title: Effect of novel 1-phenyl-3-methyl-4-acylpyrazolones on iron chelation and Fenton reaction.
abstract: Iron is an essential element in many physiological processes due to its ability to easily convert between two oxidation states Fe(III)/Fe(II). However, at a pathological state, unbound iron may promote the production of highly toxic hydroxyl radicals via Fenton reaction, particularly when it is present in the excess.Iron chelators forming tight complexes with iron may prevent this reaction. In this study, novel synthetic 1-phenyl-3-methyl-4-acyl-pyrazol-5-ones were analyzed for their iron-chelating properties at four pathophysiologically relevant pH conditions (4.5-7.5) as well as for their effects on iron-based Fenton reaction. For the former competitive ferrozine spectrophotometric assay and for the latter HPLC method using salicylic acid as the indicator of hydroxyl radical production were used. All of the tested acylpyrazolones were efficient ferric chelators, however, their ferrous-chelating properties were clearly dependent on an acyl substitution. Interestingly, several acylpyrazolones had ferrous-chelating properties superior to those of the standard iron chelator - deferoxamine. Of particular interest is H2QpyQ, i.e. 2,6-bis[4(1-phenyl-3-methylpyrazol-5-one)carbonyl]pyridine, whose ferrous-chelating properties were increasing while pH was decreasing. In spite of large differences in ferrous chelation, a majority of the tested acylpyrazolones were powerful inhibitors of Fenton reaction as deferoxamine. In conclusion, the novel 1-phenyl-3-methyl-4-acyl-pyrazol-5-ones are efficient iron chelators and H2QpyQ may represent a prototype of specific iron chelators designed for chelation at acidic conditions in particular.
authors.affiliation: Charles University in Prague (Faculty of Pharmacy in Hradec Králové), Department of Pharmacology and Toxicology, Czech Republic. Electronic address: tomas.filipsky@faf.cuni.cz.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Filipský
authors.affiliation: Charles University in Prague (Faculty of Pharmacy in Hradec Králové), Department of Pharmacology and Toxicology, Czech Republic.
authors.forename: Premysl
authors.initials: P
authors.lastname: Mladenka
authors.affiliation: Charles University in Prague (Faculty of Pharmacy in Hradec Králové), Department of Pharmaceutical Botany and Ecology, Czech Republic.
authors.forename: Katerina
authors.initials: K
authors.lastname: Macáková
authors.affiliation: Charles University in Prague (Faculty of Pharmacy in Hradec Králové), Department of Pharmacology and Toxicology, Czech Republic.
authors.forename: Radomír
authors.initials: R
authors.lastname: Hrdina
authors.affiliation: Sapienza University of Rome ( Faculty of Pharmacy), Department of Physiology and Pharmacology "Vittorio Erspamer", Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Saso
authors.affiliation: University of Camerino (School of Science and Technology), Chemistry Section, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Marchetti
authors.affiliation: University of Camerino (School of Pharmacy), General and Inorganic Chemistry Unit, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Pettinari