Ligand dissociation kinetics

Adtveoitages. The antibody technology is remarkably convenient. It requires only that a significant fraction of FLPEP be receptor bound ( 10%). The assay can be set up in a few minutes and is applicable to membranes, permeabilized cells, cells, or any other preparation in which the receptor concentration is in the range of 1 niV or greater. We use this assay routinely to analyze ligand dissociation kinetics. 

For each of these reactions kinetic data were obtained. The reactions were first order in complex concentration, and zero order in isocyanide, as expected. The complex Ni(CNBu )4, and presumably other Ni(CNR)4 complexes as well, undergo ligand dissociation in solution. In benzene solution, a molecular weight determination for this compound gives a low value (110). This is in accord with the presumed mechanism of substitution. 

Consequences of unsaturation. Unsaturation in the macrocyclic ring may have major steric and electronic consequences for the nature of the ring. Extensive unsaturation will result in loss of flexibility with a corresponding restriction of the number of possible modes of coordination. Further, loss of flexibility tends to be reflected in an enhanced macrocyclic effect . For example, if the metal ion is contained in the macrocyclic cavity, the loss of flexibility reduces the possible pathways for ligand dissociation and this tends to increase the kinetic stability of the system. As explained in later chapters, enhanced thermodynamic stabilities will usually also result. 

The dissociation kinetics of macrocyclic complexes have received considerable attention, especially during investigations of the nature of the macrocyclic effect. Before discussing the dissociation of cyclic ligand species, it is of benefit to consider some aspects of the dissociation of open-chain ligand complexes. 

Formation and dissociation kinetics of nine Ni(II)-macrocyclic tetra-thiaether complexes (eight macrocyclic, one linear in acetonitrile) have been compared with those for Cu(II) analogues and for Ni(II) complexes with macrocylic tetramines (262). Whereas for the tetramine complexes conformational changes may be apparent in the kinetics this is not the case for the tetrathiaether complexes, where there is no kinetic evidence for slow conformational changes after initial bonding of the ligand to... 

Fe(III) displacement of Al(III), Ga(III), or In(III) from their respective complexes with these tripodal ligands, have been determined. The M(III)-by-Fe(III) displacement processes are controlled by the ease of dissociation of Al(III), Ga(III), or In(III) Fe(III) may in turn be displaced from these complexes by edta (removal from the two non-equivalent sites gives rise to an appropriate kinetic pattern) (343). Kinetics and mechanism of a catalytic chloride ion effect on the dissociation of model siderophore-hydroxamate iron(III) complexes chloride and, to lesser extents, bromide and nitrate, catalyze ligand dissociation through transient coordination of the added anion to the iron (344). A catechol derivative of desferrioxamine has been found to remove iron from transferrin about 100 times faster than desferrioxamine itself it forms a significantly more stable product with Fe3+ (345). 

Chelating ligands have a much lower propensity for dissociation. Yet detailed kinetic studies on similar systems with bidentate phosphine ligands, /ac-(L2)PtMe3X (L2 = dppe (bis(diphenylphosphino)ethane), dppbz (bis(diphenylphosphinobenzene) X = I, OAc, OPh) also showed that ligand dissociation was required prior to any C-C coupling (48-51). In this case, however, the X- group rather than the phosphine was lost to form a five-coordinate intermediate, as shown in Scheme 11. A competitive C-X reductive elimination also occurs from these complexes and involves the same five-coordinate cation (Section V. A). 

If the metals bound in complexes exchange with biological ligands, the dissociation kinetics of these complexes, the ligand-exchange kinetics and the association kinetics with the biological ligands must be considered. Simple dissociation kinetics of complexes are related to their thermodynamic stability constants by the relationship ... 

To describe the dynamics of metals at biological interphases in the presence of various ligands, the kinetics of dissociation of the complexes have to be taken into account in relation to the diffusion and to the uptake kinetics ([14] and Chapters 3 and 10 in this volume). Based on kinetic criteria, labile and inert complexes can be distinguished as limiting cases with regard to biological uptake ([14] and Chapter 3, this volume). 

H. E. Bryndza, P. J. Domaille, R. A. Paciello, J. E. Bercaw. Kinetics and Mechanism of Phosphine Exchange for Rutheniumill) Complexes in the Series (r 5-CsMes)(PMeo,)2RuX. Ancillary Ligand Effects on Dative Ligand Dissociation. Organometallics 1989, 8, 379-385. 

The rhodium dimer has two Lewis acidic sites and thus the catalyst could coordinate to two substrate molecules under saturation kinetics, which would make the Michaelis-Menten plots complicated. This does not happen and the second site becomes less acidic once the other site is occupied by the substrate. What does happen, though, is that other Lewis bases compete with the substrate, as might be expected. The ligand dissociation reaction may be part of the rate equation of the process. Coordination of one Lewis base reduces already the activity of the catalyst. The solvent of choice is often anhydrous dichloromethane. The polar group may also be part of one of the substrates and in this instance one cannot avoid inhibition. 

After the interaction between the ligand and receptor has reached equilibrium, dissociation kinetics are initiated either by dilution or by the introduction of unlabelled ligand which competes for the receptor binding sites. The purpose, in both cases, is to ensure that once the radiolabelled ligand has dissociated from the receptor, it is not able to reassociate with the receptor. This allows the following reaction to occur in isolation ... 

Also, very slow dissociation kinetics can contribute to slow clearing of a drug, which can be problematic in the event of adverse reactions such as an undesired allergic response. Therefore, methods to accurately determine the dissociation kinetics for protein-ligand interactions are of great value to the drug discovery process. 

Fig. 3.14 Simulated ALIS-based dissociation rate measurements. See text for details. (A) Quench experiments modeled at varying inhibitor association rates. Even with a very slow-binding inhibitor, the decay curve resembles pure first-order dissociation kinetics. (B) Data in (A), shown on a log axis. (C) Simulated ALIS quench experiment with varying protein-ligand dissociation rates,...

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