Schröder David C, Kracker Oliver, Fröhr Tanja, Góra Jerzy, Jewginski Michał, Nieß Anke, Antes Iris, Latajka Rafał, Marion Antoine, Sewald Norbert
Organic and Bioorganic Chemistry, Department of Chemistry, Bielefeld University, Bielefeld, Germany.
Department of Bioorganic Chemistry, Wrocław University of Science and Technology, Wrocław, Poland.
Front Chem. 2019 Mar 26;7:155. doi: 10.3389/fchem.2019.00155. eCollection 2019.
Peptidotriazolamers are hybrid foldamers with features of peptides and triazolamers, containing alternation of amide bonds and 1,4-disubstituted 1-1,2,3-triazoles with conservation of the amino acid side chains. We report on the synthesis of a new class of peptidomimetics, containing 1,4-disubstituted 1-1,2,3-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)-OAll as well as Boc-Ala-(d-AlaΨ[4Tz]Ala)-OAll and Boc-Ala-(GlyΨ[4Tz]Ala)-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.
肽基三唑聚合物是具有肽和三唑聚合物特征的杂合折叠体，含有酰胺键和1,4 - 二取代的1,2,3 - 三唑的交替排列，并保留氨基酸侧链。我们报道了一类新型拟肽的合成，这类拟肽含有与酰胺键交替排列的1,4 - 二取代的1,2,3 - 三唑，并阐明了它们在溶液中的构象性质。基于在炔丙基位置带有立体中心的对映体纯炔丙胺和α - 叠氮基酯，通过铜催化的叠氮 - 炔环加成反应获得了构建模块。利用这些构建模块，通过溶液相合成很容易得到肽基三唑聚合物。合成了一组同手性和异手性的四聚体、六聚体和七聚体，七聚体Boc - Ala - Val - Ψ[4Tz]Phe - LeuΨ[4Tz]Phe - LeuΨ[4Tz]Val - OAll以及一个异手性和一个含甘氨酸的类似物通过基于核磁共振的分子动力学模拟进行了结构表征，使用专门定制的力场来确定它们的构象和溶剂化性质。所有这三种变体在二甲基亚砜和水中都采用紧凑的折叠构象。除了七聚体，我们还预测了类似的更长寡聚物的构象行为，即Boc - Ala - (AlaΨ[4Tz]Ala) - OAll以及Boc - Ala - (d - AlaΨ[4Tz]Ala) - OAll和Boc - Ala - (GlyΨ[4Tz]Ala) - OAll。我们的计算预测前两个分子在二甲基亚砜中有清晰的二级结构，但由于侧链的疏水性，在水中会坍塌。同手性化合物折叠成规则的螺旋结构，异手性化合物呈现扭曲的“S”形，而含甘氨酸的变体没有清晰的二级结构。
