Synthesis of Low-Hemolytic Antimicrobial Dehydropeptides Based on Gramicidin S

Abstract
The synthesis and biological activity of a novel cyclic β-sheet-type antimicrobial dehydropeptide based on gramicidin S (GS) is described. The GS analogue, containing two (Z)-(β-3-pyridyl)-α,β-dehydroalanine (ΔZ3Pal) residues at the 4 and 4‘ positions (2), was synthesized by solution-phase methodologies using Boc-Leu-ΔZ3Pal 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)-α,β-dehydrophenylalanine (ΔZPhe) analogue (1).