Synthesis and Properties of Gramicidin S Analogs Containing Pro–d-Phe Sequence in Place of d-Phe–Pro Sequence in the β-Turn Part of the Antibiotic

Abstract
Two analogs of gramicidin S, [l-Pro4, d-Phe5]-gramicidin S and [l-Pro4,4′, d-Phe5,5′]-gramicidin S, were synthesized in order to investigate the relationships among positions of Pro residues, antibiotic activity and CD spectra. [l-Pro4,4′, d-Phe5,5′]-gramicidin S showed little activity. On the other hand, the activity of [l-Pro4, d-Phe5]-gramicidin S against Bacillus subtilis and Micrococcus flavus was the same as that of gramicidin S, and its activity toward other microorganisms tested was 1/2 that of gramicidin S. The CD spectra of these analogs and gramicidin S in an aqueous solution differ from each other, indicating that these peptides have different conformations in aqueous solutions. The CD spectrum of [l-Pro4, d-Phe5]-gramicidin S resembles a graphical average of the CD spectra of gramicidin S and [l-Pro4,4′, d-Phe5,5′]-gramicidin S.