Evaluation of stereochemically dense morpholine-based scaffolds as proline surrogates in β-turn peptides

Abstract

Four peptides differing for the structure of the new morpholine-based heterocyclic compound acting as a turn inducer were synthesized in solution phase, and the conformational preferences were assessed by means of NMR analysis. All spectroscopic data revealed an adaptive behaviour of the turn peptides in generating turn conformations stabilized by intramolecular hydrogen-bonds, despite the conformational changes of the turn inducer. Thus, this study suggests the possibility of functionalizing morpholine-containing beta-turn peptides with no significant loss of the secondary framework. The 3,4-dihydro-2H-[1,4]oxazine-containing peptide showed a more compact structure stabilized by an additional gamma-turn-forming hydrogen-bond experienced by the Gly amide proton.

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

“…In addition, upon going from CDCl 3 to [D 6 ]DMSO, the amide NH chemical shift is only moderately influenced for the tt conformers of 24 and ( R , R,S )‐ 23 b , which supports the solvent‐shielding of their amide protons, and thereby the possibility of forming an intramolecular hydrogen bond. This solvent‐shielding effect was also observed for the tt conformer of ( R , R,S )‐ 23 b upon performing a titration of [D 6 ]DMSO to CDCl 3 , which showed only a small downfield shift (0.03 ppm; see the Supporting Information) . The ability of the tt conformers of 24 and ( R , R,S )‐ 23 b to form a hydrogen bond is further supported by their temperature coefficients, as determined in [D 6 ]DMSO, which show a significantly higher value than those of the other conformers .…”

“…Various pseudopeptidic motifs were reported, such as morpholines I and diketopiperazines II (Figure ), but pioneering work in the field by the group of Robinson undoubtedly highlighted the use of heterochiral ( R )‐Pro–( S )‐Pro dipeptide III as one of the most convenient turn inducers . Of course, proline is known to give way to amide bond cis–trans isomerization, as illustrated by NMR spectroscopy analysis of multiple conformational states involving the ( R )‐Pro–( S )‐Pro motif, and a reduced conformational stability of designed β‐hairpin mimetics can be observed.…”

Trifluoromethylated proline surrogates as part of ‘Pro-Pro’ turn-inducingtemplates for the design of b -hairpin mimetics

“…This solvent-shielding effect was also observed fort he tt conformer of (R,R,S)-23 b upon performing at itration of [D 6 ]DMSO to CDCl 3 ,w hich showed only as mall downfield shift (0.03 ppm;s ee the Supporting Information). [7] The ability of the tt conformers of 24 and (R,R,S)-23 b to form ah ydrogen bond is further supported by their temperature coefficients, as determined in [D 6 ]DMSO, which showasignificantly higher value than those of the other conformers. [23] Altogether these data show that (R,R,S)-23 b only populates a trans-amide bond Figure 5).…”

“…Macrocyclization appeared rapidly as ap owerful strategy through the successful mimicry of b-hairpins, [5] which was achieved by grafting epitope sequences onto as emirigid turn-inducing template. [6] Various pseudopeptidicm otifs were reported, such as morpholines I [7] and diketopiperazines II (Figure 1), [8] but pioneering work in the field by the group of Robinson undoubtedly highlighted the use of heterochiral (R)-Pro-(S)-Pro dipeptide III as one of the most convenient turn inducers. [9,10] Of course, proline is known to give way to amide bond cis-trans isomerization, [11] as illustrated by NMR spectroscopy analysis of multiple conformational states involving the (R)-Pro-(S)-Pro motif, [12,13] and ar educed conformational stabilityo fd esigned b-hairpin mimetics can be observed.…”

From glucose to enantiopure morpholino β-amino acid: a new tool for stabilizing γ-turns in peptides

“…7 The importance of non-natural amino acids able to induce this motif emerged from the recent literature. [8][9][10][11] In our research group, we actively work on the development of new non-coded amino acids. [12][13][14][15] Some of them were recently used to prepare peptides characterized by defined secondary conformations as well as by different interesting applications.…”