Synthesis and Biological Evaluation of Novel Gramicidin S Analogues

Abstract

The synthesis of three new analogues of the cyclic cationic antimicrobial peptide Gramicidin S is described. These derivatives contain a modified turn region in which the DPhe‐Pro motif has been replaced by a constrained furanoid sugar amino acid or a flexible linear aminoethoxy acetic acid moiety. Structural analysis revealed conformational changes in the modified turn region compared to GS. The biological profile of these compounds however resembles that of Gramicidin S and previously described analogues.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Scaling the Amphiphilic Character and Antimicrobial Activity of Gramicidin S by Dihydroxylation or Ketal Formation

“…Interestingly, the dimethylketal modified GS analogue 16 was inactive and has no hemolytic activity. Enhanced polarity and decreased amphiphilic character, as well as polar residues at the d -Phe position, are supposed to cause these findings. , GS analogue 18 modified with a C13-alkyl chain, as well as analogue 19 modified with two C7-alkyl chains, restored the activity and showed a drastic increase of hemolytic activity and a lower activity against Gram-positive bacteria tested, as well as no activity against the Gram-negative bacteria Escherichia coli . For 18 , this can be explained by the length of the C13 alkyl chain, which enhanced the hemolytic activity, lowering the selectivity index.…”

Exploring the Conformational and Biological Versatility of β‐Turn‐Modified Gramicidin S by Using Sugar Amino Acid Homologues that Vary in Ring Size

“…Furanoid SAA 5 was prepared as its azide derivative by following a previously reported procedure. [15] To get access to the azide of SAA 4 and 6, we developed new procedures as outlined below.…”

“…Previously we reported [15] the synthesis of 3-benzyloxy-2,5-cis-furanoid azido acid and the use of this building block in the synthesis of GS5. By following a similar protocol, the sugar azido acids 14 and 22 were used to obtain the cyclic peptides GS4 and GS6 (Scheme 1).…”

“…NMR spectroscopy: 1 H and 13 C NMR spectra for all intermediates (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) were recorded on a Bruker AV-400 (400/100 MHz). The spectra of the peptides (GS4-6) were recorded on a Bruker DMX 600 equipped with a pulsed field gradient accessory and a cryo-probe.…”

“…[14] Encouraged by this observation we here set out to study the influence of ring-size of the incorporated SAA building block on the structure and activity of GS analogues. Going from a four-membered ether ring (oxetane SAA 4) through a five-membered ether ring (furanoid, SAA 5) [15] to a sixmembered ether ring (pyranoid, SAA 6), while leaving all other features intact, leads to a gradual increase in the distance between the cis-oriented carboxyl and the aminomethyl substituents of the SAA in the b-turn region. [16] We were curious to find out what effect this has on the overall structural integrity and biological activity of GS analogues thus designed.…”