Antibiotics, alkali metal complexes

Group 1. The complexation reactions between murexide and Li+, Na and K+ in DMSO-MeCN mixtures have been studied by Li NMR spectroscopy. C1 NMR spectroscopy has been used to study ion pairing between CL or [CIOJ and alkali metal complexes of ionophore antibiotics. ... 

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. 

There are two general classes of naturally-occurring antibiotics which influence the transport of alkali metal cations through natural and artificial membranes. The first category contains neutral macrocyclic species which usually bind potassium selectively over sodium. The second (non-cyclic) group contains monobasic acid functions which help render the alkaline metal complexes insoluble in water but soluble in non-polar solvents (Lauger, 1972 Painter Pressman, 1982). The present discussion will be restricted to (cyclic) examples from the first class. 

The crowns as model carriers. Many studies involving crown ethers and related ligands have been performed which mimic the ion-transport behaviour of the natural antibiotic carriers (Lamb, Izatt Christensen, 1981). This is not surprising, since clearly the alkali metal chemistry of the cyclic antibiotic molecules parallels in many respects that of the crown ethers towards these metals. As discussed in Chapter 4, complexation of an ion such as sodium or potassium with a crown polyether results in an increase in its lipophilicity (and a concomitant increase in its solubility in non-polar organic solvents). However, even though a ring such as 18-crown-6 binds potassium selectively, this crown is expected to be a less effective ionophore for potassium than the natural systems since the two sides of the crown complex are not as well-protected from the hydro-phobic environment existing in the membrane. 

Through the isolation of crystalline complexes of dectrically neutral carrier antibiotics with alkali metal salts (10—13) it has become possible to study their detailed structure by X-ray analysis (14). Results... 

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. 

For the alkali metal cations, the stability (14) and permeability (43) sequences for dicyclohexyl-18-crown-6 have been found to be the same (K+ > Rb+ > Cs+ > Na+ > Li+). Thus, a direct relationship exists between the ability of a macrocyclic compound to complex a particular cation (as measured by the log K value for complex formation) and its influence on the biological transport of that cation. Furthermore, it would appear that the biological ion-transport mechanism may in part be due to the complexation properties of the macrocyclic carrier molecules. This subject with respect to cyclic antibiotics has been treated extensively by Si wow and co-workers (2). 

An example of a channel- or pore-forming antibiotic is gramicidin A (9.57), a peptide consisting of 15 amino acids. It induces the transmembrane transport of protons, alkali-metal ions, and thallium ions at concentrations as low as 10 ° M, even though it is unable to complex these ions in solution. Gramicidin also forms several dimers with itself. 

In the Ba2+ complex with (145), two anions coordinate to the cation in different ways (Figure 32b). The metal ion sits primarily in a cavity provided by one of the anions and is six-coordinated by two ether, two hydroxy, one keto and one carboxylate oxygen atoms. A nine-fold coordination is completed by further coordination to two oxygen atoms from the second anion and a water molecule. 73 A review of the structures of polyether antibiotic complexes is available and includes a compilation of structural data.372 The stoichiometries of alkali and alkaline earth complexes of (145) in methanol, have been determined potentiometri-cally and show 1 1 neutral complexes for the alkali metal cations, and high stability 1 1 (charged) and 1 2 (neutral) complexes for the alkaline earth cations.574... 

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). 

Kirch and Lehn have studied selective alkali metal transport through a liquid membrane using [2.2.2], [3.2.2], [3.3.3], and [2.2.C8] (146, 150). Various cryptated alkali metal picrates were transported from an in to an out aqueous phase through a bulk liquid chloroform membrane. While carrier cation pairs which form very stable complexes display efficient extraction of the salt into the organic phase, the relative rates of cation transport were not proportional to extraction efficiency and complex stability (in contrast to antibiotic-mediated transport across a bulk liquid membrane). Thus it is [2.2.Ca] which functions as a specific potassium ion carrier, while [2.2.2] is a specific potassium ion receptor (Table VI). 

The types of alkali and alkaline earth metal complexes subjected to molecular mechanics modeling fall into four categories crown ethers[U9,486 491], cryp-tands[492 493], spherands[494,495], and other biologically important ligands, such as ionophores and cyclic antibiotics [496 499]. 

Polyether metabolites are ionophoric antibiotics which have their major applications in the area of animal husbandry. The distribution of oxygen atoms in these structures predisposes them towards the complexation of alkali metal ions, and their mode of action is considered to depend upon the ability to disrupt the sodium-potassium ion balance across cell membranes. Monensin A from Streptomyces cinnamonensis and tetronasin from Streptomyces longisporoflavus are extensively studied examples of these metabolites. 

Truter, M. R. Structures of Organic Complexes with Alkali Metal Ions. Vol. 16, pp. 71-111. Umezawa, H., Takita, T. The Bleomycins Antitumor Copper-Binding Antibiotics. Vol. 40,... 

It was the first naturally occurring crown ether, and the earliest for which the antibiotic activity could be traced to its ionophoric properties (4). The actins give one-to-one complexes with many alkali and alkaline earth metal ions, with nonactin showing selectivity in the order NH4+ > K+ = Rb+ > Cs+ > Na+ > Ba2+ (5). The first X-ray crystal structure of an ionophore-metal complex was obtained from the nonactin-potassium thiocyanate complex (6). The potassium is bound by coordination to all four tetrahydrofuran oxygens and to the four ester carbonyl oxygens, which creates overall a "tennis ball seam" conformation to the carbon framework as it wraps around the metal. 

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