Bidentate hydroxypyridinones are under active development as orally active iron chelators. With a... more Bidentate hydroxypyridinones are under active development as orally active iron chelators. With applications for the treatment of general body iron overload, for instance with thalassaemia, the distribution of the chelators should be limited to peripheral tissue and they should not enter the central nervous system. This study compares the predictive abilities of LogPoctanol and LogPcyclohexane and reports the existence of
... 50 H. Verhagen, HE Poulsen, S. Loft, G. van Poppel, MI Willems, and PJ van Bladeren, Carcino-... more ... 50 H. Verhagen, HE Poulsen, S. Loft, G. van Poppel, MI Willems, and PJ van Bladeren, Carcino-genesis 16, 969 (I 995). 51 XS Deng, J. Tuo, HE Poulsen, and S. Loft, Free Radic. ... 2 p. S. Dobbin, RC Hider, L. Venkatramani, J. Siripitayananon, and D. Vanderhelm, J. Heterocycl. ...
A novel manganese(iii) complex with a water soluble cis,cis-1,3,5-triaminocyclohexane-based ligan... more 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.
The flavonoids constitute a large group of polyphenolic phytochemicals with antioxidant propertie... more The flavonoids constitute a large group of polyphenolic phytochemicals with antioxidant properties in vitro. The interactions of four structurally related flavonoids (quercetin, kaempferol, rutin and luteolin) with Cu2+ ions were investigated in terms of the extent to which they undergo complex formation through chelation or modification through oxidation, as well as in their structural dependence. The ortho 3ʹ,4ʹ-dihydroxy substitution in the B ring is shown to be important for Cu2+-chelate formation, thereby influencing the antioxidant activity. The presence of a 3-hydroxy group in the flavonoid structure enhances the oxidation of quercetin and kaempferol, whereas luteolin and rutin, each lacking the 3-hydroxy group, do not oxidize as readily in the presence of Cu2+ ions. The results also demonstrate that the reactivities of the flavonoids in protecting low-density lipoprotein (LDL) against Cu2+ ion-induced oxidation are dependent on their structural properties in terms of the res...
Graminaceous plant species acquire soil iron by the release of phytosiderophores and subsequent u... more Graminaceous plant species acquire soil iron by the release of phytosiderophores and subsequent uptake of iron(III)-phytosiderophore complexes. As plant species differ in their ability for phytosiderophore hydroxylation prior to release, an electrophoretic method was set up to determine whether hydroxylation affects the net charge of iron(III)-phytosiderophore complexes, and thus chelate stability. At pH 7.0, non-hydroxylated (deoxymugineic acid) and hydroxylated (mugineic acid; epi-hydroxymugineic acid) phytosiderophores form single negatively charged iron(III) complexes, in contrast to iron(III)-nicotianamine. As the degree of phytosiderophore hydroxylation increases, the corresponding iron(III) complex was found to be less readily protonated. Measured pKa values of the amino groups and calculated free iron(III) concentrations in presence of a 10-fold chelator excess were also found to decrease with increasing degree of hydroxylation, confirming that phytosiderophore hydroxylation...
Nicotianamine (NA) occurs in all plants and chelates metal cations, including FeII, but reportedl... more Nicotianamine (NA) occurs in all plants and chelates metal cations, including FeII, but reportedly not FeIII. However, a comparison of the FeII and ZnII affinity constants of NA and various FeIII-chelating aminocarboxylates suggested that NA should chelate FeIII. High-voltage electrophoresis of the FeNA complex formed in the presence of FeIII showed that the complex had a net charge of 0, consistent with the hexadentate chelation of FeIII. Measurement of the affinity constant for FeIII yielded a value of 1020.6, which is greater than that for the association of NA with FeII (1012.8). However, capillary electrophoresis showed that in the presence of FeII and FeIII, NA preferentially chelates FeII, indicating that the FeIINA complex is kinetically stable under aerobic conditions. Furthermore, Fe complexes of NA are relatively poor Fenton reagents, as measured by their ability to mediate H2O2-dependent oxidation of deoxyribose. This suggests that NA will have an important role in scave...
... We thank the DFG Bonn for financial support to NVW (Grant WI 1728/6-1); the BBSRC for financi... more ... We thank the DFG Bonn for financial support to NVW (Grant WI 1728/6-1); the BBSRC for financial support to RCH; and CREST (Care Research for Evolutional Science and Technology) of Japan Science and ... Web of Science®. Ling HQ, Koch G, Bäumlein H, Ganal MW. 1999. ...
To investigate the possibility of targeting chelators into the lysosomal iron pool, nine bidentat... more 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. The pKa values of the ligands together with their distribution coefficients between 1-octanol and 4-morpholinepropane sulphonic acid (MOPS) buffer pH 7.4 have been determined. The in-vivo iron mobilization efficacy of these basic 3-hydroxypyridin-4-ones has been investigated in a 59Fe-ferritin-loaded rat model. No obvious correlation was observed between efficacy and the pKa value of the side chain, although those with pKa > 7.0 tended to be more efficient than those with pKa < 7.0. The imidazole-containing molecules are much less effective than the tertiary amine derivatives. A dose-response study suggested that basic pyridinones are relatively more effective at lower doses whe...
Novel 3-hydroxypyridin-4-one containing tridentate ligands were synthesised and their physicochem... more 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.
Regular blood transfusion can lead to iron overload and associated toxicity. Desferrioxamine (DFO... more 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.
