Polyether ionophore antibiotic

Coccidiosis is a proto2oal disease of the intestinal tract of animals that leads to severe loss of productivity and death. The development and widespread use of anticoccidials has revolutionized the poultry industry. The estimated world market for anticoccidial agents in 1989 was 425 million and this was dominated by the polyether ionophore antibiotics monensin, salinomycin [53003-10-4], n imsm [55134-13-9], la.s9locid, and maduramicin [84878-61-5] (26). 

Chemical modification of monensin, polyether ionophoric antibiotic with bound tetrahydropyran, two tetrahydrofuran, and octahydrospiro-2,2 -furopyran fragments 97YZ583. 

Fig. 5.4 Chemical structures of commonly used polyether ionophore antibiotics.

Robinson JA (1991) Chemical and biochemical aspects of polyether-ionophore antibiotic biosynthesis. Prog Chem Org Nat Prod 58, 1-81. 

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... 

Strategy and methodology for the total synthesis of polyether ionophore antibiotics 00CRV2407. 

Because of their complex chemical structures and significant biological properties, polyether ionophore antibiotics have stimulated intensive studies of their total synthesis, which primarily require new synthetic methodologies for the control of stereochemistry in acyclic systems two excellent reviews covered the results until 1981 [1]. However, since then, only a few total syntheses have been achieved, because the extremely complex structures of the polyethers have required formidable efforts for synthesis, and much attention has focussed on efficient and stereoselective synthesis of the molecular framework of substituted tetrahydrofurans and tetrahydropyrans and spiroketal systems [2]. This review deals with the total synthesis of three representative complex polyethers, okadaic acid (1), antibiotic X-206 (2), and salinomycin (3) mainly focussing on the latter half of their synthesis. 

Faul MM, Huff BE. Strategy and methodology development for the total synthesis of polyether ionophore antibiotics. Chem. Rev. 2000 100 2407-2474. 

Figure 3 Epoxides as key intermediate in the biosynthesis of the polyether ionophore antibiotic monensin A.

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). 

D.A. Volmer, C.M. Lock, ESI and CID of antibiotic polyether ionophores. Rapid Commun. Mass Spectrom., 12 (1998) 157. 

Penicillin, the first natural antibiotic produced by genus Penicillium, discovered in 1928 by Fleming, as well as sulfonamides, the first chemotherapeutic agents discovered in the 1930s, lead a long list of currently known antibiotics. Besides 3-lactams (penicillins and cephalosporines) and sulfonamides, the list includes aminoglycosides, macrolides, tetracyclines, quinolones, peptides, polyether ionophores, ri-famycins, linkosamides, coumarins, nitrofurans, nitro heterocytes, chloramphenicol, and others. 

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. 

The polyether ionophore class of antibiotics includes lasalocid, maduramicin, monensin, narasin, salinomycin, and semduramicin. These dmgs are used exclusively in... 

Polyether ionophores (Table 1.10) have a distinctly different mode of action from therapeutic antibiotics. 

Cha JM, Yang S, Carlson KH, Rapid analysis of trace levels of antibiotic polyether ionophores in surface water by solid-phase extraction and liquid chromatography with ion trap tandem mass spectrometric detection, J. Chromatogr. A 2005 1065(2) 187-198. 

Antibiotic X-206 (2), produced from Streptomyces X-206, is known as one of the first three polyether ionophores discovered almost 40 years ago [9] and after 25 years its structure was determined by X-ray analysis [10]. In 1988, the first convergent asymmetric synthesis of 2 was achieved by Evans and co-workers through the synthesis and aldol couphng of the and C17-C37 synthons... 

Urban, F.J. Chappel, L.R. Girard, A.E. Mylari, B.L. Pimblett, I.J. Lipophilic l,3-xylyl-21-crown-6 macrocy-clic polyether 2-carboxylic acids as biological mimics of the ionophore antibiotics. J. Med. Chem. 1990. 33. 765-771. 

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