Trifluoromethylated Proline Surrogates as Part of “Pro–Pro” Turn‐Inducing Templates

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 CF3 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.

Design of Pseudodiproline Dimers as Mimetics of Pro-Pro Units: Stereocontrolled Synthesis, Configurational Relevance, and Structural Properties

“…Of interest is a study by Lim which demonstrated that the proline residue in proline-rich sequences of peptides binding to SRC homology 3 (SH3) domain and rsp5-domain (WW) could be exchanged for an unnatural N-substituted amino acid, showing that the proline residue is most likely the main recognition feature in PRD binding grooves . Mimicking a Pro-X motif also proved useful toward the development of prolyl oligopeptidase (POP) inhibitors as well as to induce specific secondary structures. − …”

Divergent, C–C Bond Forming Macrocyclizations Using Modular Sulfonylhydrazone and Derived Substrates

“…The model substrate 9 was designed to test this hypothesis (Scheme ) and was constructed from building blocks that were envisioned to template macrocyclization by enforcing proximity of the reactive groups . A meta- formylbenzoic acid derived hydrazone and a gem - di -methylated terminal alkyne were used for the A-block and C-block fragments, respectively, flanking a gabapentin B-block which was envisioned to enforce a GABA-type turn .…”

Analyzing a sport for development program’s logic model by using key actors’ perceptions: The case of Pour 3 Points organization in Montreal

“…The complexity of most SFD contexts require the development of operative research method for direct data extraction [ 28 , 29 ]. Second, should the research be used to support/reinforce the field practices or criticize and question actions and achievements [ 30 ]? Ridde and Dagenais [ 31 ] recommended engaging practitioners in a collaborative research, also identified by some SFD researchers to address contextual challenges [ 25 – 27 , 32 ].…”