Cyclic antibiotics

Bradshaw and his coworkers have listed several motivations for their explorations in this area. One objective of [the] research program is to prepare and study a series of multi-dentate compounds which resemble naturally occurring macrocyclic compounds . Further, Bradshaw and his coworkers have said that it is our hope that we can prepare macrocycles to mimic the selectivities of the naturally occurring cyclic antibiotics and thereby make available models for the investigation of biological cation transportation and selectivity processes . These workers have presented a number of comparisons with valinomy-cin . The other expressly stated goal of their research is to prepare molecules which will allow us to systematically examine the parameters which affect complex stability and to understand that stability in terms of AH and TAS values for complex formation . 

These substances include primarily depsipeptides (compounds whose structural units consist of alternating amino acid and ar-hydroxy acid units). Their best-known representative is the cyclic antibiotic, valinomycin, with a 36-membered ring [L-Lac-L-Val-D-Hy-i-Valac-D-Val]3, which was isolated from a culture of the microorganism, Streptomyces fulvissimus. Figure 6.13 depicts the structure of free valinomycin and its complex with a potassium ion, the most important of the coordination compounds of valinomycin. 

In this chapter, representatives of the natural macrocycles are presented and selected model studies are also described. Emphasis will be given in the following discussion to a few of the better understood areas involving natural macrocyclic systems. Initially, the nature and function of the cyclic antibiotic category of macrocycles are discussed. Subsequently, aspects of the roles of the natural N4-donor systems are presented. 

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. 

Ward TJ, Farris AB III. 2001. Chiral separations using macro-cyclic antibiotics a review. J Chromatogr A 906 73-89. 

For the alkali metal cations, the stability (14) and permeability (43) sequences for dicyclohexyl-18-crown-6 have been found to be the same (K+ > Rb+ > Cs+ > Na+ > Li+). Thus, a direct relationship exists between the ability of a macrocyclic compound to complex a particular cation (as measured by the log K value for complex formation) and its influence on the biological transport of that cation. Furthermore, it would appear that the biological ion-transport mechanism may in part be due to the complexation properties of the macrocyclic carrier molecules. This subject with respect to cyclic antibiotics has been treated extensively by Si wow and co-workers (2). 

As an example of a more dispersed system, H 2Q- and 3Q-HoMQC spectra of the cyclic antibiotic primycin [30] recorded at 800 MHz [31] are shown in fig. 6. This molecule has a sequence of alternating CH(OR) and CH2 groups, establishing correlations both within, and between the two extreme regions of the spectrum. The spectral windows could be still chosen to be equal with no serious overlap introduced on the final spectrum. 

Figure 17. AH-TA.S plot for cation binding by (pseudo)cyclic antibiotics.

Our approach has been essentially empirical in nature with less emphasis on the theoretical. We have isolated single substances, proved their purity, and determined their covalent structure by classical methods of organic chemistry we have then used these substances of molecular weight ranging from 1,000 to 14,000 as model solutes for the study of conformation and intermolecular interaction. Solutes of special interest have been gramicidin SA (2), bacitracin A (3), polymyxin B, and the tyrocidines A, B, and C (4). All are cyclic antibiotic polypeptides. The first three behave in aqueous solution as reasonably ideal solutes and do not associate, but the tyrocidines associate strongly and are interesting models for the study of association phenomena. Other model solutes of... 

Aboul-Enein, H.Y. and Serignese, V., Enantiomeric separation of several cychc imides on a macro-cyclic antibiotic (vancomycin) chiral stationary phase under normal and reverse phase conditions, Chirality, 10, 358, 1998. 

The types of alkali and alkaline earth metal complexes subjected to molecular mechanics modeling fall into four categories crown ethers[U9,486 491], cryp-tands[492 493], spherands[494,495], and other biologically important ligands, such as ionophores and cyclic antibiotics [496 499]. 

D. W. Armstrong, Y. Tang, S. Chen, Y. Zhou, C. Bagwill, and J.-R. Chen, Macro-cyclic antibiotics as a new class of chiral selectors for liquid chromatography, Ana/. Chem. 66 (1994), 1473. 

When the cyclic antibiotic valinomycin forms a complex with K"", Rb" or Cs"" ions, the carbonyl C signals are shifted 4-5 ppm downfield [116]. The shift differences upon complexation with Na are much less pronounced, which is presumably related to the ability of the antibiotic to distinguish between Na" and K. ... 

Despite these evident drawbacks, a broad variety of SOs have been used in CMPA-based enantiomer separations, including cyclodextrins, proteins, macro-cyclic antibiotics, chiral ion-pairing agents, amino acids in combination with transition metal salts, and crown ethers. Recent application for the separation of pharmaceutically relevant chiral compounds utilized P-cyclodextrins [46-48] charged cyclodextrins [49, 50], macrocyclic antibiotics [51, 52] and chiral ion-pairing agents [53, 54]. A more detailed discussion of CMPA-based enantiomer separation is beyond the scope of this chapter. The interested reader is referred to dedicated reviews [55, 56]. 

Zhou,Y., Bagwill, C., Chen, J.-R. Macro-cyclic Antibiotics as a New Class of... 

Ekborg-Ott, K., Liu,Y.,Armstrong, D.W. Highly enantioselective HPLC separations using the covalently bonded macro-cyclic antibiotic, ristocetin A, chiral stationary phase. Chirality, 1998,10, 434-483. 

Replacement of amide by ester linkages gives a class of compounds known as depsipeptides. An example is the cyclic antibiotic valincmycin (VII), ... 

From the biogenetic viewpoint, the tyrothricins are interesting because they contain, unlike the other antibiotic families, two different types of peptides on the one hand the cyclic tyrocidines, and on the other the linear gramicidins A, B, C and D, which are also protected on the amino end by the unusual formyl group and by an ethanolamine residue on the carboxyl end. The latter are the only non-cyclic antibiotics known to the present day Table 1.4). 

Many other peptides whose mode of interaction with the lipid hilayer differs from that of the transmemhrane a-helices, e.g. cyclic antibiotic peptides, have also been stndied by DSC from the point of view of their interaction with saturated PC. Not unexpectedly, several different patterns of thermogram alteration have been obtained, witnessing the varying ways of interaction of those peptides with the phospholipid bilayer. 

Synthesis of Special Target Peptides 139 the synthesis of the cyclic antibiotic peptide gramicidin S ... 

In an early example, commercial bacitracin ( ), a cyclic antibiotic (the structure of bacitracin F is given) was found to hydrolyze L-(P) about twice as fast as the d-enantiomer. No selectivity was found for the corresponding alanine enantiomers. Most likely an imidazole group from histidine is involved in the hydrolysis, but owing to the structural complexity of the peptide it is not possible to determine the origin of the enantioselectivity. 

Applying some antibiotics as stationary or mobile-phase additives for chiral separations. The macro-cyclic antibiotics (ansamycins, glycopeptides, and... 

Esperin a cyclic antibiotic depsipeptide from Bacillus mesentericus. It contains a long-chain a-hydro-xy-fatty acid which is linked by an amide bond to the A-terminus of the sequence Glu-Leu-Leu-Val-Asp-Leu-Leu, and also forms a lactone with the y-carboxyl group of the Asp residue. 

Ghosh S, Palmer KR (1994) Prevention of biliary stent occlusion using cyclical antibiotics and ursodeoxycholic acid. Gut 35 1757-1759... 

---