Hide/Show Apps

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

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