title: 4-fluoro-2-methoxyphenol, an apocynin analog with enhanced inhibitory effect on leukocyte oxidant production and phagocytosis.
abstract: Apocynin, a methoxy-substituted catechol (4-hydroxy-3-methoxyacetophenone), originally extracted from the roots of Picrorhiza kurroa, has been extensively used as a non-toxic inhibitor of the multienzymatic complex NADPH oxidase. We discovered that the analogous methoxy-substituted catechol, 4-Fluoro-2-methoxyphenol (F-apocynin), in which the acetyl group present in apocynin was changed to a fluorine atom, was significantly more potent as an inhibitor of NADPH oxidase activity, myeloperoxidase (MPO) chlorinating activity and phagocytosis of microorganisms by neutrophils; it was also as potent as apocynin in inhibiting tumor necrosis factor-alpha (TNFα) release by peripheral blood mononuclear cells. We attribute the increased potency of F-apocynin to its increased lipophilicity, which could facilitate the passage of the drug through the cell membrane. The inhibition of MPO chlorination activity, phagocytosis and TNFα release shows that apocynin and F-apocynin actions are not restricted to reactive oxygen species inhibition, but further studies are needed to clarify if these mechanisms are related. Like apocynin, F-apocynin did not show cell toxicity, and is a strong candidate for use in the treatment of inflammatory diseases.
authors.affiliation: Departamento de Química, Faculdade de Ciências, UNESP-Universidade Estadual Paulista Julio de Mesquita Filho, Bauru, SP, Brazil. carualmeida@gmail.com
authors.forename: Ana Carolina
authors.initials: AC
authors.lastname: de Almeida
authors.forename: Otávio
authors.initials: O
authors.lastname: Cabral Marques
authors.forename: Christina
authors.initials: C
authors.lastname: Arslanian
authors.forename: Antonio
authors.initials: A
authors.lastname: Condino-Neto
authors.forename: Valdecir F
authors.initials: VF
authors.lastname: Ximenes
mesh_terms: D000098:Acetophenones / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D002176:Candida albicans / Q000502:physiology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006139:Guaiacol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D006997:Hypochlorous Acid / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D016877:Oxidants / Q000096:biosynthesis*; D009195:Peroxidase / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013211:Staphylococcus aureus / Q000502:physiology; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000098:Acetophenones; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016877:Oxidants; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; C072304:4-fluoroguaiacol; D006139:Guaiacol; D006997:Hypochlorous Acid; C056165:acetovanillone; D009195:Peroxidase