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

Gadais, Charlène and Van holsbeeck, Kevin and Moors, Samuel L. C. and Buyst, Dieter and Fehér, Krisztina (2019) Trifluoromethylated Proline Surrogates as Part of "Pro-Pro" Turn-Inducing Templates. CHEMBIOCHEM, 20 (19). pp. 2513-2518. ISSN 1439-4227 (print); 1439-7633 (online)

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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 beta-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 CF3 group can aid in conformational control. Herein, the impact of alpha-trifluoromethylated proline analogues is examined for the design of enhanced beta-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 beta-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 beta-turn-inducer criteria.

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