title: Synthesis and conformational studies of a beta-turn mimetic incorporated in Leu-enkephalin.
abstract: A beta-turn mimetic in which the four amino acids of a beta-turn have been replaced by a 10-membered ring has been designed, synthesized, and subjected to conformational studies. In the mimetic, the intramolecular CO(i)-HN(i)(+3) hydrogen bond that is often found in beta-turns has been replaced by an ethylene bridge. In addition, the amide bond between residues i and i + 1 was exchanged for a methylene ether isoster. Such a beta-turn mimetic, based on the first four residues of Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu), was prepared in 15 steps. The synthesis relied on a beta-azido alcohol prepared in five steps from Cbz-Tyr(tBu)-OH as a key, i-position building block. tert-Butyl bromoacetate, glycine, and a Phe-Leu dipetide were then used as building blocks for positions i + 1, i + 2, and i + 3, respectively. Conformational studies based on (1)H NMR data showed that the beta-turn mimetic was flexible, but that it resembled a type-II beta-turn at low temperature. This low energy conformer closely resembled the structure determined for crystalline Leu-enkephalin.
authors.affiliation: Organic Chemistry, Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Blomberg
authors.forename: Mattias
authors.initials: M
authors.lastname: Hedenström
authors.forename: Paul
authors.initials: P
authors.lastname: Kreye
authors.forename: Ingmar
authors.initials: I
authors.lastname: Sethson
authors.forename: Kay
authors.initials: K
authors.lastname: Brickmann
authors.forename: Jan
authors.initials: J
authors.lastname: Kihlberg
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D004743:Enkephalin, Leucine / Q000138:chemical synthesis* / Q000737:chemistry; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D018716:Molecular Mimicry; D015394:Molecular Structure; D011487:Protein Conformation; D017433:Protein Structure, Secondary
chemical_list: D000596:Amino Acids; D004743:Enkephalin, Leucine