American Chemical Society
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Synthesis and Iron Sequestration Equilibria of Novel Exocyclic 3-Hydroxy-2-pyridinone Donor Group Siderophore Mimics

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journal contribution
posted on 2010-09-20, 00:00 authored by James M. Harrington, Sumathi Chittamuru, Suraj Dhungana, Hollie K. Jacobs, Aravamudan S. Gopalan, Alvin L. Crumbliss
The synthesis of a novel class of exocyclic bis- and tris-3,2-hydroxypyridinone (HOPO) chelators built on N2 and N3 aza-macrocyclic scaffolds and the thermodynamic solution characterization of their complexes with Fe(III) are described. The chelators for this study were prepared by reaction of either piperazine or N,N′,N′′-1,4,7-triazacyclononane with a novel electrophilic HOPO iminium salt in good yields. Subsequent removal of the benzyl protecting groups using HBr/acetic acid gave bis-HOPO chelators N2(etLH)2 and N2(prLH)2, and tris-HOPO chelator N3(etLH)3 in excellent yields. Solution thermodynamic characterization of their complexes with Fe(III) was accomplished using spectrophotometric, potentiometric, and electrospray ionization-mass spectrometry (ESI-MS) methods. The pKa's of N2(etLH)2, N2(prLH)2, and N3(etLH)3, were determined spectrophotometrically and potentiometrically. The Fe(III) complex stability constants for the tetradentate N2(etLH)2 and N2(prLH)2, and hexadentate N3(etLH)3, were measured by spectrophotometric and potentiometric titration, and by competition with ethylenediaminetetraacetic acid (EDTA). N3(etLH)3 forms a 1:1 complex with Fe(III) with log β110 = 27.34 ± 0.04. N2(prLH)2 forms a 3:2 L:Fe complex with Fe(III) where log β230 = 60.46 ± 0.04 and log β110 = 20.39 ± 0.02. While N2(etLH)2 also forms a 3:2 L:Fe complex with Fe(III), solubility problems precluded determining log β230; log β110 was found to be 20.45 ± 0.04. The pFe values of 26.5 for N3(etLH)3 and 24.78 for N2(prLH)2 are comparable to other siderophore molecules used in the treatment of iron overload, suggesting that these hydroxypyridinone ligands may be useful in the development of new chelation therapy agents.