Abstract
Peptidotriazolamers are hybrid foldamers with features of peptides and triazolamers, containing alternation of amide bonds and 1,4-disubstituted 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 α-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-Ψ[4Tz]Phe-LeuΨ[4Tz]Phe-LeuΨ[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-(AlaΨ[4Tz]Ala)6-OAll as well as Boc-Ala-(d-AlaΨ[4Tz]Ala)6-OAll and Boc-Ala-(GlyΨ[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.
Highlights
Inspired by the Arora triazolamers, we embarked on a project directed toward the synthesis and characterization of peptidotriazole foldamers, where both components, the propargylamine and the α-azido carboxylic acids are chiral
There are two strategies for the synthesis of peptidotriazole foldamers: the building block approach (Figure 5), where the triazole is formed from the propargylamine and the azide by CuAAC and coupled by amide bond formation, and the submonomer approach (Figure 5), where first
We present a new class of peptidomimetics containing 1,4-disubstituted 1H-1,2,3-triazoles and amide bonds in an alternating fashion
Summary
Since the discovery of the CuI catalyzed azide-alkyne cycloaddition (CuAAC) by the groups of Meldal (Tornøe et al, 2002) and Sharpless (Rostovtsev et al, 2002), this so-called “click”-reaction proved to be suitable for a broad number of applications in bioorganic and pharmaceutical chemistry (Kolb and Sharpless, 2003; Bock et al, 2006a; 1,4-Disubstituted 1H-1,2,3-Triazole Containing PeptidotriazolamersAngell and Burgess, 2007; Gil et al, 2007; Moses and Moorhouse, 2007; Hein et al, 2008; Tron et al, 2008; Nwe and Brechbiel, 2009) The CuAAC is compatible with most functional groups present in biomolecules and the 1,4-disubstituted 1H-1,2,3triazole obtained as reaction product is metabolically inert (Kolb and Sharpless, 2003). Clustering based on the backbone RMSD of the oligomers for the second half of the simulations in DMSO and in water resulted in the following populations for the main structural clusters: 94 and 52% for the homochiral molecule in DMSO and in water, respectively, 71 and 59% for the heterochiral, and 60 and 76% for the homochiral∗ compound.
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