Ionophores stability

By considering the stability constant and the lipophilicity of host molecules, Fyles et al. synthesized a series of carboxylic ionophores having a crown ether moiety and energetically developed the active transport of alkali metal cations 27-32). Ionophores 19-21 possess appropriate stability constants for K+ and show effective K+-selective transports (Fig. 5). Although all of the corresponding [15]crown-5 derivatives (22-24) selectively transport Na+, their transport rates are rather slow compared with... 

Table 8. Stability constants and competitive transport ability of ionophores (50-57) for potassium and sodium cations...

Calcium-binding proteins, 6, 564, 572, 596 intestinal, 6, 576 structure, 6, 573 Calcium carbonate calcium deposition as, 6, 597 Calcium complexes acetylacetone, 2, 372 amides, 2,164 amino acids, 3, 33 arsine oxides, 3, 9 biology, 6, 549 bipyridyl, 3, 13 crown ethers, 3, 39 dimethylphthalate, 3, 16 enzyme stabilization, 6, 549 hydrates, 3, 7 ionophores, 3, 66 malonic acid, 2, 444 peptides, 3, 33 phosphines, 3, 9 phthalocyanines, 2,863 porphyrins, 2, 820 proteins, 2, 770 pyridine oxide, 3,9 Schiff bases, 3, 29 urea, 3, 9... 

If the photoequilibrium concentrations of the cis and trans isomers of the photoswitchable ionophore in the membrane bulk and their complexation stability constants for primary cations are known, the photoinduced change in the concentration of the complex cation in the membrane bulk can be estimated. If the same amount of change is assumed to occur for the concentration of the complex cation at the very surface of the membrane, the photoinduced change in the phase boundary potential may be correlated quantitatively to the amount of the primary cation permeated to or released from the membrane side of the interface under otherwise identical conditions. In such a manner, this type of photoswitchable ionophore may serve as a molecular probe to quantitatively correlate between the photoinduced changes in the phase boundary potential and the number of the primary cations permselectively extracted into the membrane side of the interface. Highly lipophilic derivatives of azobis(benzo-15-crown-5), 1 and 2, as well as reference compound 3 were used for this purpose (see Fig. 9 for the structures) [43]. Compared to azobenzene-modified crown ethers reported earlier [39 2], more distinct structural difference between the cis... 

The sample solution contains a fixed concentration of supporting electrolyte E" L and a varying concentration of primary salt M X . The ionophore I is confined in the membrane. Only the primary cation can be complexed with the ionophore I (given stoichiometry 1 1 stability constant The complex MI and the anionic site are the lipophilic species that are present only in the membrane phase. In this system, the electroneutrality condition at the membrane bulk leads to... 

When a membrane based on a derivative of azobis(benzo-15-crown-5) in contact with a solution of a primary cation is exposed to visible light, we assume that the iono-phore within the membrane phase is exclusively in the trans isomer and forms a 1 1 ionophore (I)-cation (M+) complex with a stability constant, trans. According to Eq. (10), the corresponding charge density at the membrane side of the interface, o is > can be expressed as... 

Under UV light irradiation, cis-trans photoisomerization of the ionophore in the membrane occurs. We assume that the cis and trans isomers are both present in the membrane and the cis isomer forms a 1 1 (ionophore-cation) complex with a stability constant, Am.cb- In this case, the surface charge density, and the phase boundary... 

Especially sensitive and selective potassium and some other ion-selective electrodes employ special complexing agents in their membranes, termed ionophores (discussed in detail on page 445). These substances, which often have cyclic structures, bind alkali metal ions and some other cations in complexes with widely varying stability constants. The membrane of an ion-selective electrode contains the salt of the determined cation with a hydrophobic anion (usually tetraphenylborate) and excess ionophore, so that the cation is mostly bound in the complex in the membrane. It can readily be demonstrated that the membrane potential obeys Eq. (6.3.3). In the presence of interferents, the selectivity coefficient is given approximately by the ratio of the stability constants of the complexes of the two ions with the ionophore. For the determination of potassium ions in the presence of interfering sodium ions, where the ionophore is the cyclic depsipeptide, valinomycin, the selectivity coefficient is Na+ 10"4, so that this electrode can be used to determine potassium ions in the presence of a 104-fold excess of sodium ions. 

A number of substances have been discovered in the last thirty years with a macrocyclic structure (i.e. with ten or more ring members), polar ring interior and non-polar exterior. These substances form complexes with univalent (sometimes divalent) cations, especially with alkali metal ions, with a stability that is very dependent on the individual ionic sort. They mediate transport of ions through the lipid membranes of cells and cell organelles, whence the origin of the term ion-carrier (ionophore). They ion-specifically uncouple oxidative phosphorylation in mitochondria, which led to their discovery in the 1950s. This property is also connected with their antibiotic action. Furthermore, they produce a membrane potential on both thin lipid and thick membranes. 

Data are available for plasticizers and ionophores, and indicate the operational stability (the higher the log P value, the higher the lipophilicity). The minimal lipophilicity log P required for membrane components with a lifetime of 30 x 24 h upon exposure to aqueous solution is estimated to be around 10 whereas it has to be as high as 25 for direct measurement in blood, serum and plasma. 

There are two main factors that influence the selectivity of a sensor limits in discrimination of an interfering ion and upper limits in stability constant of an analyte-ionophore complex. While an ideal ionophore does not form complexes with interfering ions, too strong complexation with the primary ion leads to a massive extraction of analyte into membrane phase coupled with a coextraction of sample counter-ions, known as Donnan exclusion failure. In such cases, at high activities and lipophilicities of sample electrolytes, fli(org) increases and a breakdown of membrane permselectivity prevents the Nemst equation to hold. 

