Divalent complexes with ionophores

Polyethers. Antibiotics within this family contain a number of cycHc ether and ketal units and have a carboxyHc acid group. They form complexes with mono- and divalent cations that ate soluble ia aoapolar organic solvents. They iateract with bacterial cell membranes and allow cations to pass through the membranes causiag cell death. Because of this property they have been classified as ionophores. Monensia, lasalocid, and maduramicia are examples of polyethers that are used commercially as anticoccidial agents ia poultry and as growth promotants ia mmiaants. 

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. 

After the marketing of monensin began, there was a rush to discover more ionophores. The second ionophore to be licensed as a coccidiostat in the U.S. was X-537A, first reported by investigators at the Nutley, NJ laboratory of Hoffmann-LaRoche in 1951 (8), 16 years prior to the announced discovery of monensin. It was their misfortune not to have tested their compounds against coc-cidia. X-537A, now named lasalocid, differs from most of the other ionophores in its ability to complex with divalent cations. 

Ionophores, or polyether (PET) antibiotics, produced by various species of Streptomyces, possess broad spectrum anticoccidial activities. They are chemically characterized by several cyclic esters, a single terminal carboxylic acid group, and several hydroxyl groups. Representative members of this class include salinomycin (SAL), monensin (MON), lasalocid (LAS), narasin (NAR), maduramicin (MAD), and semduramicin (SEM). The main chemical properties of interest in the extraction methodology are their low polarities and instability under acidic conditions. They are able to form stable complexes with alkaline cations. All of these compounds, with the exception of LAS, bind monovalent cations (e.g., Na+ and K+). Lasalocid has a tendency to form dimers and can form complexes with divalent cations such as Mg2+ and Ca2+. The formation of metal complexes results in all of these compounds adopting a quasi-cyclic formation consequent to head-to-tail hydrogen bonding. No MRLs have yet been set by the EU for any of the carboxylic acid PETs (98). 

Q1H72O9, Mr 709.02, oil, soluble in DMSO and ethanol Ca salt Mr 747.07, mp. 205-206°C. As a highly specific ionophore for divalent cations it is markedly more effective than calcimycin. The microbial producer is Streptomyces conglobatus. Complexes with Ca at pH 7.0 and 9.5 show strong UV-absorption. In contrast to calcimycin, I. is not fluorescent. It is used in investigations on transmembrane calcium transport and in measurements of free cytoplasmatic Ca. The ion specificities are reported as follows ... 

A mixture of ionophoric polyether antibiotics produced by Streptomyces lasaliensis, from which the components A to E have been separated. L. exert antibacterial and antiviral (HIV) activities, LD50 (mouse p.o.) 146 mg/kg. L. A mp. 110-114°C, (aJo -7.5° (CH3OH), which preferentially forms complexes with divalent cations, is formed biosynthetically by the polyketide pathway from five acetate units, four propionate units, and three butanoate units, the benzene ring arises through cyclization. L. A (Bovatec ) in the form of its sodium salt (Avatec ) is used in fowl breeding as a coccidostatic. 

Table 7b. Divalent polyether antibiotics Bonding distances in their complexes with metal ions. In the case of 2 1 complexes, the ionophore molecules are referred to as A and B ...

Lipophilic ionophores are essential to achieving a high sensing selectivity with liquid membrane ISEs. As explained above, ion-exchanger-based membranes always show the same selectivity pattern that follows the solvation energies of the ions, but iono-phore-based membranes may show very different selectivities. This is achieved by the formation of strong complexes between the extracted analyte ion and the ionophore in the membrane. Complex formation constants have been recently determined in the membrane phase in the range of 10 for monovalent to for divalent ions. With ion-... 

To address the theoretical limitation of the Nikolsky-Eisemnan equation, a more general description of the equihbrium responses of hquid membrane ISEs in mixed ion solutions was proposed (41). The model is based on phase boundary potentials under an equilibrium exchange of an analyte and an interfering co-ion at the membrane/sample solution interface. With ionophore-based membranes, the ion-exchange process is followed by complexation of the ions with an ionophore, where free ionophore was assumed to be always present in excess to simplify the model. The charge of the ions was not fixed so that their effect on the potentiometric responses can be addressed by the model. Under equilibrium conditions, the model demonstrated that the Nikolsky-Eisemnan equation is valid only for ions with the same charge (zj = Zj). The selectivity coefficient, however, can still be used in the new model to quantify the potentiometric responses in the mixed ion solution. For example, the potentiometric responses to a monovalent cation in the presence of a divalent cation are given as... 

In order to elucidate the primary electrostatic through bond mode of electrochemical communication between a ferrocene redox centre and the heteroatoms of the crown ionophore, a variety of conjugated ferrocene benzocrown ether systems such as 60 and 61 [83, 84], 62 and 63 [85, 86], and 64 or 65 [87, 88] were synthesized and their complex formation with mono- and divalent cations studied by multinuclear NMR, X-ray crystallography and cyclic voltammetry. 

Figure 7.8 (A) Calculated phase boundary potentials as a function of the activity of a divalent cation in the sample solution for a membrane with an acidic ionophore and anionic sites. Responses are shown for sample solutions of pH 4.0, 7.0, and 10.0. Calculated equilibrium concentrations of (B) the deprotonated ionophore, L", and its complexes, LH, LM, and and (C) the depro-...

Membrane selectivities for a given ionophore may vary substantially. Membranes of relatively high polarity are normally preferred for the development of divalent-ion selective electrodes and many anion-selective electrodes, while nonpolar membranes are often more suited for monovalent cations. Many other parameters may also influence selectivity, including the tendency to form ion pairs, the availability of functional groups on the plasticizer that can compete with the ionophore, and variations of complex stoichiometries of the ionophore in different solvent environments. Optimization of ISE selectivity is therefore still done empirically. 

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