Slow Ligand Research Articles

ChemInform Abstract: The Role of Rate Determining Steps in the Decorporation of Toxic Metal Ions

AbstractReview: (117 refs.

The role of rate determining steps in the decorporation of toxic metal ions

An examination of a variety of experimental data shows that several types of rate determining steps can drastically limit the ability of a chelating agent to react with a toxic metal ion in vivo. Such limitations are important for many metal–chelate formation reactions with very favorable overall thermodynamic changes. Two of the most important of these are the slow ligand exchange reactions and slow rates of movement of ionic chelating agents across cellular membranes to achieve contact with intracellular deposits of toxic metal ions. They have drastic effects on the overall stoichiometry of the decorporation process. A simple model is developed which allow rates of mobilization to be estimated. This model is also applied to the problem of overly rapid metal mobilization which frequently leads to adverse effects. The nature of synergistic effects in chelate therapy is also examined and it is seen that many of these can be explained on the basis of the catalysis of ligand exchange processes or on the basis of the different in vivo distribution of lipophilic and hydrophilic chelating agents.

Proton and nitrogen-15 NMR spectroscopic studies of hydrogen ion-dependent pseudo-halide ion binding to chloroperoxidase.

The proton nuclear magnetic resonance spectra of several chloroperoxidase-inhibitor complexes have been investigated. Titrations of chloroperoxidase with azide, thiocyanate, cyanate, or nitrite ions indicate that only the chloroperoxidase-thiocyanate complex exhibits slow ligand exchange on the 360-MHz NMR time scale. The temperature dependence of the proton NMR spectra of the complexes suggests that, although the complexes are predominantly low-spin ferric heme iron, a spin equilibrium is present presumably between S = 1/2 and S = 5/2 states. The pH dependence of the proton NMR spectra of the psuedo-halide-chloroperoxidase complexes was examined at 360 and 90 MHz. Chloroperoxidase complexes with azide and cyanate show similar behavior; 360-MHz proton spectra are readily observed at low pH (less than 5.0) but not at high pH. At high pH, the ligand exchange rate falls in an intermediate time range. When the complexes are examined at 90 MHz, however, spectra consisting of averaged signals are observed. The chloroperoxidase-thiocyanate complex does not form at high pH values; the proton NMR spectrum observed is that of native chloroperoxidase. The pKa for the chloroperoxidase-thiocyanate heme-linked ionizable amino acid residue falls between 4.2 and 5.0. Only an averaged azide signal was observed in the nitrogen-15 NMR spectra for solutions that contained the azide complex of chloroperoxidase, horseradish peroxidase, and myoglobin.

Lanthanum-139 nuclear magnetic resonance spectra of lanthanum complexes

Lanthanum-139 n.m.r. spectra are reported for a variety of lanthanum complexes and systems. The 139La linewidths vary greatly and, as expected, an important factor appears to be the symmetry of the environment around the lanthanum. Information concerning complex formation by the La3+ ion is obtained from the variations in both the 139La chemical shifts and the linewidths when a ligand is progressively added to anhydrous La[ClO4]3 in MeCN. Slow ligand exchange is found with the [La{P(NMe2)3O}6]3+ ion, and with the ethylenediamine and diethylenetriamine complexes.

ChemInform Abstract: A STUDY OF LANTHANIDE(III) (HYDROXY)CARBOXYLATE COMPLEXES IN AQUEOUS MEDIUM USING LANTHANIDE INDUCED OXYGEN‐17 NMR SHIFTS

The complexation of dysprosium(III), as the model cation for calcium(II), with a series of (hydroxy)carboxylates in aqueous medium, has been studied by 17O NMR spectroscopy. Acetate, 3-hydroxybutyrate, glycolate, lactate, malonate, malate and citrate show fast ligand exchange on the 17O NMR time scale at 73°. The Dy(III)-induced 17O shifts of both the ligand and the water, which are mainly due to contact interaction, provide valuable information on the complexation sites of the ligands as well as on the number of coordinated waters in the complexes. The results point to a rather constant 17O contact shift upon the formation of Dy(III)-O bonds. On the other hand, oxydiacetate (ODA), (carboxymethoxy)succinate (CMOS) and nitrilotriacetate (NTA) show slow ligand exchange on the 17O NMR time scale at 73°. In these cases the Dy(III)-induced shift of the 17O water resonance provides information on the stoichiometry of the complexes, i.e. the number of coordinated waters and the number of ligands.

