ausblenden:
Schlagwörter:
-
Zusammenfassung:
NMR studies have revealed that the conformation of the monocyclic viroisin is dissimilar to that of the corresponding monocyclic derivative of phalloidin, dethiophalloidin, but has much similarity with the conformation of the bicyclic phalloidin. Obviously, one of three structural features found exclusively in the virotoxins is able to compensate for the conformational strain that in the bicyclic phallotoxins maintains the toxic conformation. Synthetic work on virotoxin analogues has shown that both the additional hydroxy group in allo-hydroxyproline and the methylsulfonyl moiety in the 2‘-position of tryptophan are unlikely to represent the structural element in question, leaving the d-serine moiety as the supposed key element. In this study we asked whether it is the hydroxy group of this amino acid or its d-configuration that is responsible for the effect. We synthesized four viroisin analogues and submitted them to conformational analysis by NMR as well as to an actin binding assay. While the rotating-frame nuclear Overhauser effect (ROESY) spectra of the analogues with l-configured amino acids showed several sets of signals, indicating the existence of conformers interconverting more slowly than the NMR time scale, the spectra of the analogues with d-configured amino acids showed only one set of signals. Remarkably, the two viroisin analogues with d-serine and d-alanine also had distinctly higher affinities for filamentous actin than their l-configured counterparts, suggesting that the high biological activity may be correlated with the absence of multiple and slowly interconverting conformers. Anyhow, d-configuration of serine is the structural element that maintains the phalloidin-like structure, while the hydroxy group does not contribute to conformational stability but is likely to be in contact with the actin surface
