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

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journal contribution
posted on 07.03.2008, 00:00 by José Luis Baeza, Guillermo Gerona-Navarro, Jesús Pérez de Vega, M. Teresa García-López, Rosario González-Muñiz, Mercedes Martín-Martínez
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.