-activated neutrophils. These pro-oxidative, priming interactions of the rimino phenazines with neutrophils were largely dependent on the nature of the alkylimino group at position 2 on the phenazine nucleus, and to a lesser extent on halogenation. Cycloalkylimino groups were generally less potent stimulants of superoxide generation by FMLP-activated neutrophils than clofazimine, and their pro-oxidative properties were independent of mono- or dichlorination. However the halogen-free cycloalkylimino compound, B669, was an exceptionally potent pro-oxidative agent. Chlorination was promotive to pro-oxidative activity in the case of dihydrophenazines with linear or branched alkylimino substituents. The pharmaco-therapeutic mechanisms of dihydrophenazines may be related to their pro-oxidative interactions with phagocytes.
Savage
J E
JE
Department of Medical Microbiology, University of Pretoria, Republic of South Africa.
O'Sullivan
J F
JF
Zeis
B M
BM
Anderson
R
R
D002991:Clofazimine / Q000032:analysis / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D010586:Phagocytes / Q000187:drug effects / Q000378:metabolism*; D010619:Phenazines / Q000032:analysis / Q000494:pharmacology*; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013481:Superoxides
D010619:Phenazines; D013481:Superoxides; D009240:N-Formylmethionine Leucyl-Phenylalanine; D002991:Clofazimine; D010741:Phospholipases A