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

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 pK_a'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.