title: Hydroxypyridinones with enhanced iron chelating properties. Synthesis, characterization and in vivo tests of 5-hydroxy-2-(hydroxymethyl)pyridine-4(1H)-one.
abstract: The synthesis of 5-hydroxy-2-(hydroxymethyl)pyridin-4(1H)-one (P1) is presented, together with the evaluation of its coordination ability towards Fe(3+), studied by a combination of chemical, computational, and animal approaches. The use of complementary analytical techniques has allowed us to give evidence of the tautomeric changes of P1 as a function of pH, and to determine their influence on the coordinating ability of P1 towards Fe(3+). The pFe(3+) value 22.0 of P1-iron complexes is noticeably higher than that of deferiprone (20.6), one of the three clinical chelating agents in therapeutic use for iron overload diseases. This is due on one side to the tautomeric change to the catechol form, and on the other to the lower protonation constant of the OH group. Bio-distribution studies on mice allowed us to confirm in vivo the efficacy of P1. Furthermore the coordinating ability toward Al(3+), Cu(2+) and Zn(2+) has been studied to evaluate the possible use of P1 against a second toxic metal ion (Al(3+)), and to envisage its potential influence on the homeostatic equilibria of essential metal ions. The chelating ability of P1 toward these ions, not higher than that of the corresponding deferiprone, contributes to render P1 a more selective iron chelator.
authors.affiliation: Department of Chemical and Geological Science, University of Cagliari, Cittadella Universitaria, 09042 Monserrato-Cagliari, Italy. lachowicz@unica.it.
authors.forename: J I
authors.initials: JI
authors.lastname: Lachowicz
authors.affiliation: Department of Chemical and Geological Science, University of Cagliari, Cittadella Universitaria, 09042 Monserrato-Cagliari, Italy. lachowicz@unica.it.
authors.forename: V M
authors.initials: VM
authors.lastname: Nurchi
authors.affiliation: Department of Chemical and Geological Science, University of Cagliari, Cittadella Universitaria, 09042 Monserrato-Cagliari, Italy. lachowicz@unica.it.
authors.forename: G
authors.initials: G
authors.lastname: Crisponi
authors.affiliation: Department of Chemical and Geological Science, University of Cagliari, Cittadella Universitaria, 09042 Monserrato-Cagliari, Italy. lachowicz@unica.it.
authors.forename: M G
authors.initials: MG
authors.lastname: Jaraquemada-Pelaez
authors.affiliation: Department of Chemical and Geological Science, University of Cagliari, Cittadella Universitaria, 09042 Monserrato-Cagliari, Italy. lachowicz@unica.it.
authors.forename: M
authors.initials: M
authors.lastname: Arca
authors.affiliation: Department of Chemical and Geological Science, University of Cagliari, Cittadella Universitaria, 09042 Monserrato-Cagliari, Italy. lachowicz@unica.it.
authors.forename: A
authors.initials: A
authors.lastname: Pintus
authors.affiliation: Centro Quimica Estrutural, Instituto Superior Tecnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal.
authors.forename: M A
authors.initials: MA
authors.lastname: Santos
authors.affiliation: Centro Quimica Estrutural, Instituto Superior Tecnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal.
authors.forename: C
authors.initials: C
authors.lastname: Quintanova
authors.affiliation: Campus Tecnológico e Nuclear, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10, 2695-066 Bobadela LRS, Portugal.
authors.forename: L
authors.initials: L
authors.lastname: Gano
authors.affiliation: Faculty of Chemistry, University of Wroclaw, F. Joliot-Curie 14, 50-383 Wroclaw, Poland.
authors.forename: Z
authors.initials: Z
authors.lastname: Szewczuk
authors.affiliation: Dipartimento di Chimica e Farmacia, Università di Sassari, Via Vienna 2, 07100 Sassari, Italy.
authors.forename: M A
authors.initials: MA
authors.lastname: Zoroddu
authors.affiliation: Dipartimento di Chimica e Farmacia, Università di Sassari, Via Vienna 2, 07100 Sassari, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Peana
authors.affiliation: Department of Inorganic Chemistry, Faculty of Pharmacy, Campus Cartuja, University of Granada, E-18071, Granada, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Domínguez-Martín
authors.affiliation: Laboratorio de Estudios Cristalográficos, IACT, CSIC-Universidad de Granada, Av. de las Palmeras 4, E-18100, Armilla, Granada, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Choquesillo-Lazarte
mesh_terms: D000818:Animals; D060326:Chemistry Techniques, Synthetic; D018360:Crystallography, X-Ray; D005260:Female; D057927:Hydrophobic and Hydrophilic Interactions; D007501:Iron / Q000737:chemistry*; D007502:Iron Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D011522:Protons; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: C000613082:5-hydroxy-2-(hydroxymethyl)pyridine-4(1H)-one; D007502:Iron Chelating Agents; D011522:Protons; D011725:Pyridines; D011728:Pyridones; D007501:Iron