Bidentate hydroxypyridinones are under active development as orally active iron chelators. With a... more Bidentate hydroxypyridinones are under active development as orally active iron chelators. With applications for the treatment of general body iron overload, for instance with thalassaemia, the distribution of the chelators should be limited to peripheral tissue and they should not enter the central nervous system. This study compares the predictive abilities of LogPoctanol and LogPcyclohexane and reports the existence of
... 50 H. Verhagen, HE Poulsen, S. Loft, G. van Poppel, MI Willems, and PJ van Bladeren, Carcino-... more ... 50 H. Verhagen, HE Poulsen, S. Loft, G. van Poppel, MI Willems, and PJ van Bladeren, Carcino-genesis 16, 969 (I 995). 51 XS Deng, J. Tuo, HE Poulsen, and S. Loft, Free Radic. ... 2 p. S. Dobbin, RC Hider, L. Venkatramani, J. Siripitayananon, and D. Vanderhelm, J. Heterocycl. ...
A novel manganese(iii) complex with a water soluble cis,cis-1,3,5-triaminocyclohexane-based ligan... more 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.
The flavonoids constitute a large group of polyphenolic phytochemicals with antioxidant propertie... more The flavonoids constitute a large group of polyphenolic phytochemicals with antioxidant properties in vitro. The interactions of four structurally related flavonoids (quercetin, kaempferol, rutin and luteolin) with Cu2+ ions were investigated in terms of the extent to which they undergo complex formation through chelation or modification through oxidation, as well as in their structural dependence. The ortho 3ʹ,4ʹ-dihydroxy substitution in the B ring is shown to be important for Cu2+-chelate formation, thereby influencing the antioxidant activity. The presence of a 3-hydroxy group in the flavonoid structure enhances the oxidation of quercetin and kaempferol, whereas luteolin and rutin, each lacking the 3-hydroxy group, do not oxidize as readily in the presence of Cu2+ ions. The results also demonstrate that the reactivities of the flavonoids in protecting low-density lipoprotein (LDL) against Cu2+ ion-induced oxidation are dependent on their structural properties in terms of the res...
Graminaceous plant species acquire soil iron by the release of phytosiderophores and subsequent u... more Graminaceous plant species acquire soil iron by the release of phytosiderophores and subsequent uptake of iron(III)-phytosiderophore complexes. As plant species differ in their ability for phytosiderophore hydroxylation prior to release, an electrophoretic method was set up to determine whether hydroxylation affects the net charge of iron(III)-phytosiderophore complexes, and thus chelate stability. At pH 7.0, non-hydroxylated (deoxymugineic acid) and hydroxylated (mugineic acid; epi-hydroxymugineic acid) phytosiderophores form single negatively charged iron(III) complexes, in contrast to iron(III)-nicotianamine. As the degree of phytosiderophore hydroxylation increases, the corresponding iron(III) complex was found to be less readily protonated. Measured pKa values of the amino groups and calculated free iron(III) concentrations in presence of a 10-fold chelator excess were also found to decrease with increasing degree of hydroxylation, confirming that phytosiderophore hydroxylation...
Nicotianamine (NA) occurs in all plants and chelates metal cations, including FeII, but reportedl... more Nicotianamine (NA) occurs in all plants and chelates metal cations, including FeII, but reportedly not FeIII. However, a comparison of the FeII and ZnII affinity constants of NA and various FeIII-chelating aminocarboxylates suggested that NA should chelate FeIII. High-voltage electrophoresis of the FeNA complex formed in the presence of FeIII showed that the complex had a net charge of 0, consistent with the hexadentate chelation of FeIII. Measurement of the affinity constant for FeIII yielded a value of 1020.6, which is greater than that for the association of NA with FeII (1012.8). However, capillary electrophoresis showed that in the presence of FeII and FeIII, NA preferentially chelates FeII, indicating that the FeIINA complex is kinetically stable under aerobic conditions. Furthermore, Fe complexes of NA are relatively poor Fenton reagents, as measured by their ability to mediate H2O2-dependent oxidation of deoxyribose. This suggests that NA will have an important role in scave...
... We thank the DFG Bonn for financial support to NVW (Grant WI 1728/6-1); the BBSRC for financi... more ... We thank the DFG Bonn for financial support to NVW (Grant WI 1728/6-1); the BBSRC for financial support to RCH; and CREST (Care Research for Evolutional Science and Technology) of Japan Science and ... Web of Science®. Ling HQ, Koch G, Bäumlein H, Ganal MW. 1999. ...
To investigate the possibility of targeting chelators into the lysosomal iron pool, nine bidentat... more 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. The pKa values of the ligands together with their distribution coefficients between 1-octanol and 4-morpholinepropane sulphonic acid (MOPS) buffer pH 7.4 have been determined. The in-vivo iron mobilization efficacy of these basic 3-hydroxypyridin-4-ones has been investigated in a 59Fe-ferritin-loaded rat model. No obvious correlation was observed between efficacy and the pKa value of the side chain, although those with pKa > 7.0 tended to be more efficient than those with pKa < 7.0. The imidazole-containing molecules are much less effective than the tertiary amine derivatives. A dose-response study suggested that basic pyridinones are relatively more effective at lower doses whe...
Novel 3-hydroxypyridin-4-one containing tridentate ligands were synthesised and their physicochem... more 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.
Regular blood transfusion can lead to iron overload and associated toxicity. Desferrioxamine (DFO... more 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.
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