Antibiotics ionophores

Anthraquinone, 1-hydroxy-calcium aluminum chelate compound, 1,2 metal complexes dyes, 6,86 Antiarthritis drugs labelled gold compounds, 6, 969 metal complexes, 6,758 Antibiotic M139163,2, 974 Antibiotics ionophoric, 6, 553 metal complexes selective binding, 6, 552... 

There is a family of antibiotics (ionophores) whose effectiveness results from disrupting this crucial ion gradient. 

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). 

In this manner, antibiotic ionophores like nonactin transport ions across a cell membrane of bacteria. This disrupts the normal ionic balance in the cell, thus interfering with cell function and causing the bacteria to die. 

A quantitative 1,4-chirality transfer is observed in the construction of the acyclic segment C-l to C-ll 11 of the antibiotic ionophore A-23187 (12, calcimycin)441. Both the wanted and unwanted stereoisomer 9 and 10, obtained from the alcohol 8 by pyridinium chlorochromate oxidation followed by Grignard reaction with vinylmagnesium bromide, can be rearranged by the ester enolate procedure simply by changing the reaction conditions to give the stereoisomer 11 with the correct configuration at C-10. 

Figure 6 Stereoplot of the antibiotic ionophore valinomycin-K" complex.

The mechanism of action of these new compounds is unknown. It has been shown that annonacin improved extrusion of K+ from lymphocytes (28) through a possible mechanism similar to antibiotic ionophores. The strong activity recently observed against complex I in mitochondrias could explain the high cytotoxicity found for such compounds (29). 

In his enantioselective total synthesis of the antibiotic ionophore X-14547A (in-danomycin), Boeckman was one of the first to employ a stereoselective reductive lithiation in a natural product synthesis [21]. Both alkyl substituents on the tetra-hydropyran ring function to effectively lock the ring into a defined conformation. 

From the multitude of microbial peptides only a few selected compounds can be discussed here. Several biologically active substances will be treated, however, in subsequent chapters of this book, for instance peptide hormones in Chap. 7, antibiotics, ionophores and toxins in Chap. 9. Here we describe three long-known compounds which attracted the interest of the, at that time still small, circle of peptide chemists. 

In a seminal paper appearing in 1969, Dietrich, Lehn, and Sauvage" described the first synthesis of a series of cryptands of the type 14. In part, it was the known alkali metal binding (and membrane transport behavior) of the natural antibiotic ionophores that provided the inspiration for the design of these then novel cage systems." ... 

In the synthesis of natural antibiotic ionophores, Burke et al. [48] encountered the requirement for a one-pot procedure for the reduction of alkoxy esters to syn- or anti-diols. The need for a complementary procedure to afford both diastereomers prompted the development of a new method (Scheme 3.27). 

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