Lasalocid ionophore

The lasalocids have several unique features such as a salicyclic acid moiety and a carbonyl group. Furthermore, their ligand backbones are considerably shorter than those of the other polyether antibiotics (see Fig. 15). This accounts for the inability of lasalocid ionophores to fully shield the complexed metal ion from the solvent by folding around it. The resulting complex has two distinct surfaces one of which is much more polar than the other, as demonstrated in Fig. 18 for lasalocid A, the most abundant species. In non-polar media, this unfavorable situation is overcome by the formation of dimeric complexes of stoichiometries (M L") and M (L")j for mono- and divalent metal ions, respectively. In fact, these aggregates present a highly lipophilic surface to the solvent. 

Extensive studies including both inner-sphere and outer-sphere complexation of cations were performed with lasa-locid A, which is a small natural ionophore containing a salicylic acid fragment (Figure 1). The ability of lasalocid to form neutral outer-sphere complexes with species like Co(NH3)(5 +, Cr(bpy)3 ", Pt(bpy)(NH3)2 " " allows one to use it as an ionophore for the membrane transport (including chiroselective transport) of such species. The lasalocid ionophore also was shown to be an efficient carrier for toxic water-soluble metal cations such as Pb + and Cd + across artificial flat-sheet-supported liquid membranes, which represent a potential system for separation of these cations. 

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. 

Anticoccidial Activity. The 1968 report that claimed monensin has activity against Eimeria sp., particularly E. tenella E. macdma., and E. acervulina greatly altered the prevention and control of coccidiosis in poultry (172). It is estimated that the polyether ionophores presently constitute more than 80% of the total worldwide usage of anticoccidials (173). Lasalocid and monensin have been approved for use in control of coccidiosis in cattle. 

The total world market for the use of ionophores for feed efficiency improvement in mminants is approximately 80— 90 million. The United States is the largest market. Lasalocid and monensin are the only members of this class cleared for use. Outside the United States, salinomycin is used in limited quantities. Worldwide usage is about 1.5 million kg. 

Anti-protozoa agents are utilized to treat diseases such as coccidiosis, which affects many farm animals, particularly poultry. Coccidiostats include polyether monocar-boxylic acid ionophores and other types of compounds. Polyether monocarboxylic acid ionophores include monesin, narasin, lasalocid, and salinomycin. The most common of these is salinomycin. Nonionophore coccidiostats include dimetridazole and halofunginone. Stanker et al. reviewed immunoassays available for coccidio-static agents. 

After the marketing of monensin began, there was a rush to discover more ionophores. The second ionophore to be licensed as a coccidiostat in the U.S. was X-537A, first reported by investigators at the Nutley, NJ laboratory of Hoffmann-LaRoche in 1951 (8), 16 years prior to the announced discovery of monensin. It was their misfortune not to have tested their compounds against coc-cidia. X-537A, now named lasalocid, differs from most of the other ionophores in its ability to complex with divalent cations. 

Three broad groupings, of the antibiotic substances presently used in animal production, include (a) broad-spectrum antibiotics, including penicillins and tetracyclines, which are effective against a wide variety of pathogenic and non-pathogenic bacteria (b) several narrow-spectrum antibiotics that are not used in human medicine and. (c) the ionophore antibiotics, monensin. lasalocid and salinomycin Monensin and lasalocid are used as rumen fermentation regulators in beef cattle, and the three ionophores are used as coccidiostats in poultry production. The ionophores. which are not used in human medicine, were first introduced in the 1970 s and account for most of the increase in antibiotic usage in animal production since the 1960 s. 

Weiss and MacDonald (87) recently reviewed methods for determination of ionophore antibiotics. lonophores approved for use in animal agriculture in the U.S. are lasalocid, monensin, and salinomycin. An HPLC ( ) and GLC-MS ( ) procedure have been described for lasalocid. For other ionophores, TLC-bioautography is the preferred procedure because of lack of any useful UV absorbance. However, a few TLC colorimetric procedures have been described for monensin residues in tissues (90-92). 

Lasalocids, SaUnomycin, Narasin guard against coccocidiosis. These ionophores are also used in cattle and swine as growth promoters. They generally have a different mode of action compared to other antibiotics. 

Despite almost 10 years of intensive use in the production of broilers, this drug is remarkably free of resistance problems. Other ionophores have been tested and found to possess anticoccidial activity. Lasalocid (64) is in commerical use whilst salinomycin (65) and narasin (66) have recently been evaluated in field trials. 

The a-pyrone (635) undergoes an exothermic Diels-Alder reaction with 1-diethylamino-1-propyne to afford the cycloadduct (636) (77JOC2930). Only a single regioisomer is produced, which is in line with the expected polarization of these reagents (Scheme 144). A Diels-Alder reaction of the same a-pyrone with 1-dibenzylamino-l-propyne affords an aniline derivative which has been employed in a chiral synthesis of the aromatic portion of the ionophore antibiotic lasalocid (80JA6178). 

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). 

Important naturally occurring tetrahydrofuran compounds which have attracted much attention in recent years as synthetic goals are the ionophores, some possessing considerable antibiotic activity examples include monensin (196) (79JA260), nonactin (194) (76CB2628) and lasalocid A (195) (78JA2933). 

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). 

Ionophores X-573A (lasalocid A) and A23187 are usually regarded as carriers for Ca2+, but they will bind Na+. If formed from non-polar solvents the Na+/X-573A complex is dimeric, but if prepared in methanol it is monomeric, in which the Na+ is complexed by five oxygen donor atoms and the sixth position is filled by water. In the dimer, the water is absent and the coordination of the cation is completed by dimer formation.37 These results suggest that monomeric Na+-... 

Ionophores Mitra [89] showed that an ionophore such as lasalocid can also be used to enhance the corneal permeability of pilocarpine. 

The sapphyrin unit connected to natural ionophore lasalocid [78] has been used for the design of ligand 48. Membrane transport was measured for this ligand using a traditional U-tube arrangement. It was found that the ligand is able to transport amino acids in their zwitterionic form with a preference for the L-enantiomer of Phe. 

Outer-sphere complexes of lasalocid A (LAS) anion with [Co(NH3)6], [Co(en)3], and [Co(sep)] + cations were isolated as reported in Ref 321. The X-ray data for these complexes demonstrated that three lasalocid anions (in cyclic conformation) surround the cobalt complexes so that the overall shape is approximately spherical. In consequence of its hydrophobic outer surface, the adduct is soluble in nonpolar solvents such as chloroform. Lasalocid anion was showed to act as an ionophore for selective enantiomeric transport of the [Co(sep)]- + cation through a chloroform membrane. 

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