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

Abstract

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 hydrogenolysis 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) has been accomplished using spectrophotometric, potentiometric and ESI-MS methods. The pKas 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 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.

Synthesis, Physicochemical Studies, Molecular Dynamics Simulations, and Metal‐Ion‐Dependent Antiproliferative and Antiangiogenic Properties of Cone ICL670‐Substituted Calix[4]arenes

“…The pFe values are 23.12, 26.44, and 23.23 for Fe–ICL670, Fe– 5a , and Fe– 5b , respectively. The ICL670 pFe value determined in this study is close to the one reported in the literature (pFe =23.5), [29] which validates our calculation procedure for water-insoluble systems. The pFe values determined in this study for ICL670-based calix[4]arene ligands (pFe >20) met the criteria for application as iron chelation therapy agents.…”

Synthesis of novel Iron(III) chelators based on triaza macrocycle backbone and 1-hydroxy-2(H)-pyridin-2-one coordinating groups and their evaluation as antimicrobial agents

“…Very few polyaza macrocycles bearing HOPO coordinating groups have been described [48,[51][52][53][54]. Macrocycles offer the potential to fine tune the metal chelating properties by varying the cycle's size and fexibility.…”

The Role of Aluminum-Organo Complexes in Soil Organic Matter Dynamics

“…A proportional decrease was observed for the absorbance at 220 and 270 nm for gallic acid (GA) and at 240 and 300 nm for salicylic acid (SA). The two isosbestic points (IUPAC 2007) confirmed the formation of the metal-organo complexes and are indicative of a transition between two light absorbing species in all recorded spectra (Harrington et al 2010).…”