Oligo(N-aryl glycines): A New Twist on Structured Peptoids

Abstract

We explore strategies to enhance conformational ordering of N-substituted glycine peptoid oligomers. Peptoids bearing bulky N-alkyl side chains have previously been studied as important examples of biomimetic "foldamer" compounds, as they exhibit a capacity to populate helical structures featuring repeating cis-amide bonds. Substantial cis/trans amide bond isomerization, however, gives rise to conformational heterogeneity. Here, we report the use of N-aryl side chains as a tool to enforce the presence of trans-amide bonds, thereby engendering structural stability. Aniline derivatives and bromoacetic acid are used in the facile solid-phase synthesis of a diverse family of sequence-specific N-aryl glycine oligomers. Quantum mechanics calculations yield a detailed energy profile of the folding landscape and substantiate the hypothesis that the presence of anilide groups establishes a strong energetic preference for trans-amide bonds. X-ray crystallographic analysis and solution NMR studies verify this preference. Molecular modeling indicates that the linear oligomers can adopt helical structures resembling a polyproline type II helix. High resolution structures of macrocyclic oligomers incorporating both N-alkyl and N-aryl glycine units confirm the ability to direct the presence of trans-amide bonds specifically at N-aryl positions. These results are an important step in developing strategies for the rational de novo design of new structural motifs in biomimetic oligopeptoid systems.

Cis–Trans Amide Bond Rotamers in β-Peptoids and Peptoids: Evaluation of Stereoelectronic Effects in Backbone and Side Chains

“…Finally, the thioamide analog 15, like β-peptoid 12e, exhibited higher K cis/trans values than its oxoamide analog (13) in polar solvents, and a significant decrease in the cisamide fraction in CDCl 3 (Chart 1). This again indicates that there is an interaction between the sulfur and the aromatic residue, which results in favoring of the cis-amide conformation.…”

“…9,29 Finally, peptoid studies have also shown that direct attachment of a phenyl group to the nitrogen atom (i.e., prepared from aniline subunits) leads to a very strong preference for trans-amides. 13 A single β-peptoid model system of this type (5h) was evaluated and exhibited the expected selectivity, by virtually giving rise to single sets of signals in all tested solvents when analyzed by 1 H NMR. As mentioned, we also evaluated the entire series of side chains a−h in model systems having C-terminal amides (6a−6h) instead of esters, to mimic the environment of a β-peptoid residue within an oligomer more appropriately.…”

Peptidic modulators of protein‐protein interactions: Progress and challenges in computational design

“…17 It has become clear that proteinpeptide interactions are very abundant in the cell and estimates suggest they represent 15-40% of all interactions, 18 making peptide discovery and development of wide applicability and interest. Cyclic peptides [19][20][21][22] and other modified peptides 23,24 can be highly potent as well as selective, providing a compromise between structural preorganization and sufficient flexibility to mold to a target surface and maximize binding interactions. There is much evidence that despite having molecular masses well above Lipinski's rule constraints, cyclic peptides and other macrocycles can possess drug-like physicochemical and pharmacokinetic properties such as good solubility, lipophilicity, metabolic stability and bioavailability.…”

De novo structure prediction and experimental characterization of folded peptoid oligomers

“…For the N-aryl peptoid, local structure is controlled by incorporation of side chain groups that restrict the possible backbone conformational states through both steric and electronic effects. N-aryl side chains restrict the amide backbone nearly exclusively to the trans state (19) and the bulky iodo-and tert-butyl-substituents lead to additional biasing of the φ torsion (30). Unbranched N-alkyl side chains provide fewer local restrictions to the peptoid backbone (31), but can contribute to long-range interactions that can direct chain folding (12).…”

“…Such helices have been used to form tertiary assemblies (11, 16), and have been incorporated into enzymes with minimal loss of function (17). Alternatively, peptoid N-aryl side chains have been used to induce trans-amide helices that can mimic polyproline II structure (18,19). It remains to be determined how these local rules can be used to control the global three-dimensional structure of peptoid macromolecules (20).…”