New chelating agents for the treatment of thalassemia

Maria Lucia Vitolo nee Wis

The research described in this thesis was carried out in the context of the development and evaluation of new iron chelators for the treatment of iron overload. The chemistry of pyridoxal isonicotinoyl hydrazone (PIH) and structurally related compounds : pyridoxal benzoyl hydrazone (PBH), 3-hydroxyisonicotinaldehyde isonicotinoyl hydrazone (IIH), salicylaldehyde isonicotinoyl hydrazone (SIH) and salicylaldehyde benzoyl hydrazone (SBH) was investigated with emphasis on the chemical characteristics pertinent to the assessment of their value as biological iron chelators. As oral effectiveness is a highly desirable feature of any drug. a detailed study into the behaviour of PIH and related compounds in acidic environment was carried out. The results indicate that these compounds are remarkably stable, as a decomposition of < 3% is observed after 72 hr at pH 2 and 37°C. The acid dissociation constants of the several ionizable groups present in the ligands were determined by potentiometric titration and the formation of their iron complexes was studied subsequently by potentiometry and UV-vis spectrophotometry. All these systems are quite complex due to the number of dissociable protons in both the free and coordinated ligands. the high affinity of these compounds towards iron(III) and the formation of sparingly soluble species at pH~5. The affinity of PIH and related compounds for iron(III) was compared to that of known ligands (including desferrioxamine and transferrin) At pH via the respective pM values. 7.4, [Fe3+ ]= 10“6 M and a 1000-fold excess of ligand, the three chelating agents PIH, PBH and SIH have pM values of 27.7, 39.7 and 50.0 respectively, which, when compared to 25.6 of transferrin, indicates that these compounds are thermodynamically capable of removing iron from transferrin. This is not the case with IIH, which has a pM value of 24.5. The distribution of the complex species as a function of pH shows that in each case a significant fraction is present as the electrically neutral Fe(L)(HL) at pH 7.4. A model of the coordination geometry of this species, supported by spectroscopic data, is proposed. The affinity of PIH for iron(II) is significantly lower than for iron(III), as indicated by a formation constant of 6.98 for [Fe(II)(HL)2] compared to 12.47 for [Fe(III)(HL)2]. The mobilization of ferritin iron by PIH and related compounds was studied by UV-vis spectrophotometry and equilibrium dialysis. Both PIH and its analogs were able to mobilize ferritin iron in significant amounts, up to 80% of that achieved with desferrioxamine. The hydrazones under study possess therefore the chemical features desirable in an effective iron chelating drug. Further studies of their toxicity and metabolism are certainly justified to establish their pharmacological and clinical value.

New chelating agents for the treatment of thalassemia

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