Direct resolution of a-amino acid enantiomers by ligand exchange: stereoselection mechanism on silica packings coated with a chiral polymer

A chiral polymer easily obtained by treatment of a linear polyacrylamide with l-proline was adsorbed on a silica support treatment of a linear polyacrylamide with l-proline. After complexation with copper(II), and in spite of a rather low efficiency due to slow ligand exchange, such packings are very convenient for the resolution of amino acid enantiomers eluted in water (relative retentions, k′ L/ k′ D, higher than 2 may be observed). Other eluents may also be used. The chiral polymer was studied in solution by potentiometry and nuclear magnetic resonance spectroscopy ( 13C relaxation measurements). A model of the complex involved in the stereoselection is proposed which accounts for the chromatographic results obtained.

A study of lanthanide(III) (hydroxy)carboxylate complexes in aqueous medium using lanthanide induced oxygen‐17 NMR shifts

AbstractThe complexation of dysprosium(III), as the model cation for calcium(II), with a series of (hydroxy)carboxylates in aqueous medium, has been studied by 17O NMR spectroscopy. Acetate, 3‐hydroxybutyrate, glycolate, lactate, malonate, malate and citrate show fast ligand exchange on the 17O NMR time scale at 73°. The Dy(III)‐induced 17O shifts of both the ligand and the water, which are mainly due to contact interaction, provide valuable information on the complexation sites of the ligands as well as on the number of coordinated waters in the complexes. The results point to a rather constant 17O contact shift upon the formation of Dy(III)‐O bonds.On the other hand, oxydiacetate (ODA), (carboxymethoxy)succinate (CMOS) and nitrilotriacetate (NTA) show slow ligand exchange on the 17O NMR time scale at 73°. In these cases the Dy(III)‐induced shift of the 17O water resonance provides information on the stoichiometry of the complexes, i.e. the number of coordinated waters and the number of ligands.

Ligand-induced conformation changes in Torpedo californica membrane-bound acetylcholine receptor.

A time-dependent increase in ligand affinity has been studied in cholinergic ligand binding to Torpedocalifornica acetylcholine receptor by inhibition of the kinetics of of [125I]-alpha-bungarotoxin-receptor complex formation. The conversion of the acetylcholine receptor from low to high affinity form was induced by both agonists and antagonists of acetylcholine and was reversible upon removal of the ligand. The slow ligand induced affinity change in vitro resembled electrophysiological desensitization observed at the neuromuscular junction and described by a two-state model (Katz, B., & Thesleff, S. (1957) J. Physiol. 138, 63). A quantitative treatment of the rate and equilibrium constants determined for binding of the agonist carbamoylcholine to membrane bound acetylcholine receptor indicated that the two-state model is not compatible with the in vitro results.

Axial perturbations on the electronic and magnetic properties of ferric porphyrins I. Effect of axial ligand basicity in bis-substituted pyridine complexes of synthetic porphyrins

The proton NMR spectra of the bis-4-substituted pyridinates of ferric tetrapheylporphyrin and octaethylporphyrin complexes have been recorded and analyzed fort he purpose of ascertaining the influence of variable axial lignad basicity on the bonding and magnetic properties of the iron. Under the conditions of slow ligand exhange where the bis stoichiometry can be established, all complexes exist exlusively in the low-spin, S = 1 2 , state. The hyperfine shifts at −60° C for both the porphyrins and axial ligands are shown to be very sensitive to the basicity of the substituted pyridine, as measured by its p K a. For the tetraphenylporphyrin complexes, we illustrate that the pattern of the meso-phenyl hyperfine shifts permits a quantitative separation of the contact and dipolar contributions to these shifts. This separation reveals that the shift variations with pyridine p K a are dominated by changes in the magnetic susceptibility anisotropy (dipolar shift), which decreases markedly upon lowering the pyridine basicity; ESR data support this conclusion in the few samples investigated. However, this trend in magnetic anisotropy with ligand basicity is not valid when comparing pyridines with other ligands such as imidazoles. The important change in the contact shift reflects a decrease in porphyrin → iron π change transfer as the ligand basicity is lowered. A correlation between increase in proton NMR linewidth and magnetic anisotrophy of the iron suggests that electron spin relaxation occurs via a process which couples the same levels that control the magnetic anisotropy.