title: 4'-Aminochalcones as novel inhibitors of the chlorinating activity of myeloperoxidase.
abstract: The excessive activation of neutrophils generates reactive oxygen species (ROS) and the secretion of primary granular enzymes, such as myeloperoxidase (MPO), which is implicated in numerous inflammatory diseases. The aim of this study was to evaluate chalcones as inhibitors of the chlorinating activity of MPO using in vitro and ex vivo assays. In addition to cytotoxic properties, the inhibition of respiratory burst, the scavenger capacity, and the oxidation potential were measured. 4'-Aminochalcone (1), 4'-amino-4- fluorochalcone (2), and 4'-amino-4-methylchalcone (3) exhibited potent inhibition of the chlorinating activity of MPO, as evaluated in a neutrophil system and a free cell system, to the following degree: (1) IC50 = 0.265 � 0.036 μmol L-1; (2) IC50 = 0.250 � 0.081 μmol L-1; and (3) IC50 = 0.250 � 0.012 μmol L-1. These values were similar to those for 5-fluorotryptamine (IC50 = 0.192 � 0.012 μmol L-1), a compound considered to be a potent MPO inhibitor. These aminochalcones were not toxic to neutrophils at concentrations below 100 μmol L- 1, as determined by the trypan blue exclusion assay. Compounds 1-3 presented a high oxidation potential (Epa1 ≉ 0.80 V), low scavenger capacity against DPPH• and HOCl, and low inhibition of respiratory burst. These data indicated that aminochalcones are potent inhibitors of MPO chlorinating activity, a new property for chalcone derivatives, given that they are neither antioxidant agents nor inhibitors of respiratory burst. In conclusion, the selected aminochalcones have potential as pharmacological agents for inflammatory diseases.
authors.affiliation: Department of Organic Chemistry, Nuclei of Bioassays, Ecophysiology and Biosynthesis of Natural Products (NuBBE), Institute of Chemistry, Sao Paulo State University (UNESP), P. O. Box 355, 14800- 900, Araraquara, Sao Paulo, Brazil.
authors.forename: M L
authors.initials: ML
authors.lastname: Zeraik
authors.forename: V F
authors.initials: VF
authors.lastname: Ximenes
authors.forename: L O
authors.initials: LO
authors.lastname: Regasini
authors.forename: L A
authors.initials: LA
authors.lastname: Dutra
authors.forename: D H S
authors.initials: DH
authors.lastname: Silva
authors.forename: L M
authors.initials: LM
authors.lastname: Fonseca
authors.forename: D
authors.initials: D
authors.lastname: Coelho
authors.forename: S A S
authors.initials: SA
authors.lastname: Machado
authors.forename: V S
authors.initials: VS
authors.lastname: Bolzani
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D047188:Chalcones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D054879:Halogenation; D006801:Humans; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D013481:Superoxides / Q000378:metabolism
chemical_list: D047188:Chalcones; D004791:Enzyme Inhibitors; D013481:Superoxides; D009195:Peroxidase