title: A new bis-3-hydroxy-4-pyrone as a potential therapeutic iron chelating agent. Effect of connecting and side chains on the complex structures and metal ion selectivity.
abstract: This work reports the synthesis, characterization and study of complex formation equilibria of the new ligand 6,6'-(2-(diethylamino)ethylazanediyl)bis(methylene)bis(5-hydroxy-2-hydroxymethyl-4H-pyran-4-one) with Fe(III), Al(III), Cu(II) and Zn(II). On the basis of previous encouraging results with tetradentate bis-kojic acid chelators, this ligand was designed to improve the pharmacokinetic properties: increase the solubility, neutral at physiological pH7.4, and enhancement of membrane crossing ability. Fe(III) and Al(III) complexation gave evidence of high metal-sequestering capacity of L9. Cellular assays showed that the ligand is capable of crossing cellular membranes and it does not present toxic effects. Complex formation equilibria with the essential metal ions Cu(II) and Zn(II) have been furthermore studied to evaluate disturbances of this chelator on the homeostatic equilibria of these essential metal ions. A variety of techniques (potentiometry, UV-visible spectrophotometry, 1D and 2D NMR spectroscopy, ESI-MS (electrospray ionization-mass spectrometry), quantum mechanical calculations and X-ray diffraction) have facilitated the characterization of the ligand, and the corresponding iron and zinc complexes, together with an exhaustive analysis of the protonation and complex equilibria.
authors.affiliation: Dipartimento di Scienze Chimiche e Geologiche, Università di Cagliari, Cittadella Universitaria, 09042 Monserrato-Cagliari, Italy. Electronic address: nurchi@unica.it.
authors.forename: Valeria M
authors.initials: VM
authors.lastname: Nurchi
authors.affiliation: Dipartimento di Scienze Chimiche e Geologiche, Università di Cagliari, Cittadella Universitaria, 09042 Monserrato-Cagliari, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Crisponi
authors.affiliation: Dipartimento di Scienze Chimiche e Geologiche, Università di Cagliari, Cittadella Universitaria, 09042 Monserrato-Cagliari, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Arca
authors.affiliation: Dipartimento di Scienze Chimiche e Geologiche, Università di Cagliari, Cittadella Universitaria, 09042 Monserrato-Cagliari, Italy.
authors.forename: Miriam
authors.initials: M
authors.lastname: Crespo-Alonso
authors.affiliation: Dipartimento di Scienze Chimiche e Geologiche, Università di Cagliari, Cittadella Universitaria, 09042 Monserrato-Cagliari, Italy.
authors.forename: Joanna I
authors.initials: JI
authors.lastname: Lachowicz
authors.affiliation: Dipartimento di Scienze Chimiche e Geologiche, Università di Cagliari, Cittadella Universitaria, 09042 Monserrato-Cagliari, Italy.
authors.forename: Delara
authors.initials: D
authors.lastname: Mansoori
authors.affiliation: Dipartimento di Scienze Chimiche e Geologiche, Università di Cagliari, Cittadella Universitaria, 09042 Monserrato-Cagliari, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Toso
authors.affiliation: Dipartimento di Scienze Chimiche e Geologiche, Università di Cagliari, Cittadella Universitaria, 09042 Monserrato-Cagliari, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Pichiri
authors.affiliation: Centro Quimica Estrutural, Instituto Superior Tecnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal.
authors.forename: M
authors.initials: M
authors.lastname: Amelia Santos
authors.affiliation: Centro Quimica Estrutural, Instituto Superior Tecnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal.
authors.forename: Sergio M
authors.initials: SM
authors.lastname: Marques
authors.affiliation: Department of Inorganic Chemistry, Faculty of Pharmacy, Campus Cartuja, University of Granada, E-18071, Granada, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Niclós-Gutiérrez
authors.affiliation: Department of Inorganic Chemistry, Faculty of Pharmacy, Campus Cartuja, University of Granada, E-18071, Granada, Spain.
authors.forename: Josefa M
authors.initials: JM
authors.lastname: González-Pérez
authors.affiliation: Department of Inorganic Chemistry, Faculty of Pharmacy, Campus Cartuja, University of Granada, E-18071, Granada, Spain.
authors.forename: Alicia
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: Duane
authors.initials: D
authors.lastname: Choquesillo-Lazarte
authors.affiliation: Faculty of Chemistry, University of Wroclaw, F. Joliot-Curie 14, 50-383 Wroclaw, Poland.
authors.forename: Zbigniew
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
authors.initials: M
authors.lastname: Antonietta Zoroddu
authors.affiliation: Dipartimento di Chimica e Farmacia, Università di Sassari, Via Vienna 2, 07100 Sassari, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Peana
mesh_terms: D000535:Aluminum / Q000737:chemistry; D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism; D002463:Cell Membrane Permeability; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000494:pharmacology; D003300:Copper / Q000737:chemistry; D005029:Ethylenediamines / Q000138:chemical synthesis* / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007501:Iron / Q000737:chemistry*; D007700:Kinetics; D008024:Ligands; D011522:Protons; D011753:Pyrones / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry*
chemical_list: C000599650:6,6'-(2-(diethylamino)ethylazanediyl)bis(methylene)bis(5-hydroxy-2-hydroxymethyl-4H-pyran-4-one); D002614:Chelating Agents; D056831:Coordination Complexes; D005029:Ethylenediamines; D008024:Ligands; D011522:Protons; D011753:Pyrones; D003300:Copper; D000535:Aluminum; D007501:Iron; D015032:Zinc
keywords: Complex formation equilibria; Iron chelators; NMR; Speciation; X-ray structures