Kinetics of Gallium Removal from Transferrin and Thermodynamics of Gallium-Binding by Sulfonated Tricatechol Ligands

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Abstract
The thermodynamics of complexation of gallium by tricatechol ligand analogues of enterobactin and the kinetics of gallium removal from human serum transferrin (Tf) by one of those ligands have been studied by UV spectrophotometry. The ligands are a sulfonated monomeric catechoylamide, DMBS (N,N-dimethyl-2,3-dihydroxy-5-sulfonatobenzamide), and four sulfonated triscatechoylamides, MECAMS (1,3,5-N,N',N”-tris(5-sulfonato-2,3-dihydroxybenzoyl)-triaminomethylbenzene), Me3MECAMS (N, N', N-trimethyl-MECAMS), 3,4-LICAMS (N, N', N”-tris(5-sulfonato-2,3-dihydroxybenzoyl)-1,5,10-triazadecane), and (DiP)LICAMS (N, N”-diisopropyl-LICAMS). The individual orthohydroxyl protonation constants are 7.15 (DMBS), and (average values for the three protons of the tricatechols) 7.09 (MECAMS), 7.01 (LICAMS), 7.62 (Me3MECAMS), and 7.75 ((DiP(LICAMS), in good agreement with average values obtained potentiometrically. The overall formation constants for binding of Ga3+ by these ligands are β113 = 41.9 for DMBS, β110 = 41.1 for LICAMS, 36.6 for (DiP)-LICAMS, and 39.1 for Me3MECAMS. Gallium is removed from the two metal binding sites of Ga2Tf in a process by 3,4-LICAMS that is first order in both Tf and ligand at different rates (277M−1 min−1 and 17M−1 min−1). These are 12 and 3.4 times the corresponding rates of iron removal from Fe2Tf. The dissociation pathways of the gallium-ligand complexes upon protonation of the ligands were probed by whole spectrum analysis with the non-linear least-squares program REFSPEC. For all three triscatechoylamide complexes, protonation occurs in sequential one-proton reactions wth logK MLHn (n = 1, 2, 3) equal to 5.93, 5.00, 2.4 for MECAMS: 5.8, 5.7, 3.0 for 3,4-LICAMS; 6.81,6.34, 3.0 for Me3MECAMS; 6.34, 6.33, 4.3 for (DiP)LICAMS. First- and second-derivative spectra show that for complexes of trimeric ligands the last two protonations result in a complex with a completely dissociated catecholate arm, Ga(cat)2-catH2, similar to the Ga(DMBS)2 complex observed with the monomer. In the linear complexes, the middle ligand arm is detached from the metal first. Addition of a fourth proton resulted in decomposition of the gallium-trimeric ligand complex.