Valinomycin alkali metal complexes

Wong PSH, Antonio BJ, Dearden DV. Gas-phase studies of valinomycin-alkali metal cation complexes attachment rates and cation affinities. J Am Soc Mass Spectrom. 1994 5 632-7. 

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. 

Complexation between the alkali metal cations and the flexible crowns in methanol approaches the rates expected for methanol exchange in the inner sphere of these cations. The rates are similar to those for the interaction of the natural ionophores such as valinomycin. 

Fig. 7.5. Dependence of the stability constants of valinomycin complexes of alkali metal ions on the cation radius. (After A. Hofmanovd et al. [79].)...

The alkali metal cation complexes of compounds of the valino-mycin group (valinomycin, enniatins, macrotetrolides, beauveridn, antamanide) are positively charged. 

Impetus was given to work in the field of selective cation complex-ation by the observation of Moore and Pressman (5) in 1964 that the macrocyclic antibiotic valinomycin is capable of actively transporting K+ across mitochondrial membranes. This observation has been confirmed and extended to numerous macrocyclic compounds. There is now an extensive literature on the selective complexation and transport of alkali metal ions by various macrocyclic compounds (e.g., valinomycin, mo-nactin, etc.) (2). From solution spectral (6) and crystal X-ray (7) studies we know that in these complexes the alkali metal cation is situated in the center of the inwardly oriented oxygen donor atoms. Similar results are found from X-ray studies of cyclic polyether complexes of alkali metal ions (8) and barium ion (9). These metal macrocyclic compound systems are especially noteworthy since they involve some of the few cases where alkali metal ions participate in complex ion formation in aqueous solution. 

Natural macrocycles displaying antibiotic propenies are also very efficient in the recognition of alkali metal ions. For instance, valinomycin (5 in Fig, 3) gives a strong and selective complex in which a K+ ion is included in the macrocyclic cavity in octahedral environment of six carbonyl oxygens (Fig. 4). 

Until the late 1960s, whereas there had been considerable interest in the transition metal complexes of natural and synthetic macrocyclic ligands (1—4), relatively few reports described complexes of alkaline earth and more particularly alkali metal cations. Research in this area was stimulated by the recognition of the importance of the biological role of Na+, K, Ca2 , and Mg2 and also the discovery and characterization of the natural antibiotic ionophores (5, 6). These macrocyclic antibiotics, such as valinomycin and nonactin, were shown to complex alkali metal cations with remarkable selectivity (7-9). 

Polarography of alkaline metals and ammonium ion has proved successful for studying complexes of alkali metals with biologically important macrocyclic compounds such as valinomycin [18], macrotetrolides [19,20] and polyethers [20,21]. 

The peptide analog of valinomycin, cyclo-(D-Val-L-Pro-L-Val-D-Pro)3 (= PV) forms more stable complexes with alkali metal cations than valinomycin (cf. Section 5.3). From NMR data, dissociation rate constants of 5 s 1 for the Li+ complex and < 1 s x for the Na+ and K+ complexes in solution have been estimated61). At lipid bilayers, a 104 times higher concentration of PV than of valinomycin is required to produce a comparable increase in K+ conductance282). It has been proposed that the dissociation of the complex could be the rate limiting factor of the ion transport by PV in bilayer membranes61). 

Substances of the amphotericin D (a polyene), polyether (for example crown cyclic ethers), Antamanide (a peptide), and valinomycin (a depsi-peptide) represent structural types capable of complexing with alkali metal ions and thereby promoting their dissolution in fairly nonpolar solvents. Such compounds are known as ion carriers and some display antibiotic properties which may in part reside with activity in natural membranes. In order to evaluate structural changes upon such interesting functions, Gisin and Merri-field have synthesized a cyclododecapeptide (Chart 15) where the D-a-hy-droxyisovaleric acid and L-lactic acid units of valinomycin were replaced respectively with D-Pro and L-Pro. In MeCl-Aq the valinomycin analog was found to exhibit a seven times greater affinity for potassium picrate (to form a 1 1 hydrophobic complex) than that of the parent depsipeptide. 

Until recently, valinomycin has been regarded as a classic monocarrier, which only forms complexes of 1 1 stoichiometry with alkali metal ions. However, in 1974 a Soviet team reported evidence for the formation of adducts with 2 1 valinomycin cation ratio, and they proposed a sandwich-type structure for the latter [311]. 

The compounds form 1 1 complexes with all alkali ions and with a large number of other metal ions in organic solvents267,268,307. Among the alkali ions, K+ is bound most strongly, but K+-complex stability as well as K+ > Na+ selectivity are much less pronounced than with valinomycin. In concentrated enniatin solutions, non-equimolar complexes are formed. NMR- und CD-spectroscopic titrations have demonstrated that 2 1 enniatin-cation complexes are formed with a stability order of K+ > Cs+ > Na+. Evidence for formation of a 3 2 complex with Cs+ was also obtained133,216 ... 

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