Antamanide alkali-metal complex

A cyclo-nonapeptide, isolated from linseed by Kaufmann and Tobschirbel [48] which also prevents the uptake of phalloidin (and other substances) by hepatocytes, cyclolinopeptide A, shows a certain similarity with AA in its amino acid sequence (Fig. 20) but does not form alkali-metal complexes. With the accumulation of aromatic amino acids between proline residues as an active region in mind, Kessler et al. designed some smaller cyclopeptides of which one, c(D-ProPhePheProPhePhe), exhibited somewhat stronger protection and a second less related one, called 008, showed even better protection of liver cells against phalloidin than antamanide [49]. 

The alkali metal cation complexes of compounds of the valino-mycin group (valinomycin, enniatins, macrotetrolides, beauveridn, antamanide) are positively charged. 

The conformation of uncomplexed antamanide is entirely different from that of the alkali metal ion complexes. Not only is the cyclic backbone elongated and flattened, but sequences 4,5,6 and 9,10,1 turn inside-out so that the... 

As mentioned in Chap. 9 (p. 215) the cyclic decapeptide antamanide exists in several conformations depending on the presence or absence of alkali metal ions and on the polarity of the solvents. The transition of the free form to a complexed one can be easily followed by CD spectra (Fig. 7). On the addition of Na ions or water the large negative ellipticity (Cotton effect) observed in apolar solvents, such as dioxane, disappears and changes into a positive Cotton effect in the same wave length region. 

Substances of the amphotericin D (a polyene), polyether (for example crown cyclic ethers), Antamanide (a peptide), and valinomycin (a depsi-peptide) represent structural types capable of complexing with alkali metal ions and thereby promoting their dissolution in fairly nonpolar solvents. Such compounds are known as ion carriers and some display antibiotic properties which may in part reside with activity in natural membranes. In order to evaluate structural changes upon such interesting functions, Gisin and Merri-field have synthesized a cyclododecapeptide (Chart 15) where the D-a-hy-droxyisovaleric acid and L-lactic acid units of valinomycin were replaced respectively with D-Pro and L-Pro. In MeCl-Aq the valinomycin analog was found to exhibit a seven times greater affinity for potassium picrate (to form a 1 1 hydrophobic complex) than that of the parent depsipeptide. 

The structure of antamanide was confirmed by total systheses based on several approaches 125-128). The molecular geometry in different solvents and in the presence or absence of metal ions has been thoroughly investigated by X-ray (729) and NMR 130,131) methods. It was found that antamanide and some of its analogs are capable of complex formations in water-free solvents with alkali and alkaline earth metal ions. The complexes with ions like Na and Ca ", with a radius of about 1 A, appeared to be especially stable. 

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