Studies of Peptide Antibiotics. XLV. Syntheses of Gramicidin S-like Analogs with Macro-ring Structures

Abstract Three cyclic tetradecapeptides related to gramicidin S (GS): cyclo(–Leu–Orn–Leu–Orn–Leu–d-Phe–Pro-)2, cyclo(–Leu–Orn–Leu–Orn–Leu–d-Phe–Sar–)2, and cyclo(–Leu–Orn–Leu–Orn–Leu–d-Phe–Gly–)2, were synthesized to investigate the contributions of the ring size of cyclic peptides and of the number of the basic amino acid residues to the antibacterial activity. The protected cyclic tetradecapeptides were synthesized through a cyclization reaction of the linear tetradecapeptide azide in pyridine. Hydrogenolysis of the protected cyclic peptides afforded crystalline tetrahydrochlorides of the analogs. The homogeneity of the analogs was ascertained by TLC, paper electrophoresis, and elemental analysis. In the experiment of circular dichroism, the two analogs with 7,7′-Pro or 7,7′-Sar gave spectra similar in shape to that of GS, while the analog with 7,7′-Sar gave a slightly different spectrum from that of GS. The antibacterial assays showed that the analog with 7,7′-Pro exhibited considerable activities against the microorganisms tested, particularly against Gram-negative bacterias such as Escherichia coli and Shigella sonnei. On the other hand, the analogs with 7,7′-Sar or 7,7′-Gly exhibited weaker activities than that of GS.