Hicham Khodr

Synthesis of 2-amido-3-hydroxypyridin-4(1H)-ones: novel iron chelators with enhanced pFe3+ values.

The synthesis of a range of 2-amido-3-hydroxypyridin-4-ones as bidentate iron(III) chelators with potential for oral administration is described. The pKa values of the ligands together with the stability constants of their iron(III) complexes have been determined. Results indicate that the introduction of an amido substituent at the 2-position leads to an appreciable enhancement of the pFe3+ values. The ability of these novel 3-hydroxypyridin-4-ones to facilitate the iron excretion in bile was investigated using a 59Fe-ferritin loaded rat model. The optimal effect was observed with the N-methyl amido derivative 15b, which has an associated pFe3+ value of 21.7, more than two orders of magnitude higher than that of deferiprone (1,2-dimethyl-3-hydroxypyridin-4-one) 1a (pFe3+ = 19.4). Dose response studies suggest that chelators with high pFe3+ values scavenge iron more effectively at lower doses when compared with simple dialkyl substituted hydroxypyridinones.

Comparative Radical Scavenging Ability of Bidentate Iron(III) Chelators.

Iron chelators can reduce radical damage inflicted on cells by two mechanisms, either direct scavenging of the radicals or by scavenging loosely bound iron which under aerobic conditions can generate radicals. Frequently it is not possible to distinguish between these two modes of action. 3-Hydroxypyridin-4-ones, in contrast to many iron(III) chelators are poor radical scavengers and therefore have potential in analysing mechanisms involved in biochemical and physiological processes which are centered on radical-induced cell injury.

Synthesis, physico-chemical and iron(III)-chelating properties of novel hexadentate 3-hydroxy-2(1H)pyridinone ligands

Synthesis of hexadentate ligands via the in situ formation of 1-hydroxy benzotriazolyl active ester in the presence of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, TBTU as a coupling agent is described. The pKa values and distribution coefficient values (1-octanol/water) of the ligands and the stability constants of their iron(III) complexes are reported.

Design, synthesis and evaluation of N-basic substituted 3-hydroxypyridin-4-ones : Orally active iron chelators with lysosomotrophic potential

To investigate the possibility of targeting chelators into the lysosomal iron pool, nine bidentate 3‐hydroxypyridin‐4‐ones with basic chains have been synthesized. As the turnover of ferritin iron is centred in the lysosome, such strategy is predicted to increase chelator efficacy of bidentate ligands.

Synthesis and physicochemical assessment of novel 2‐substituted 3‐hydroxypyridin‐4‐ones, novel iron chelators

Novel 3‐hydroxypyridin‐4‐one containing tridentate ligands were synthesised and their physicochemical properties characterised, including ionisation constants and stoichiometric titration with Fe(III). There is an urgent demand for orally active iron chelators with potential for the treatment of thalassaemia. In principle, tridentate ligands are likely to be more kinetically stable than bidentate molecules, but to date no satisfactory molecules have been identified. Fe(III) stability constants were assessed by competition with the hexadentate ligand EDTA. In all cases no evidence was found for a tridentate mode of iron chelation; instead the ligands behaved as bidentate hydroxypyridinones. As a consequence they provide no advantage over the more simple alkyl hydroxypyridinones.

Spectrophotometric competition study between molybdate and Fe(III) hydroxide onN,N′-bis(2,3-dihydroxybenzoyl)-l-lysine, a naturally occurring siderophore synthesized byAzotobacter vinelandii

The solubilization of Fe(III) hydroxide by the naturally occurring siderophoreN,N′-bis(2,3-dihydroxybenzoyl)-l-lysine has been investigated spectrophotometrically in the presence and the absence of a stoichiometric amount of molybdate in aqueous medium at pH 7. In the absence of molybdate the reaction is 50% complete after 115 min. In contrast, the addition of an equimolar amount of molybdate results in an instantaneous formation of the molybdenum siderophore complex and a significant delay in the formation of the corresponding iron complex: 50% of the iron complex is present after 44 h and equilibrium is only reached after 2 weeks. The results are discussed with regard to metal acquisition by the nitrogen fixing cells ofAzotobacter vinelandii.

A manganese superoxide dismutase mimic based on cis,cis-1,3,5-triaminocyclohexane

A novel manganese(iii) complex with a water soluble cis,cis-1,3,5-triaminocyclohexane-based ligand was synthesised and shown to exhibit superoxide dismutase activity.

Design of 3-hydroxypyridin-4-one chelators with high pFe3+ values

Regular blood transfusion can lead to iron overload and associated toxicity. Desferrioxamine (DFO) has been used to scavenge excess iron, however because of the inconvenient administration, we have attempted to identify an orally active, nontoxic and selective iron chelator. 3-Hydroxypyridin-4-one (HPO) chelators have currently been developed as an alternative to DFO (Tilbrook and Hider, 1998). CP20 (1,2-dimethy1-3-hydroxypyridin-4-one), is currently in clinical trials but has been found to be (Brittenham, 1992). improvement.