3-Phenylcoumarin derivatives selectively modulate different steps of reactive oxygen species production by immune complex-stimulated human neutrophils

Immune complex (IC) deposition in tissues triggers the release of harmful oxidant and lytic compounds by neutrophils. We examined how ten 3-phenylcoumarin derivatives affect the reactive oxygen species (ROS) production by IC-stimulated human neutrophils. Most of the 3-phenylcoumarins inhibited the l...

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Bibliographic Details
Published in:	International immunopharmacology Vol. 15; no. 2; pp. 387 - 394
Main Authors:	Andrade, Micássio F., Kabeya, Luciana M., Azzolini, Ana Elisa C.S., Santos, Everton O.L., Figueiredo-Rinhel, Andréa S.G., Paris, Márcio R.P., Emery, Flávio S., Pupo, Mônica T., Lucisano-Valim, Yara M.
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier B.V 01-02-2013
Subjects:	3-Phenylcoumarin Antigen-Antibody Complex - immunology Cells, Cultured Coumarins - chemistry Coumarins - pharmacology Drug Discovery Free Radical Scavengers - chemistry Free Radical Scavengers - pharmacology Humans Immune complex Immune Complex Diseases - immunology Immunomodulation Luminescent Measurements Molecular Targeted Therapy Myeloperoxidase NADPH oxidase Neutrophil Neutrophils - drug effects Neutrophils - immunology Oxidation-Reduction - drug effects Peroxidase - metabolism Reactive oxygen species Reactive Oxygen Species - metabolism Structure-Activity Relationship NADPH HBSS-gel Reactive oxygen species DMSO TMB CL MPO p-AB AUC CL-luc LDH NADPH oxidase IC50 ROS CL-lum Myeloperoxidase IC HBSS Neutrophil DMF DPI Immune complex 3-Phenylcoumarin
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Summary:	Immune complex (IC) deposition in tissues triggers the release of harmful oxidant and lytic compounds by neutrophils. We examined how ten 3-phenylcoumarin derivatives affect the reactive oxygen species (ROS) production by IC-stimulated human neutrophils. Most of the 3-phenylcoumarins inhibited the luminol-enhanced chemiluminescence (CL-lum) more strongly than they inhibited the lucigenin-enhanced chemiluminescence (CL-luc), without clear signs of toxicity. The most effective CL-lum inhibitors, 6,7-dihydroxy-3-[3′,4′-methylenedioxyphenyl]-coumarin (5) and 6,7-dihydroxy-3-[3′,4′-dihydroxyphenyl]-coumarin (19), also inhibited myeloperoxidase activity more potently and had higher hypochlorous acid scavenging ability, but did not affect the NADPH-oxidase activity. The type, number, and position of the substituent influenced the pharmacological effects of 3-phenylcoumarins; however, the structural requirements for CL-lum and CL-luc inhibition were a little different. Compounds 5 and 19 are promising prototypes of therapeutic molecules to modulate ROS production by neutrophils in IC-mediated inflammatory diseases. ► Different structural features guide luminol and lucigenin-luminescence inhibition. ► 3-Phenylcoumarins selectively inhibit neutrophil ROS generation without toxicity. ► NADPH oxidase activity was not affected by the 3-phenylcoumarins. ► The catechol group is important for MPO activity inhibition and HOCl scavenging.
ISSN:	1567-5769 1878-1705
DOI:	10.1016/j.intimp.2013.01.001