Prooxidative activities of 10 phenazine derivatives relative to that of clofazimine

Zeis, Birgit M.; O’Sullivan, John

doi:10.1128/aac.31.5.789

Cited by 19 publications

(12 citation statements)

References 15 publications

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“…only riminophenazines were potentially pro-oxidative while the aposafra none derivatives B3722 and B685 and the imidazophenazine B62 1 were inactive. 4,16,17 However, this study indicated that the unchlorinated riminophenazines B670 and B718 had no effect on AA release by neutrophils compared to their chlorinated analogues B663 (clofazimine) and B746, which is also in accordance with previous findings. 16 Lack of chlorination of the anilino and phenyl rings in the paraposition could however be compensated for by a chlorine substituent in position 7 of the phenazine molecule as in BI865 and B402 1.…”

Section: Discussionsupporting

confidence: 82%

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

Zeis¹,

Savage²,

O’Sullivan³

1990

Leprosy Review

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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.

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Section: Discussionsupporting

confidence: 82%

“…16,17 The nature of the chemical group in position 2 of the phenazine ring was fo und to be particularly important for these activities. In the present study we have extended our previous investigations and attempted to correlate molecular structures with both pro-oxidative activity and the mobilization of AA by human neutrophils.…”

mentioning

confidence: 99%

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

Zeis¹,

Savage²,

O’Sullivan³

1990

Leprosy Review

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“…The need for new antibiotics to combat resistant strains has renewed interest CFZ and in the development of new CFZ derivatives (4,6,49). In this study, we describe a more soluble analog of CFZ with a similar redox potential.…”

Section: Discussionmentioning

confidence: 99%

Reduction of Clofazimine by Mycobacterial Type 2 NADH:Quinone Oxidoreductase

Yano¹,

Kassovska-Bratinova²,

Teh³

et al. 2011

Journal of Biological Chemistry

290

162

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The mechanism of action of clofazimine (CFZ), an antimycobacterial drug with a long history, is not well understood. The present study describes a redox cycling pathway that involves the enzymatic reduction of CFZ by NDH-2, the primary respiratory chain NADH:quinone oxidoreductase of mycobacteria and nonenzymatic oxidation of reduced CFZ by O 2 yielding CFZ and reactive oxygen species (ROS). This pathway was demonstrated using isolated membranes and purified recombinant NDH-2. The reduction and oxidation of CFZ was measured spectrally, and the production of ROS was measured using a coupled assay system with Amplex Red. Supporting the ROS-based killing mechanism, bacteria grown in the presence of antioxidants are more resistant to CFZ. CFZ-mediated increase in NADH oxidation and ROS production were not observed in membranes from three different Gram-negative bacteria but was observed in Staphylococcus aureus and Saccharomyces cerevisiae, which is consistent with the known antimicrobial specificity of CFZ. A more soluble analog of CFZ, KS6, was synthesized and was shown to have the same activities as CFZ. These studies describe a pathway for a continuous and high rate of reactive oxygen species production in Mycobacterium smegmatis treated with CFZ and a CFZ analog as well as evidence that cell death produced by these agents are related to the production of these radical species.

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“…Phenazines are multifunctional versatile compounds with antioxidant, antibiotic, anticancer and antimicrobial activities, which is mainly associated with their redox activity and their capacity to intercalate between DNA subunits. Furthermore, the heteroaromatic phenazine π‐core is present in a vast array of heterocyclic compounds such as pharmaceuticals, sensors and biosensors, OLEDS, chemical switches, photovoltaic cells for renewable energy and in nanotechnology .…”

Section: Introductionmentioning

confidence: 99%

A Sustainable Synthesis of Asymmetric Phenazines and Phenoxazinones Mediated by CotA‐Laccase

et al. 2017

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An efficient and sustainable one-step procedure for the synthesis of new asymmetric phenazines and phenoxazinones from commercially available ortho-substituted diamines and orthosubstituted hydroxyamines is reported. In this study we have expanded the substrate scope of CotAlaccase-catalyzed aerobic oxidations through the use of aromatic amines presenting variable functional groups, including N-substitution, contributing to the rational synthesis of different heterocyclic scaffolds. The transformations proceed smoothly through a cascade of oxidative reactions to the benzoquinonediimine intermediates followed by nucleophilic addition, intramolecular cyclization and aromatization, all performed in mild conditions.

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Prooxidative activities of 10 phenazine derivatives relative to that of clofazimine

Cited by 19 publications

References 15 publications

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

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

Reduction of Clofazimine by Mycobacterial Type 2 NADH:Quinone Oxidoreductase

A Sustainable Synthesis of Asymmetric Phenazines and Phenoxazinones Mediated by CotA‐Laccase

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