Ionophores ethers , ionophore antibiotic

We now proceed to more complicated ionophores in order to testify the validity of this extrathermodynamic relationship and its hypothetical interpretation as an attempt to understand the nature of supramolecular interactions more generally and deeply. The thermodynamic parameters are plotted in Figures 16-19 for long glymes, (pseudo)cyclic ionophore antibiotics, lariat ethers with donating side-arm(s), and bis(crown ethers), whose structural changes upon complexation are schematically illustrated in Figure 20. 

As with the TMS ethers discussed in the previous section, TES ethers are subject to widely variable rates of cleavage depending on the steric and electronic environment, For example, in a synthesis of the polyether ionophore antibiotic Salinomycin, a primary TES ether was cleaved in preference to a tertiary TES ether by using HF pyridine complex at room temperature [Scheme 4.18].21... 

Enniatin B [Fusarium orthoceras var. enniatum] 639.83 chloroform, petroleum ether ionophore antibiotic binding to calmodulin and inhibiting phosphodiesterase in a Ca -dependent manner... 

As noted above, a goal of the lariat ether work was to develop eompounds that might function in a fashion similar to valinomycin. A dozen crown ethers, including two 1.3-xylyl-21-crown-6 macrocyclic poly ether 2-car-boxylic acid lariat ethers, were prepared and tested in vitro for biological activity. Several of the compounds showed activity and are thought to be functional mimics of ionophore antibiotics. 

Either neutral or charged carrier molecules (e.g. crown ethers, natural antibiotics, synthetic ionophores, etc.) can be doped into polymeric membranes to achieve desired selectivities. However, despite successes in the fabrication of selective and stable cation electrodes (1-5), the development of analogous devices for anions has thus far been limited by the inability to identify appropriate anion-selective ionophores. 

As we have seen, X-ray studies of the ionophorous antibiotics and their cation complexes were able to explain many of the steric factors that determine the selectivity patterns shown by these ligands. However, more systematic investigations on the relationship between host-cavity size and guest-ion radius could only be carried out using simpler synthetic ligands as models. In 1967, Pedersen reported the synthesis and complexing properties of a new class of compounds named crown ethers which are able to mimic effectively their natural counterpieces. 

Tetronomycin (102), a structurally challenging 3-acyltetronic acid ionophore antibiotic, was isolated from a Streptomyces strain in the early 1980s [71]. The only total synthesis reported so far was accomplished in 1992 by Yoshii and coworkers (Scheme 1.14) [72]. By using as chiral building blocks the ethoxyethyl ether 98 and L-rhamnal diacetate 99, Yoshii reached aldehyde 100, a suitable precursor for the installation of the tetronic moiety. This was achieved by a reaction with the lithium anion of methyl tetronate 101 at —100°C that led to the target after pyridinium chlorochromate (PCC) oxidation and careful deprotection. 

Chemical modification of monensin, poly ether ionophoric antibiotic withbound tetrahydropyran, two tetrahydrofuran, and octahydrospiro-2,2 -furopyian fragments 97YZ583. 

Biological systems have evolved to exploit the reactivity of epoxides in the synthesis of a number of secondary metabolites (Fig. 4.1) [1], including ionophore antibiotics such as monensin (1) [2], terpene ethers, represented by thyrsiferol (2) [3], ladder toxins, represented by brevetoxin (3) [4], and annonaceous acetogenins, represented by murisolin (4) [5]. Chemical synthesis of cyclic ethers also frequently utilizes epoxides, often in the context of cascade cyclizations in which the hydroxyl group that is liberated... 

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. 

Table 1 Hsts the polyether antibiotics arranged by the number of carbons in the skeleton. Many of these compounds were isolated independendy in separate laboratories and thus have more than one designation. The groups are subdivided depending on the number of spiroketals. Two classes fall outside this scheme the pyrrole ether type containing a heterocycHc ring, and the acyltetronic acid type, that has an acyHdene tetronic acid instead of a carboxyHc acid. These compounds are ionophores and because of their common features are included as polyethers.

A second source of inspiration for studying the open-chained equivalents of crown ethers was the observation that a number of naturally occurring antibiotics enhance cation transport and bear a structural similarity to open-chained crown ethers. A number of groups have examined neutral synthetic ionophores and a variety of novel cation carriers is now available. This is discussed in Sect. 7.4, below. 

There are several antibiotics called ionophores, most notably nonactin and valinomycin, that coordinate with metal cations in a manner similar to that of crown ether. 

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. 

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