M.M. Shultz, O.K. Stefanova, S.S. Mokrov, and K.N. Mikhelson, Potentiometric estimation of the stability constants of ion-ionophore complexes in ion-selective membranes by the sandwich membrane method theory, advantages, and limitations. Anal. Chem. 74, 510-517 (2002). 

Siderophore-ionophore supramolecular assembly formation via host-guest complexation of the pendant protonated amine arm of ferrioxamine B has been confirmed by X-ray crystallography (Fig. 28) (203). The stability and selectivity of this interaction as a function of ionophore structure, metal ion identity, and counter anion identity were determined by liquid-liquid extraction, isothermal calorimetry, and MS (204 -211). Second-sphere host-guest complexation constants fall in the range 103— 106M-1 in CHC13 and methanol depending on ionophore structure. 

Calcium-selective electrodes have long been in use for the estimation of calcium concentrations - early applications included their use in complexometric titrations, especially of calcium in the presence of magnesium (42). Subsequently they have found use in a variety of systems, particularly for determining stability constants. Examples include determinations for ligands such as chloride, nitrate, acetate, and malonate (mal) (43), several diazacrown ethers (44,45), and methyl aldofuranosides (46). Other applications have included the estimation of Ca2+ levels in blood plasma (47) and in human hair (where the results compared satisfactorily with those from neutron activation analysis) (48). Ion-selective electrodes based on carboxylic polyether ionophores are mentioned in Section IV.B below. Though calcium-selective electrodes are convenient they are not particularly sensitive, and have slow response times. 

Stability constants, measured in methanol solution, for alkaline earth complexes of a number of ionophores are given in Table XVI (280,289,571-577).8 The values for the complexes of valinomycin and enniatin B lie between the values for the crown ethers 15C5 and 18C6 (cf. Section II.C.5 above), for the middle four entries the values are slightly higher. Stabilities of enniatin B complexes show a modest maximum for Ca2+, and of valinomycin complexes show stabilities increasing up to Ba2+ (281). LogAi values for the Ca2+ complexes of acetate, benzoate, and salicylate are between 4.5 and 4.7 in methanol (578) - the... 

The equilibrium constant for this reaction depends on the stability constants of the ionophore-M+ complexes and on the distribution of ions in aqueous test solution and organic membrane phases. For a membrane of fixed composition exposed to a test solution of a given pH, the optical absorption of the membrane depends on the ratio of the protonated and deprotonated indicator which is controlled by the activity of M+ in the test solution (H,tq, is fixed by buffer). By using a to represent the fraction of total indicator (Ct) in the deprotonated form ([C]), a can be related to the absorbance values at a given wavelength as... 

E-3 (Figure 10.26) is the first example of an ionophoric calixarene with appended fluorophores, demonstrating the interest in this new class of fluorescent sensors. The lower rim contains two pyrene units that can form excimers in the absence of cation. Addition of alkali metal ions affects the monomer versus excimer emission. According to the same principle, E-4 was designed for the recognition of Na+ the Na+/K+ selectivity, as measured by the ratio of stability constants of the complexes, was indeed found to be 154, while the affinity for Li+ was too low to be determined. 

Figure S An electron micrograph of unloaded liposomes or liposomal topotecan stabilized in a SO4 complex following loading using MnS04 gradients in the presence of the ionophore A23187 at a ratio of topotecan-to-lipid of 0.2 (wt wt). Source From Ref. 35.

Introduction of ionophores into the membrane should lead to a considerable increase in the ISE selectivity (in the absence of an ionophore, the selectivity coefficient would be given by constant/Texch alone, cf. (3.3.12)) however, as (3.3.10) contains only the square root of the stability constant ratio, this increase in selectivity is not extremely high. Better results are obtained in the second system, where the membrane contains an excess constant ionophore concentration. 

The first factor, especially important with ion-selective microelectrodes, can be eliminated by a suitable modification of the measuring instrument, notably by the use of a coaxial microelectrode (see [167] and section 4.2). If an inter-ferent is present in the solution at a concentration at which it does not affect the ISE potential, factors 4 and 6 are not operative. Penetration of the deter-minand into the membrane, factor 5, is very important for the response times of ISEs with ionophores in their membranes, provided that no hydrophobic anion is present in the membrane solution, as has been theoretically treated by Morf et aL [114]. As shown in section 3.3, the presence of a hydrophobic anion stabilizes the conditions in the membrane, with a marked effect on the shortening of the response time [93]. 

If the ligand (neutral carrier) is capable of completely enveloping the cations, the terms Ky and Eq of the membrane depend only on the ratio of the complex stability constants K JK of the ions with the ionophore. 

When the ion-pair partitioning is indicated in the quadrant diagram (below) it becomes obvious that a circle of equilibria is present. Knowing the octanol pKa, the log P and the aqueous pKa should allow one to calculate the partition coefficient of the ion pair. From these equilibria one can write that the difference in log P between the acid and its salt is the same as the difference between the pKa s (Equation 9). The closer the pKa s, the more lipid soluble the ion pair will be, relative to the acid. Internal hydrogen bonding or chelation that stabilizes an ion pair will affect the octanol stability more than the aqueous stability, where it is less needed, and so will decrease the delta pKa. Chelation should therefore favor biolipid solubility of ion pairs. Ultimate examples are available in some ionophores. This is one of the properties of some of the herbicides I pointed out earlier. 

---