New Perspectives in Chelation Therapy of Aluminium(III) and Iron(III) Overload

The overload of metal ions may produce several pathologies because of toxic degenerative processes in the involved parenchyma[1]. In particular, iron (Fe) overload is a common adverse consequence of the chronic transfusional therapies for thalassemic patients, and aluminium (Al) overload may be observed in uremic patients. The overload of Fe and Al in central nervous system has been suggested to be involved in neurodegenerative disorders like Alzheimer’s and Parkinson’s disease. Current treatment options for metal ion overload are designed to remove tissue deposits which cause the toxic effects. Chelation therapy is the most efficient therapeutic approach for metal ion overload[2]. The chelators presently used for Al(III) and Fe(III) overload therapies, desferal and deferiprone, have several drawbacks. A multidisciplinary research for alternative molecules is being actively pursued [2-5]. We proposed some isomeric 3,4- and 4,3-hydroxypyridinecarboxylic acids (HP) ([7] and references therein) as potential chelating agents for aluminium and iron, as they have several requirements of an ideal chelator [3]. They have negligible or low toxicity, high stability of the metal complexes at physiological conditions, low affinity towards essential metal ions to reduce undesired metal depletion, low molecular mass (less than 400 Dalton) to allow oral administration, no redox activity in vivo. Their metal complexes at physiological pH are hydrophilic so to enhance metal ion urinary elimination. In the present poster, the following results for some HP derivatives will be reported: synthesis of the ligands, metal/HP solution chemistry, cytotoxicity, octanol/water partitioning, and chelation efficiency. 1. N. C. Andrews, N. Eng. J, Med., 1999, 341, 1986 2. C. Hershko (Guest Editor), Sem. Hematol. 2005, 42, Issue 2, Supplement 1 3. M. J. Cunningham and D. G. Nathan, Curr. Opin. Hematol., 2005, 12, 129. 4. R. C. Hider and T. Zhou, Ann. N.Y. Acad. Sci., 2005, 1054, 141. 5. R. A. Yokel, Coord. Chem. Rev., 2002, 228, 97. 6. G. J. Kontoghiorghes, Drugs Fut., 2005, 30, 1241. 7. A. Dean, M. G. Ferlin, P. Brun, I. Castagliuolo, D. Badocco, P. Pastore, A. Venzo, G. G. Bombi and V. B. Di Marco, Dalton Trans., 2008, 1689.