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

Abstract

Seven ascidiacyclamide [cyclo(-Ile-oxazoline-d-Val-thiazole-)₂ ] (ASC) analogues incorporating the β-amino acids βIle, βoxazoline, and/or d-βVal were synthesized. We then investigated the effects of the position and number of incorporated β-amino acids on the structure, cytotoxicity, and copper binding by these seven analogues. The structural analyses revealed that both βIle and d-βVal favor a gauche-type θ torsion angles, while βoxazoline favors a trans-type θ torsion angle. Expansion of the macrocycle by incorporation of βIle or d-βVal readily induced molecular folding. On the other hand, the incorporation of two βoxazoline 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 β-amino acids had a large impact on the structure of the metal complex and may contribute to its stabilization.

Keywords: CD spectrum; ascidiacyclamide; copper binding; crystal structure; cytotoxicity; oxazoline; β-amino acid.