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

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Date

2019-03-26

Author

Schroeder, David C.
Kracker, Oliver
Froehr, Tanja
Gora, Jerzy
Jewginski, Michal
Niess, Anke
Antes, Iris
Latajka, Rafal
Marıon, Antoıne
Sewald, Norbert

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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.

Subject Keywords

General Chemistry

URI

https://hdl.handle.net/11511/46870

Journal

FRONTIERS IN CHEMISTRY

DOI

https://doi.org/10.3389/fchem.2019.00155

Collections

Department of Chemistry, Article

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Citation Formats

D. C. Schroeder et al., “1,4-Disubstituted 1H-1,2,3-Triazole Containing Peptidotriazolamers: A New Class of Peptidomimetics With Interesting Foldamer Properties,” FRONTIERS IN CHEMISTRY, pp. 0–0, 2019, Accessed: 00, 2020. [Online]. Available: https://hdl.handle.net/11511/46870.