Trifluoromethylated Proline Surrogates as Part of "Pro-Pro" Turn-Inducing Templates

Charlene Gadais, Kevin Van holsbeeck, Samuel L. C. Moors, Dieter Buyst, Krisztina Feher, Kristof Van Hecke, Dirk Tourwe, Thierry Brigaud, Charlotte Martin, Frank De Proft, Julien Pytkowicz, Jose C. Martins, Gregory Chaume, Steven Ballet

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

Proline is often found as a turn inducer in peptide or protein domains. Exploitation of its restricted conformational freedom led to the development of the d-Pro-l-Pro (corresponding to (R)-Pro–(S)-Pro) segment as a “templating” unit, frequently used in the design of β-hairpin peptidomimetics, in which conformational stability is, however, inherently linked to the cis–trans isomerization of the prolyl amide bonds. In this context, the stereoelectronic properties of the CF 3 group can aid in conformational control. Herein, the impact of α-trifluoromethylated proline analogues is examined for the design of enhanced β-turn inducers. A theoretical conformational study permitted the dipeptide (R)-Pro–(R)-TfmOxa (TfmOxa: 2-trifluoromethyloxazolidine-2-carboxylic acid) to be selected as a template with an increased trans–cis rotational energy barrier. NMR spectroscopic analysis of the Ac-(R)-Pro–(R)-TfmOxa–(S)-Val-OtBu β-turn model, obtained through an original synthetic pathway, validated the prevalence of a major trans–trans conformer and indicated the presence of an internal hydrogen bond. Altogether, it was shown that the (R)-Pro–(R)-TfmOxa template fulfilled all crucial β-turn-inducer criteria.

Original languageEnglish
Pages (from-to)2513-2518
Number of pages6
JournalChemBioChem
Volume20
Issue number19
DOIs
Publication statusPublished - May 2019

Keywords

  • backbone constraints
  • beta-turn inducers
  • isomerization
  • NMR spectroscopy
  • peptidomimetics

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