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J Org Chem. 2013 Nov 15;78(22):11172-83. doi: 10.1021/jo4014113. Epub 2013 Nov 4.

"Bridged" n→π* interactions can stabilize peptoid helices.

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  • 1Department of Chemistry, Bowdoin College , 6600 College Station, Brunswick, Maine 04011-8466, United States.


Peptoids are an increasingly important class of peptidomimetic foldamers comprised of N-alkylglycine units that have been successfully developed as antimicrobial agents, lung surfactant replacements, enzyme inhibitors, and catalysts, among many other applications. Since peptoid secondary structures can be crucial to their desired functions, significant efforts have been devoted to developing means of modularly controlling peptoid backbone amide cis-trans isomerism using side chains. Strategic engineering of interactions between side chain aromatic rings and backbone cis-amides (n→π*(Ar) interactions) is an attractive strategy for stabilizing helical structures in N-a-chiral aromatic peptoids, which are among the most utilized classes of structured peptoids. Herein, we report the first detailed computational and experimental study of n→π*(Ar) interactions in models of peptoids containing backbone thioamides, which we term "thiopeptoids". Our work has revealed that these interactions significantly affect amide rotamerism in both peptoid and thiopeptoid models via a newly characterized "bridged" mode of interaction mediated by the N-α-C-H σ orbitals. Overall, this work elucidates new strategies for controlling both peptoid and thiopeptoid folding and suggests that thiopeptoids will be highly structured and therefore potentially useful as therapeutics, biological probes, and nanostructural engineering elements.

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