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Trifluoromethylated Proline Surrogates as Part of “Pro–Pro” Turn‐Inducing Templates
Author(s) -
Gadais Charlène,
Van holsbeeck Kevin,
Moors Samuel L. C.,
Buyst Dieter,
Fehér Krisztina,
Van Hecke Kristof,
Tourwé Dirk,
Brigaud Thierry,
Martin Charlotte,
De Proft Frank,
Pytkowicz Julien,
Martins José C.,
Chaume Grégory,
Ballet Steven
Publication year - 2019
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201900294
Subject(s) - chemistry , conformational isomerism , isomerization , dipeptide , turn (biochemistry) , peptidomimetic , stereochemistry , proline , amide , context (archaeology) , rational design , hydrogen bond , peptide bond , peptide , amino acid , catalysis , molecule , biochemistry , nanotechnology , organic chemistry , paleontology , materials science , biology
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‐O t Bu 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.