SYNTHESIS, SOLUTION CHEMISTRY AND IN VITRO PROPERTIES OF NEW POSSIBLE CHELATING AGENTS FOR IRON(III) AND ALUMINIUM(III)

Chelation therapy is the most efficient therapeutic approach for metal ion overload [1]. The chelators presently used for iron and aluminium overload therapies, desferal and deferiprone, have several drawbacks. A multidisciplinary search for alternative molecules is being actively pursued [1, 5], which recently lead to the production of deferasirox. We proposed some hydroxypyridinecarboxylic acids (HP) ([6,7] and references therein) as potential chelating agents for Fe(III) and Al(III), as they have several requirements for an ideal chelator [3]. They have negligible or low toxicity, high stability of the Fe(III) and Al(III) 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, and their Fe(III) and Al(III) complex at physiological pH are hydrophilic so to enhance metal ion urinary elimination. The following results of several HP derivatives will be reported here: synthesis of the ligands, Fe(III)/HP and Al(III)/HP solution chemistry, electrochemistry, cytotoxicity, octanol/water partitioning, and chelation efficiency. References [1] HERSHKO, C., 2005. Treating iron overload: the state of the art. Sem. Hematol., 42, Issue 2, Supplement 1. [2] CUNNINGHAM, M. , 2005. New developments in iron chelators. Curr. Opin. Hematol., 12, 129-134. [3] HIDER, R. C., 2005. The design of orally active iron chelators. Ann. N.Y. Acad. Sci., 1054, 141-154. [4] YOKEL, R. A., 2002. Aluminum chelation principles and recent advances. Coord. Chem. Rev., 228, 97-113. [5] KONTOGHIORGHES, G. J., 2005. New oral iron-chelating drugs for the treatment of transfusional iron overload and other diseases. Drugs Fut., 30, 1241-1251. [6] DEAN, A., 2008. Evaluation of 2-methyl-3-hydroxy-4-pyridinecar-boxylic acid as a possible chelating agent for iron and aluminium. Dalton Transactions, 1689-1697. [7] DEAN, A., 2009. 1,6-Dimethyl-4-hydroxy-3-pyridinecarboxylic acid and 4-hydroxy-2-methyl-3-pyridinecarboxylic acid as new possible chelating agents for iron and aluminium. Dalton Transactions, 1815-1824.