Azetidine-Derived Amino Acids versus Proline Derivatives. Alternative Trends in Reverse Turn Induction

• Published in: Journal of organic chemistry Vol. 73; no. 5; pp. 1704 - 1715
• Main Authors: Baeza, José Luis, Gerona-Navarro, Guillermo, Pérez de Vega, Jesús, García-López, M. Teresa, González-Muñiz, Rosario, Martín-Martínez, Mercedes
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 07.03.2008; Amer Chemical Soc
• Subjects: Amino Acids - chemical synthesis; Amino Acids - chemistry; Azetidines - chemistry; Chemistry; Chemistry, Organic; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Magnetic Resonance Spectroscopy; Mass Spectrometry; Models, Molecular; Organic chemistry; Peptides; Physical Sciences; Preparations and properties; Proline - chemistry; Science & Technology; DIPEPTIDES; BETA-TURNS; SEQUENCES; PEPTIDE CONFORMATIONS; PROTEIN-PROTEIN INTERACTIONS; GAMMA-TURNS; AROMATIC RINGS; RESIDUE; MODEL PEPTIDES; PREDICTION; Molecular rigidity; Ring size; Five membered ring; Fourier transformation; Four membered ring; Peptides; Molecular structure; Nitrogen heterocycle; NMR spectrometry; β-Structure; Hydrogen 1; Infrared spectrometry; Three dimensional structure; Tetrapeptide; Aminoacid; Analog; Azetidine derivatives; Force field method; Carboxylate; Conformation
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo701746w

The influence of 2-alkyl-2-carboxyazetidines (Aze) on the 3D structure of model tetrapeptides R2CO-2-R1Aze-l-Ala-NHMe has been analyzed by molecular modeling, 1H NMR, and FT-IR studies. The conformational constraints introduced by the four-membered ring resulted in an effective way to stabilize γ-turn-like conformations in these short peptides. The conformational preferences of these Aze-containing peptides have been compared to those of the corresponding peptide analogues containing Pro or α-MePro in the place of 2-alkyl-Aze residue. In the model studied, both Pro and Aze derivatives are able to induce reverse turns, but the nature of the turn is different as a function of the ring size. While the five-membered ring of Pro tends to induce β-turns, as previously suggested by different authors, the four-membered ring of Aze residues forces the peptide to preferentially adopt γ-turn conformations. In both cases, the presence of an alkyl group at the α-position of Pro or the azetidine-2-carboxylate ring enhances significantly the turn-inducing ability. These results might open the opportunity of using 2-alkyl-Aze residues as versatile tools in defining the role of γ-turn structures within the bioactive conformation of selected peptides, and represent an alternative to Pro derivatives as turn inducers.