Incorporation of beta-amino acids into ascidiacyclamides: Effects on conformation, cytotoxicity and interaction with copper (II) ion

摘要

Seven ascidiacyclamide [cyclo(-Ile-oxazoline-d-Val-thiazole-)(2)] (ASC) analogues incorporating the beta-amino acids beta Ile, beta oxazoline, and/or d-beta Val were synthesized. We then investigated the effects of the position and number of incorporated beta-amino acids on the structure, cytotoxicity, and copper binding by these seven analogues. The structural analyses revealed that both beta Ile and d-beta Val favor a gauche-type theta torsion angles, while beta oxazoline favors a trans-type theta torsion angle. Expansion of the macrocycle by incorporation of beta Ile or d-beta Val readily induced molecular folding. On the other hand, the incorporation of two beta oxazoline residues strongly extended the peptide conformation, and the incorporation of one was sufficient for the moderate restriction important for conformational equilibrium and cytotoxicity. Despite expansion of the macrocycles, the structure-cytotoxicity relationships were largely maintained. In studies of complexation of the analogues with Cu (II) ion, the position and number of incorporated beta-amino acids had a large impact on the structure of the metal complex and may contribute to its stabilization.