| The research presented here aims to expand our understanding of the structural factors that contribute to selectivity for iron and to iron complex stability in siderophores, as well as iron transport processes in siderophore systems. This work also investigates the factors that contribute to therapeutic applications of chelating agents, both for chelation therapy and for antimicrobial agents.;The thermodynamics of iron(III) binding of a number of molecules, both natural and synthetic, are determined using pH-dependent spectrophotometric titrations and potentiometric titrations. Three of the synthetic siderophore analogs studied here are a tris-hydroxypyridinone (N3(etLH) 3, log beta110 = 27.34 and pFe = 23.49) and two bis-hydroxypyridinone ligands (N2(prLH)2, log beta230 = 27.34 and pFe = 22.07; N2(etLH)2, log beta230 = 21.08). A determination of the solution thermodynamics of the iron(III) complex of a water-soluble analog of Brasilibactin A, a membrane-bound mycobactin-type bacterial siderophore is also presented and related to the role of mycobactins in iron uptake of mycobacteria. The analog Bbtan forms a stable complex with iron (log beta110 = 26.96, pFe = 22.73) and exhibits a relatively positive redox potential for the iron-Bbtan complex (E1/2 = -300 mV vs NHE). The thermodynamics of chelation of iron(III) by a synthetic Trojan Horse antimicrobial agent featuring a 3-hydroxy-4-pyridinone moiety, LPF were also determined. The binding by L PF occurs exclusively through the 3-hydroxy-4-pyridinone donor group and allows the formation of a 3:1 LPF:Fe 3+ complex with log beta130 = 31.91. In these studies, the thermodynamic stability constants of the iron-chelator complexes are determined through a series of spectrophotometric and potentiometric titrations. Also, the redox chemistry of the iron-chelator complexes is investigated using cyclic voltammetry. The structural features that contribute to complex stability in a series of tripodal tris-hydroxamate siderophores using computational techniques is presented, and it is shown that the position of the arm of an exocyclic siderophore system can contribute to differences in complex stability, as can the orientation of the donor group.;Kinetic studies of the iron(III) exchange reactions of the polydentate chelators desferrioxamine B, N3(etLH)3, and N 2(prLH)2 are presented. The study of the kinetics of some reactions of iron complexes featuring hydroxypyridinone donor-group chelators is performed by spectrophotometric kinetics experiments. The mechanism of exchange between desferrioxamine B and an iron(III)-trishydroxypyridinone complex is determined through spectrophotometric monitoring of the reaction. The mechanism for this reaction is found to occur by a parallel pathway mechanism, where one pathway involves initial formation of a host-guest supramolecular assembly, followed by ternary complex formation and exchange of iron to ferrioxamine B (second order rate constant k5app = 1.7 x 10-1 M-1s-1), and the other pathway involves direct reaction of the iron-N3(etLH)3 with desferrioxamine B, likely through a ternary complex intermediate (k7 = 2,1 x 10 -2 M-1 s-1). Also, a determination of the mechanism of proton-driven complex dissociation of a bishydroxypyridinone siderophore mimic is shown. The first step involves proton-driven dissociation of the Fe2L3 complex by a parallel pathway mechanism, where one pathway is proton-dependent (k39 = 570 M-1s -1) and the other pathway is proton-independent (k38 = 4.8 s-1). The second step of the reaction involves the proton-independent dissociation of the Fe{N2(prL)2} complex to form the monoprotonated Fe{N2(etL)(etLH)} complex (k40 = 1.0 x 10-2 s-1). The ability of a bidentate hydroxypyridinone chelator to catalyze the exchange of iron(III) from desferrioxamine B to EDTA is explored and the mechanism is determined. It is shown that the mechanism of catalysis likely occurs through the formation of an inner sphere ternary complex between ferrioxamine B and the bidentate chelator.;Finally, an investigation into the efficacy of chelation therapy treatments to protect from metal toxicity using the nematode C. elegans as a model organism is presented. It is shown that a high degree of metal formation is necessary, but not sufficient, to predict efficiency of chelator as having a protective effect from metal toxicity. EDTA is shown to be an effective chelating agent due to its ability to protect consistently from all four metals tested. The model developed therein can also be used as a model for soil remediation of toxic metals using chelating agents. |
