Polyether antibiotics nonactin

The advent of the polyether antibiotics with the challenging aspect of stereocontrolled construction of the substituted tetrahydrofuran units has greatly extended the chemistry of this oxygen heterocycle. The nonactins (194), lasalocid A (195) and monensin (196) are among the ionophores for which syntheses have been achieved. Detailed reviews on synthesis of reduced furans are available (65HOU(6/3)l, 80H(14)1825). 

Polyether antibiotics contain tetrahydrofuran rings. In monensin 11, three tetrahydrofuran rings are linearly connected. The molecule contains 17 asymmetric centres. Stereoselective syntheses for monensin have been elaborated [18]. In nonactin 12, the rings are interconnected in an a,a -orientation via ester groupings. Nonactin is therefore classed as a macrolide antibiotic. Polyethers of the type 11/12 are capable of facilitating ion transport across biological membranes they are, therefore, also known as ionophores. 

The polyether nonactin (174) is an antibiotic tetralide produced by the Streptomyces family of microorganisms. From a biological point of view, nonactin and the other compounds in this family of tetrameric lactones have the ablility to strongly complex potassium ion and to facilitate the transport of potassium across membranes by providing a lipophilic shell. Ion transport has been shown to have a strong influence on important biological functions such as oxidative phosphorylation and mitochondrial respiration. 

Cyclic polyethers have been shown to increase the permeability of reconstituted biological membranes to alkali metals in a similar way to naturally occurring antibiotics, such as enniatin, nonactin and valinomycin, the similarity extending to the order of preference for metal transfer across the membrane ... 

A classic temperature jump investigation from Eigen s laboratory resulted in suggestions that the specificity of carriers for membrane translocation of certain ions rested with the rate of dissociation of the complex formed. Several antibiotics act as specific carriers of alkali metal ions across membranes. The cyclic polyether nonactin, for instance, which can form complexes with either Na or K, will selectively transport only the latter. Diebler et al. (1969) found that the association rate constants for... 

In contrast to these polyethers, macrocyclic antibiotics such as the actins complex cations by much larger rings which wrap themselves completely around the cation. The wrapping of the ionophore requries complete removal of the solvent shell of the cation, and this solvent stripping was demonstrated experimentally by Prestegard and Chan in NMR studies of nonactin. Because polyether complexation requires at least partial displacement of the solvent shell surrounding the cation, the complex formation is minimized... 

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