Synthesis and evaluation of strand and turn modified ring-extended gramicidin S derivatives.

Autor: Knijnenburg AD; Leiden Institute of Chemistry, Leiden University, RA Leiden, The Netherlands., Kapoerchan VV, Grotenbreg GM, Spalburg E, de Neeling AJ, Mars-Groenendijk RH, Noort D, Otero JM, Llamas-Saiz AL, van Raaij MJ, Ravensbergen B, Nibbering PH, van der Marel GA, Overkleeft HS, Overhand M
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2011 Jun 01; Vol. 19 (11), pp. 3402-9. Date of Electronic Publication: 2011 Apr 22.
DOI: 10.1016/j.bmc.2011.04.031
Abstrakt: 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.
(Copyright © 2011 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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