1,4-Disubstituted 1H-1,2,3-Triazole Containing Peptidotriazolamers: A New Class of Peptidomimetics With Interesting Foldamer Properties


Schroeder D. C. , Kracker O., Froehr T., Gora J., Jewginski M., Niess A., ...More

FRONTIERS IN CHEMISTRY, vol.7, 2019 (Peer-Reviewed Journal) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 7
  • Publication Date: 2019
  • Doi Number: 10.3389/fchem.2019.00155
  • Journal Name: FRONTIERS IN CHEMISTRY
  • Journal Indexes: Science Citation Index Expanded, Scopus
  • Keywords: peptidotriazolamers, 1, 4-disubstituted 1H-1, 2, 3-triazole, peptide bond isoster, foldamer, molecular dynamic simulations, SOLID-PHASE SYNTHESIS, CLICK CHEMISTRY, BIOLOGICAL EVALUATION, GROWING APPLICATIONS, CYCLOADDITION, AZIDE, 1,2,3-TRIAZOLE, ANALOGS, DESIGN, PARAMETRIZATION

Abstract

Peptidotriazolamers are hybrid foldamers with features of peptides and triazolamers, containing alternation of amide bonds and 1,4-dlsubstltuted 1H-1,2,3-triazoles with conservation of the amino acid side chains. We report on the synthesis of a new class of peptidomimetics, containing 1,4-disubstituted 1H-1,2,3-triazoles in alternation with amide bonds and the elucidation of their conformational properties in solution. Based on enantiomerically pure propargylamines bearing the stereogenic center in the propargylic position and a-azido esters, building blocks were obtained by copper-catalyzed azide-alkyne cycloaddition. With these building blocks the peptidotriazolamers were readily available by solution phase synthesis. A panel of homo- and heterochiral tetramers, hexamers, and heptamers was synthesized and the heptamer Boc-Ala-Val-Psi[4Tz]Phe-Leu Psi[4Tz]Phe-Leu Psi[4Tz]Val-OAll as well as an heterochiral and a Gly-containing equivalent were structurally characterized by NMR-based molecular dynamics simulations using a specifically tailored force field to determine their conformational and solvation properties. All three variants adopt a compact folded conformation in DMSO as well as in water. In addition to the heptamers we predicted the conformational behavior of similar longer oligomers i.e., Boc-Ala-(Ala Psi[4Tz]Ala)(6)-OAll as well as Boc-Ala-(D-Ala Psi[4Tz]Ala)(6)-OAll and Boc-Ala-(Gly Psi[4Tz]Ala)(6)-OAll. Our calculations predict a clear secondary structure of the first two molecules in DMSO that collapses in water due to the hydrophobic character of the side chains. The homochiral compound folds into a regular helical structure and the heterochiral one shows a twisted "S"-shape, while the Gly variant exhibits no clear secondary structure.