Antamanide analogs

Table 10. Stability constants of complex formation of antamanide analogs with sodium and potassium in several solvents... 

Besides the antamanide analogs already mentioned, more than 50 others have been synthesized in order to study relationships between structure, biological... 

Apparently, complex formation is only one condition for the biological activity of antamanide analogs. Other molecular features, like certain lipophilic side chains and the chirality (cf. analog 12), also play an important role, thereby suggesting an interaction of the peptide with a stereospecific receptor. 

The rms deviation between the energy-minimized and refined crystal structures is a little over 0.1 A for both molecules. Since the minimizations start with models identical to the refined crystal structures, it is to be expected that the rms deviations increase as the minimizations progress. This is indeed the case. The minimization was not carried out in precisely the same way with both structures, but at a comparable stage of energy minimization the rms error is about 0.03 A greater for sodium antamanide analog than for lithium antamanide. 

Fig. 7. Distribution of shifts in crystallographic refinement of sodium antamanide analog.

Fig. 8. Distribution of the thermal parameters of sodium antamanide analog in three different classes of atoms. The thermal parameters of lithium antamanide are on the average lower but are distributed in a very similar way.

Fig. 11a, b. Scatter plots of atomic shifts vs thermal coefficients of sodium antamanide analog, (a) Energy minimization of refined structure, (b) Crystallographic least squares refinement. 

This last connection between large calculated shifts and large thermal parameters due to errors in the conformation alone is sufficient to explain why there is no correlation between shifts and thermal parameters in lithium antamanide and a slight correlation in the somewhat less refined sodium antamanide analog. 

The authors are grateful to Drs Isabella Karle and Lyle H. Jensen for providing them with the unrefined conformations of sodium antamanide analog and rubredoxin, respectively. 

Analog 10, a symmetrical antamanide, exhibits exceptionally high complex stability. Its biological activity is, however, markedly reduced. As with analog 11, perhydro-antamanide, this may be due to the disappearance of phenyl rings which are required for the binding of antamanide to membrane proteins. 

Naturally occurring valinomycin [129], nonactin [130], antamanide [131], beauvericin [ 13 21 and entcrobactin [133] are analogous to synthetic crow n ethers in that they possess polar cavities which can strongly and selectively bind cations and act as ion carriers in model and biological membranes (Fendler and Fendler,... 

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 extremely poisonous green mushroom Amanita phalloides contains a number of cyclic peptides classified as phallotoxins (heptapeptides), ama-toxins (octapeptides), and a decapeptide antagonist called antamanide (Wieland and Wieland, 1972). Crystal structure analyses have been completed on jS-amanitin, on antamanide, and on a biologically active analog, both com-plexed and uncomplexed. 

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. 

Antamanide. Antamanide is a cyclic decapeptide which occurs in the Amanita mushroom. Karle has determined and refined the structures of crystals of a complex of antamanide with lithium and of a complex of an analog of antamanide with sodium [37, 38]. Antamanide has a cyclic backbone it contains four proline residues, and four of its oxygens are ligands of the ion. Consequently, the conformation of antamanide is compact and shows a number of nonbonded contacts. The molecule is quite hydrophobic, and the crystal structure forms a hydrophobic matrix of antamanide... 

We separated the atoms into three classes the 30 N, C and C atoms of the backbone, the 24 O, and proline atoms bonded to the backbone and the remaining side chain atoms (30 in antamanide, 32 in the analog). In Figures 6 and 7 we show bar graphs of the distribution of the shifts and in Figure 8 a bar graph of the thermal factors. ... 

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