Conformation of DifferentS-Deoxo-Xaa3-amaninamide Analogues in DMSO Solution as Determined by NMR Spectroscopy. Strong CD Effects Induced by βI, βII Conformational Change

Abstract

The amatoxines form a class of naturally occurring bicyclic octapeptides responsible for the poisonous effect of Amanita mushrooms. For the investigation of structure−activity relationships many derivatives of these peptides have been synthesized and tested up to now. To examine the particular role of the configuration of the amino acid in position 3, three new analogues of S-deoxo-amaninamide have been synthesized in which residue 3 is replaced by l-Ala, d-Ala, or Gly. CD spectra in methanol show large deviations which indicate conformational differences or isomeric bridging during synthesis. To discriminate both possibilities a detailed NMR analysis was performed. The conformation of these compounds has been determined in DMSO solution by highfield NMR spectroscopy, distance geometry, and molecular dynamic calculations. The resulting structures are surprisingly similar and closely related to the x-ray structure of β-amanitin: Conformational differences are only found in the turn region of Hyp2-Xaa3. Hence, the strong differences of the CD spectra rise only from type I/type II variations of this β-turn.