1,4-Disubstituted 1H-1,2,3-Triazole Containing Peptidotriazolamers: A New Class of Peptidomimetics With Interesting Foldamer Properties
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-disubstitu...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-03-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fchem.2019.00155/full |
| _version_ | 1818176390099369984 |
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| author | David C. Schröder Oliver Kracker Tanja Fröhr Jerzy Góra Jerzy Góra Michał Jewginski Anke Nieß Iris Antes Rafał Latajka Antoine Marion Antoine Marion Norbert Sewald |
| author_facet | David C. Schröder Oliver Kracker Tanja Fröhr Jerzy Góra Jerzy Góra Michał Jewginski Anke Nieß Iris Antes Rafał Latajka Antoine Marion Antoine Marion Norbert Sewald |
| author_sort | David C. Schröder |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T20:15:25Z |
| format | Article |
| id | doaj.art-a05e243d3c2b4cdbba7001c557bdf08a |
| institution | Directory Open Access Journal |
| issn | 2296-2646 |
| language | English |
| last_indexed | 2024-12-11T20:15:25Z |
| publishDate | 2019-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Chemistry |
| spelling | doaj.art-a05e243d3c2b4cdbba7001c557bdf08a2022-12-22T00:52:13ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462019-03-01710.3389/fchem.2019.001554401441,4-Disubstituted 1H-1,2,3-Triazole Containing Peptidotriazolamers: A New Class of Peptidomimetics With Interesting Foldamer PropertiesDavid C. Schröder0Oliver Kracker1Tanja Fröhr2Jerzy Góra3Jerzy Góra4Michał Jewginski5Anke Nieß6Iris Antes7Rafał Latajka8Antoine Marion9Antoine Marion10Norbert Sewald11Organic and Bioorganic Chemistry, Department of Chemistry, Bielefeld University, Bielefeld, GermanyOrganic and Bioorganic Chemistry, Department of Chemistry, Bielefeld University, Bielefeld, GermanyOrganic and Bioorganic Chemistry, Department of Chemistry, Bielefeld University, Bielefeld, GermanyOrganic and Bioorganic Chemistry, Department of Chemistry, Bielefeld University, Bielefeld, GermanyDepartment of Bioorganic Chemistry, Wrocław University of Science and Technology, Wrocław, PolandDepartment of Bioorganic Chemistry, Wrocław University of Science and Technology, Wrocław, PolandOrganic and Bioorganic Chemistry, Department of Chemistry, Bielefeld University, Bielefeld, GermanyCenter for Integrated Protein Science, TUM School of Life Sciences, TU Munich, Freising, GermanyDepartment of Bioorganic Chemistry, Wrocław University of Science and Technology, Wrocław, PolandCenter for Integrated Protein Science, TUM School of Life Sciences, TU Munich, Freising, GermanyDepartment of Chemistry, Middle East Technical University, Ankara, TurkeyOrganic and Bioorganic Chemistry, Department of Chemistry, Bielefeld University, Bielefeld, GermanyPeptidotriazolamers 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.https://www.frontiersin.org/article/10.3389/fchem.2019.00155/fullpeptidotriazolamers14-disubstituted 1H-123-triazolepeptide bond isoster |
| spellingShingle | David C. Schröder Oliver Kracker Tanja Fröhr Jerzy Góra Jerzy Góra Michał Jewginski Anke Nieß Iris Antes Rafał Latajka Antoine Marion Antoine Marion Norbert Sewald 1,4-Disubstituted 1H-1,2,3-Triazole Containing Peptidotriazolamers: A New Class of Peptidomimetics With Interesting Foldamer Properties Frontiers in Chemistry peptidotriazolamers 1 4-disubstituted 1H-1 2 3-triazole peptide bond isoster |
| title | 1,4-Disubstituted 1H-1,2,3-Triazole Containing Peptidotriazolamers: A New Class of Peptidomimetics With Interesting Foldamer Properties |
| title_full | 1,4-Disubstituted 1H-1,2,3-Triazole Containing Peptidotriazolamers: A New Class of Peptidomimetics With Interesting Foldamer Properties |
| title_fullStr | 1,4-Disubstituted 1H-1,2,3-Triazole Containing Peptidotriazolamers: A New Class of Peptidomimetics With Interesting Foldamer Properties |
| title_full_unstemmed | 1,4-Disubstituted 1H-1,2,3-Triazole Containing Peptidotriazolamers: A New Class of Peptidomimetics With Interesting Foldamer Properties |
| title_short | 1,4-Disubstituted 1H-1,2,3-Triazole Containing Peptidotriazolamers: A New Class of Peptidomimetics With Interesting Foldamer Properties |
| title_sort | 1 4 disubstituted 1h 1 2 3 triazole containing peptidotriazolamers a new class of peptidomimetics with interesting foldamer properties |
| topic | peptidotriazolamers 1 4-disubstituted 1H-1 2 3-triazole peptide bond isoster |
| url | https://www.frontiersin.org/article/10.3389/fchem.2019.00155/full |
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