Conformationally stabilized gramicidin S analog containing dehydrophenylalanine in place of d ‐phenylalanine4,4′

Unsaturated gramicidin S analog, [ΔPhe4,4′]gramicidin S, was synthesized by conventional solution method in order to evaluate the role of the dehydrophenylalanine residues replacing d‐phenylalanine4,4′ in stabilizing the bioactive β‐shect conformation. The dehydrophenylalanine (ΔPhe) moiety was introduced by dehydroazlactonization of the β‐phenylserine residue. The [ΔPhe4,4′]gramicidin S prepared by this method showed very strong antimicrobial activities against Gram‐positive bacteria, but not against Gram‐negative ones. Several lines of spectroscopic evidence indicated that [ΔPhe4,4′] gramicidin S has a reinforced β‐sheet backbone conformation necessary for a full biological activity of gramicidin S. These results suggested that :α,β‐dehydrogenation of the amino acid residue in a cyclic peptide can stabilize the turn structure.