Beta2-amino acids in the design of conformationally homogeneous cyclo-peptide scaffolds.
Herein, we report studies on the influence of chiral beta(2)-amino acids in the design of conformationally homogeneous cyclic tetrapeptide scaffolds. The cyclic alpha-tetrapeptide cyclo(-Phe-D-Pro-Lys-Phe-) (1) and its four mixed analogues, having one of the alpha-Phe replaced by either an (S)- or an (R)-beta(2)hPhe residue (i.e., cyclo(-(R)-beta(2)hPhe-D-Pro-Lys-Phe) (2a), cyclo(-(S)-beta(2)hPhe-D-Pro-Lys-Phe-) (2b), cyclo(-Phe-D-Pro-Lys-(R)-beta(2)hPhe-) (3a), and cyclo(-Phe-D-Pro-Lys-(R)-beta(2)hPhe-) (3b)), were all synthesized through solid-phase procedures followed by solution-phase cyclization. Initially, all five cyclo-peptides were analyzed by (1)H NMR spectroscopic studies in different solvents and at variable temperatures. Subsequently, a detailed 2D NMR spectroscopic analysis of three of the mixed peptides in water was performed, and the information thus extracted was used as restraints in a computational study on the peptides' conformational preference. An X-ray crystallographic study on the side chain-protected (Boc) 2a revealed the solid-state structure of this peptide. The results presented herein, together with previous literature data on beta(3)-amino acid residues, conclusively demonstrate the potential of beta-amino acids in the design of conformationally homogeneous cyclic peptides that are homologous to peptides with known applications in biomedicinal chemistry and as molecular receptors.
Norgren
Anna S
AS
Department of Biochemistry and Organic Chemistry, Uppsala University, Box 576, SE-75123 Uppsala, Sweden.
Büttner
Frank
F
Prabpai
Samran
S
Kongsaeree
Palangpon
P
Arvidsson
Per I
PI
D000596:Amino Acids / Q000737:chemistry*; D002625:Chemistry, Organic / Q000379:methods; D018360:Crystallography, X-Ray; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D018716:Molecular Mimicry; D010456:Peptides, Cyclic / Q000737:chemistry*; D011487:Protein Conformation; D013696:Temperature
D000596:Amino Acids; D010456:Peptides, Cyclic