Antamanide metal complexes

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 association constant for ion binding of Cyclo-(Pro-Gly)3 b nearly the same as that of antamanide, but the selectivity for Ca of Cydo-(Pro-Gly)3 is inferior to that for Na" " of antamanide (144). Cyclo-(Pro-Gly)3 resembles the K -specific cyclic hexadepdpeptide aiitibiotic enniatin (145), in the aspect that both cycUc compounds form sandwich-type comjdexes with ions. It is very likely that Cyclo-(Pro y)3 transports ions across a membrane vb the formation of a club sandwich-type complex. The metal-ion complex of Cyclo-(Pro<]tly)3 is extractable with water from organic phase. A specific behavior of clo-(Pro-Gly)3 in the ion tran rt throu a membrane b expected from fhb property. 

Among the alkaline earth metal ions, Ca++ is bound strongly, whereas only weak binding occurs with Sr++ and Ba++, and no interaction with Mg++. CD spectral changes also indicated complex formation with Tl+. Antamanide exhibits clearly a preference for ions of about 1 A radius. 

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. 

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... 

Bystrov et al. (33) have compared the NMR spectra of valinomycin, beauvericin, and antamanide with those of their Na+ and K+ complexes. These compounds are being widely studied as tools in the understanding of processes associated with ion transport through membranes. The ion in these complexes is located in a central cavity and is held in place by ion-dipole interactions between carbonyls oriented toward the center of the cavity and the metal ion. The ion-dipole interaction should bring about a downfield shift of the carbonyl resonance. 

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. 

One or more stable conformations can also be assumed for cyclic peptides which can adopt more or less rigid structures stabilized by hydrogen or other bridges or, strongly, by complexing various metal ions. As an example of many published structures [41], there is the Li-complex of the antitoxic mushroom peptide antamanide (see p. 215), a structure which was determined in 1973 by Isabella L. Karle [42] using the direct method of Jerome Karle (Nobel Prize 1987, shared with J.A. Hauptmann). 

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. 

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