12/10-Helix in Mixed beta-Peptides Alternating Bicyclic and Acyclic beta-Amino Acids: Probing the Relationship between Bicyclic Side Chain and Helix Stability

Simon, Matthieu; Milbeo, Pierre; Liu, Hongtao; Andre, Christophe; Wenger, Emmanuel; Martinez, Jean; Amblard, Muriel; Aubert, Emmanuel; Legrand, Baptiste; Calmes, Monique

English Scientific Article (Journal Article)
Published: CHEMISTRY-A EUROPEAN JOURNAL 0947-6539 1521-3765 24 (70) pp. 18795-18800 2018
  • SJR Scopus - Chemistry (miscellaneous): D1
    12/10-Helices constitute suitable templates that can be used to design original structures. Nevertheless, they often suffer from a weak stability in polar solvents because they exhibit a mixed hydrogen-bond network resulting in a small macrodipole. In this work, stable and functionalizable 12/10-helices were developed by alternating a highly constrained beta(2, 3, 3)-trisubstituted bicyclic amino acid (S)-1-aminobicyclo[2.2.2]octane-2-carboxylic acid ((S)-ABOC) and an acyclic substituted beta-homologated proteinogenic amino acid (l-beta(3)-hAA). Based on NMR spectroscopic analysis, it was shown that such mixed beta-peptides display well-defined right-handed 12/10-helices in polar, apolar, and chaotropic solvents; that are, CD3OH, CDCl3, and [D-6]DMSO, respectively. The stability of the hydrogen bonds forming the C-10 and C-12 pseudocycles as well as the benefit provided by the use of the constrained bicyclic ABOC versus typical acyclic beta-amino acids sequences when designing 12/10-helix were investigated using NH/ND NMR exchange experiments and DFT calculations in various solvents. These studies showed that the beta(3)-hAA/(S)-ABOC helix displayed a more stable hydrogen-bond network through specific stabilization of the C-10 pseudocycles involving the bridgehead NH of the ABOC bicyclic scaffold.
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    2021-03-01 17:15