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. 2006 May 1;45(9):3622-31.
doi: 10.1021/ic052111a.

Synthesis and thermodynamic evaluation of mixed hexadentate linear iron chelators containing hydroxypyridinone and terephthalamide units

Rebecca J Abergel  1 , Kenneth N Raymond
Affiliations

Synthesis and thermodynamic evaluation of mixed hexadentate linear iron chelators containing hydroxypyridinone and terephthalamide units

Rebecca J Abergel et al. Inorg Chem. .

Abstract

A series of new linear iron chelators containing hydroxypyridinone and terephthalamide (TAMmeg) moieties have been prepared. All are hexadentate ligands composed of a systematically varied combination of methyl-3,2-hydroxypyridinone and 2,3-dihydroxyterephthalamide binding units; most are based on a spermidine scaffold, but one incorporates the bifunctional 2,3-dihydroxyterephthalamide unit as an integral part of the backbone. Protonation and ferric iron complex formation constants have been determined from solution thermodynamic studies, giving log beta(110) values of 25.7, 30.7, 36.3, 43.8, and 45.0, respectively. The ferric complexes display reversible reduction potentials from -276 to -1032 mV (measured relative to the normal hydrogen electrode) in alkaline solution. The incremental replacement of hydroxypyridinone units by terephthalamide binding groups progressively reduces the ligand acidity, markedly increases the iron-chelate stability, and improves the selectivity for the ferric ion over the ferrous ion. While the majority of iron chelators forming very stable ferric complexes are based on a tripodal backbone such as TREN, the ferric 5-LIO(TAMmeg)(2)(TAM) complex, despite its nontripodal scaffold, is one of the most stable iron complexes yet reported. Moreover, the high affinity for the ferric ion of the discussed linear ligands strongly correlates with their ability to remove iron in vivo.

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Figures

Figure 1
Figure 1
Desferrioxamine B (a.), previously investigated iron chelators TREN-Me-3,2-HOPO (b.), 5-LIO(Me-3,2-HOPO)2(TAM) (c.) and linear ligands presented in this study 5-LIO(TAMmeg)2(TAM) (d.), 3,4-LI(Me-3,2-HOPO) (e.), 3,4-LI(Me-3,2-HOPO)2(TAMmeg) (f.), 3,4-LI(Me-3,2-HOPO)(TAMmeg)2 (g.) and 3,4-LI(TAMmeg) (h.).
Figure 2
Figure 2
Upper panel: Square wave voltammograms at the HMDE of 5 × 10−5 M Fe[5-LIO(TAMmeg)2(TAM)] in 0.01 M ammonium acetate buffer, pH 9.0, ionic strength 0.1 M (KCl), Esw = 25 mV, Estep = 2 mV, frequencies given in hertz. Lower panel: Conversion of the voltammograms to the ε function, according to eq. 1.
Figure 3
Figure 3
Potentiometric titration curves for the two ligands 3,4-LI(Me-3,2-HOPO) and 3,4-LI(Me-3,2-HOPO)2(TAMmeg). Symbols give observed pH measurements, and lines give the calculated fits.
Figure 4
Figure 4
Spectrophotometric titrations of the ligands 3,4-LI(Me-3,2-HOPO)(TAMmeg)2, 3,4-LI (TAMmeg) and 5-LIO(TAMmeg)2(TAM). Symbols give observed absorbance measurements at a given wavelength, and lines give the calculated fits.
Figure 5
Figure 5
EDTA-competition spectrophotometric titrations of ligands. Symbols give observed absorbance measurements at a given wavelength (highest energy LMCT band), and lines give the calculated fits.
Figure 6
Figure 6
Correlation between the pM(FeIII) values and the incorporation of terephthalamide units on a same backbone for the 3,4-LI and 5-LIO series of ligands. The pM value for Fe[5-LIO(Me-3,2-HOPO)2(TAM)] was determined in a previous study.
Scheme 1
Scheme 1
Functionalization of the 2,3-dihydroxy-terephthalamide moiety.
Scheme 2
Scheme 2
Synthesis of the homogeneous 3,4-LI(Me-3,2-HOPO) and 3,4-LI(TAMmeg) ligands.
Scheme 3
Scheme 3
Synthesis of the mixed 3,4-LI(Me-3,2-HOPO)2(TAMmeg) and 3,4-LI(Me-3,2-HOPO)(TAMmeg)2 ligands.
Scheme 4
Scheme 4
Synthesis of 5-LIO(TAMmeg)2(TAM).
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