Studies on the β-Turn of Peptides. VII. Syntheses and Antibiotic Activities of Gramicidin S Analogs with l-Pro-l-Asn or l-Pro-d-Ala Sequence at the β-Turn Part

Two analogs of gramicidin S (GS), [l-Pro4,4′, l-Asn5,5′]-GS (10a) and [l-Pro4,4′, d-Ala5,5′]-GS were synthesized to investigate the possibility of replacing the β-turn part of GS by a different type of β-turn keeping the biological activity. For the synthesis of 10a, three procedures were examined and satisfactory results were obtained by the active ester method applied to cyclization of linear decapeptide with l-Pro at the C-terminus. Neither analog showed antibiotic activity indicating that the β-turn part of GS could not be replaced with l-Pro-l-Asn or l-Pro-d-Ala sequences without affecting on its activity. The CD and ORD spectra of the analogs and their 2,4-dinitrophenyl derivatives showed weaker Cotton effects than those of GS and its derivative, respectively. So, the analogs were considered not to take GS-like β-sheet conformation. The reason why the analogs did not take such conformations was investigated by the model tetrapeptides with chromophoric substituents.