Potentiometric, spectrophotometric and calorimetric study on iron(III) and copper(II) complexes with 1,2-dimethyl-3-hydroxy-4-pyridinone Valeria M. Nurchi a, * , Guido Crisponi a , Tiziana Pivetta a , Martina Donatoni b , Maurizio Remelli b a Dipartimento di Scienze Chimiche, Universita ` di Cagliari, Cittadella Universitaria di Monserrato, 09042 Monserrato-Cagliari, Italy b Dipartimento di Chimica, Universita ` di Ferrara, Via L. Borsari 46, 44100 Ferrara, Italy Received 20 July 2007; received in revised form 15 October 2007; accepted 18 October 2007 Available online 30 October 2007 Abstract The iron(III)–1,2-dimethyl-3-hydroxy-4-pyridinone (Deferiprone) system is carefully characterized by a combined potentiometric– spectrophotometric procedure at 25 and 37 °C at different ionic strengths, and by thermochemical and quantum-chemical studies. The main purpose of this work was to determine how the temperature dependence of both complex-formation and protonation constants can affect the pFe values on going from 25 °C (pFe is normally calculated using 25 °C stability constants) to the physiological temper- ature of 37 °C at which chelating agents are active in vivo. The copper(II)–Deferiprone system is also studied and the iron(III)–Deferi- prone distribution diagrams in presence of variable copper(II) amounts are shown so as to explain possible side effects due to a competing metal ion during the chelating therapy of iron overload. Ó 2007 Elsevier Inc. All rights reserved. Keywords: 1,2-Dimethyl-3-hydroxy-4-pyridinone; Iron(III) and copper(II) complexes; Potentiometry; Calorimetry; Quantum-chemical calculation 1. Introduction Iron chelators are used in medicine to protect patients from the consequences of iron overload and iron toxicity. One of the most serious health problems in the world is b-thalassemia major, where iron overload plays a very important role. The only iron chelating drug in use up to the year 2000 was desferrioxamine (Desferal). However, in spite of its success, it presents drawbacks, such as high cost, non-oral effectiveness, and a short half-life inside the organism. An orally effective and cheaper drug, 1,2- dimethyl-3-hydroxy-4-pyridinone, known as Deferiprone or simply L1 (Scheme 1), was introduced in 2000 and has been used in clinical practice since then, but the new drug cannot totally replace Desferal. Though Deferiprone over- comes the main shortcoming limits of Desferal, it has its own limits. Thus, research on new orally effective iron che- lating drugs is of the greatest importance [1–3] and new interesting molecules have recently been proposed. Among these 4-[(3,5-bis-(2-hydroxyphenyl)-1,2,4)triazol-1-yl]-ben- zoic acid (ICL670) has successfully concluded phase III clinical trials [4] and after USFDA approval is nowadays available with the trade name of Exjade. The introduction of the pFe [5] concept by Raymond [6] was a brilliant revolution. Unlike formation constants, it allowed directly to compare ligands of dissimilar chemical behaviour (denticity and proton competition). Physiologi- cal temperature is not considered by definition, and pFe is usually calculated using equilibrium constants at 25 °C. 1 0162-0134/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.jinorgbio.2007.10.012 * Corresponding author. Tel.: +39 0706754476; fax: +39 0706754478. E-mail address: nurchi@unica.it (V.M. Nurchi). 1 Few data on complex formation and protonation constants are available in the literature, either at 37 °C or accompanied by thermo- chemical results: an analysis of the literature data on iron complexes in aqueous solution using the SC Query program shows that compared to 1179 data reported at 25 °C there are only 6 data at 37 °C. www.elsevier.com/locate/jinorgbio Available online at www.sciencedirect.com Journal of Inorganic Biochemistry 102 (2008) 684–692 JOURNAL OF Inorganic Biochemistry