Synthesis of low-hemolytic antimicrobial dehydropeptides based on gramicidin S

The synthesis and biological activity of a novel cyclic beta-sheet-type antimicrobial dehydropeptide based on gramicidin S (GS) is described. The GS analogue, containing two (Z)-(beta-3-pyridyl)-alpha,beta-dehydroalanine (Delta(Z)3Pal) residues at the 4 and 4' positions (2), was synthesized by solution-phase methodologies using Boc-Leu-Delta(Z)3Pal azlactone. Analogue 2 exhibited high antimicrobial activity against Gram-positive bacteria and had much lower hemolytic activity than wild-type GS and the corresponding (Z)-alpha,beta-dehydrophenylalanine (Delta(Z)Phe) analogue (1).