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

Unsaturated gramicidin S analog, [ΔPhe^4,4′]gramicidin S, was synthesized by conventional solution method in order to evaluate the role of the dehydrophenylalanine residues replacing d -phenylalanine^4,4′ in stabilizing the bioactive β-shect conformation. The dehydrophenylalanine (ΔPhe) moiety was introduced by dehydroazlactonization of the β-phenylserine residue. The [ΔPhe^4,4′]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 [ΔPhe^4,4′] 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.