title: Synthesis and evaluation of strand and turn modified ring-extended gramicidin S derivatives.
abstract: In this paper, we describe the crystal structure of previously reported ring-extended gramicidin S (GS) derivative 2 (GS14K4), containing a d-amino acid residue in one of the β-strand regions. This structure is in agreement with a previously reported modeling study of the same molecule. The polar side chain of the additional d-amino acid residue is positioned at the same face of the molecule as the hydrophobic side chains, and we believe that because of this compound 2 is considerably less hydrophobic than extended GS derivatives in which the strand regions are exclusively composed of l-amino acids. Using this backbone structure as our benchmark we prepared a small series of ring-extended GS analogues featuring sugar amino acid dipeptide isosteres of varied hydrophobicity at the turn region. We show that via this approach hydrophobicity of extended GS analogues can be tuned without affecting the secondary structure (as observed from NMR and CD spectra). Biological evaluation reveals that hydrophobicity correlates to cell toxicity, but still bacteriolysis is induced with GS analogues that are too hydrophilic to efficiently lyse human red blood cells.
authors.affiliation: Leiden Institute of Chemistry, Leiden University, RA Leiden, The Netherlands.
authors.forename: Annemiek D
authors.initials: AD
authors.lastname: Knijnenburg
authors.forename: Varsha V
authors.initials: VV
authors.lastname: Kapoerchan
authors.forename: Gijsbert M
authors.initials: GM
authors.lastname: Grotenbreg
authors.forename: Emile
authors.initials: E
authors.lastname: Spalburg
authors.forename: Albert J
authors.initials: AJ
authors.lastname: de Neeling
authors.forename: Roos H
authors.initials: RH
authors.lastname: Mars-Groenendijk
authors.forename: Daan
authors.initials: D
authors.lastname: Noort
authors.forename: José M
authors.initials: JM
authors.lastname: Otero
authors.forename: Antonio L
authors.initials: AL
authors.lastname: Llamas-Saiz
authors.forename: Mark J
authors.initials: MJ
authors.lastname: van Raaij
authors.forename: Bep
authors.initials: B
authors.lastname: Ravensbergen
authors.forename: Peter H
authors.initials: PH
authors.lastname: Nibbering
authors.forename: Gijs A
authors.initials: GA
authors.lastname: van der Marel
authors.forename: Herman S
authors.initials: HS
authors.lastname: Overkleeft
authors.forename: Mark
authors.initials: M
authors.lastname: Overhand
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D004912:Erythrocytes / Q000187:drug effects; D006096:Gramicidin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008826:Microbial Sensitivity Tests; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D000900:Anti-Bacterial Agents; D006096:Gramicidin