Synthesis and conformational studies of a beta-turn mimetic incorporated in Leu-enkephalin.
A beta-turn mimetic in which the four amino acids of a beta-turn have been replaced by a 10-membered ring has been designed, synthesized, and subjected to conformational studies. In the mimetic, the intramolecular CO(i)-HN(i)(+3) hydrogen bond that is often found in beta-turns has been replaced by an ethylene bridge.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.
Blomberg
David
D
Organic Chemistry, Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
Hedenström
Mattias
M
Kreye
Paul
P
Sethson
Ingmar
I
Brickmann
Kay
K
Kihlberg
Jan
J
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
D000596:Amino Acids; D004743:Enkephalin, Leucine