Synthesis and Circular Dichroism Spectroscopic Investigations of Oligomeric β-Peptoids with α-Chiral Side Chains

Norgren, Anna S.; Zhang, Suode; Arvidsson, Per I.

doi:10.1021/ol061717f

Cited by 46 publications

(42 citation statements)

References 29 publications

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“…Somewhat surprisingly, the intensity of the minimum near λ =220 nm decreased with an increasing chain length of the α‐aminoxy peptoids. This phenomenon might indicate that this signal is not caused by secondary structure formation but is related to the N ‐( S )‐1‐phenylethyl‐containing amide motif itself . To verify this hypothesis we synthesized an acetylated monomer containing the N ‐( S )‐1‐phenylethyl group (see the Supporting Information).…”

Section: Resultsmentioning

confidence: 96%

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α‐Aminoxy Peptoids: A Unique Peptoid Backbone with a Preference for cis‐Amide Bonds

Krieger

Ciglia

Thoma

et al. 2017

Chemistry A European J

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α-Peptoids, or N-substituted glycine oligomers, are an important class of peptidomimetic foldamers with proteolytic stability. Nevertheless, the presence of cis/trans-amide bond conformers, which contribute to the high flexibility of α-peptoids, is considered as a major drawback. A modified peptoid backbone with an improved control of the amide bond geometry could therefore help to overcome this limitation. Herein, we have performed the first thorough analysis of the folding propensities of α-aminoxy peptoids (or N-substituted 2-aminoxyacetic acid oligomers). To this end, the amide bond geometry and the conformational properties of a series of model α-aminoxy peptoids were investigated by using 1D and 2D NMR experiments, X-ray crystallography, natural bond orbital (NBO) analysis, circular dichroism (CD) spectroscopy, and molecular dynamics (MD) simulations revealing a unique preference for cis-amide bonds even in the absence of cis-directing side chains. The conformational analysis based on the MD simulations revealed that α-aminoxy peptoids can adopt helical conformations that can mimic the spatial arrangement of peptide side chains in a canonical α-helix. Given their ease of synthesis and conformational properties, α-aminoxy peptoids represent a new member of the peptoid family capable of controlling the amide isomerism while maintaining the potential for side-chain diversity.

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Section: Resultsmentioning

confidence: 96%

“…Similarly, it has been hypothesized that β‐peptoids ( N ‐alkyl β‐alanines) can exhibit foldamer properties . A recent study by Olsen and co‐workers provided a high‐resolution X‐ray crystal structure of a β‐peptoid hexamer containing strongly cis ‐inducing N ‐( S )‐1‐(1‐naphthyl)ethyl side chains.…”

Section: Introductionmentioning

confidence: 99%

α‐Aminoxy Peptoids: A Unique Peptoid Backbone with a Preference for cis‐Amide Bonds

Krieger

Ciglia

Thoma

et al. 2017

Chemistry A European J

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“…65 The CD spectra of the N-1-phenylethyl series (19−23), on the other hand, did not provide any new insight compared to previous studies. 20,21 To provide further support for the existence of helical folding in solution, molecular dynamics simulations were performed on hexamer 29 (Figure 9b). Starting from the fully folded helical conformation obtained by X-ray crystallography, these calculations showed a dynamic system accessing a range of conformations, which after a 1 μs simulation time adopted a conformation remarkably close to the initial structure ( Figure 9c).…”

Section: Accounts Of Chemical Researchmentioning

confidence: 99%

“…19 However, two following circular dichroism (CD) studies provided ambiguous conclusions regarding folding due to the lack of high-resolution structural data. 20,21 In response to the initial difficulties in achieving robustly folded conformers, we decided to pursue peptide/β-peptoid hybrids to include the hydrogen bonding capability of the α-amino acids as well as easy access to oligomers by dimer coupling on solid-phase. 22 Both antimicrobial, antiplasmodial, and cell-penetrating compounds were discovered using this backbone design.…”

Section: Introductionmentioning

confidence: 99%

β-Peptoid Foldamers at Last

2015

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For a long time, peptides were considered unsuitable for drug development due to their inherently poor pharmacokinetic properties and proteolytic susceptibility. However, this paradigm has changed significantly in the past decade with the approval of numerous antibodies and proteins as drugs. In parallel, research in the field of synthetic molecules that are able to mimic or complement folding patterns exhibited by biopolymers, but are not recognized by proteases, have received considerable attention as well. Such entities were coined "foldamers" by Professor Gellman in an Account published in this journal in the late 1990s. Oligomers of N-alkylated 3-aminopropionic acid residues have been called β-peptoids due to their structural similarity to β-peptides and peptoids (N-alkylglycines), respectively. Because bona fide foldamer behavior has been demonstrated for both parent architectures, we wondered if the β-peptoids could serve as a successful addition to the known ensemble of peptidomimetic foldamers. When we entered this field, only the seminal description of libraries of β-peptoid dimers and trimers by Hamper et al. had been published a number of years earlier [ J. Org. Chem. 1998 , 63 , 708 ]. Perhaps somewhat naïvely in retrospect, we envisioned that elongation of chain length combined with introduction of bulky α-chiral side chains would deliver folded structures as reported for the α-peptoid counterparts. Initially, we, and others, were unsucessful in obtaining stable secondary structures of β-peptoid oligomers, and instead, these residues were either incorporated in cyclic structures or in combination with other types of residues to give peptidomimetic constructs with heterogeneous backbones. Amphiphilic architectures with various membrane-targeting activities, such as mimics of antimicrobial peptides or cell-penetrating peptides, have thus been particularly successful. Introduction of β-peptoid residues in histone deacetylase inhibitors mimicking nonribosomal cyclotetrapeptides have also been reported. In the present Account, we will sketch the scientific journey that ultimately delivered robustly folded β-peptoid oligomers. Contributions involving biological evaluation of peptidomimetic constructs containing β-peptoid residues, as mentioned above, which were investigated leading up to these recently reported high-resolution helical structures, will thus be discussed. On the basis of the work described in this Account, we envision that β-peptoids will find future utility as peptidomimetics for biomedical investigation containing both heterogeneous and homogeneous backbones. The recent demonstration of control over the secondary structure of a homogeneous β-peptoid backbone now enables structure-based design of scaffolds with predictable display of desired functionalities in three dimensions.

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“…An alternative approach, in which Fmoc‐protected pre‐formed building blocks were used (the monomer approach) caused an insignificant improvement in the yields . More acceptable productivity was afforded by Norgren et al who synthesized β‐peptoids composed of up to 11 residues using TentaGel® resin and a solvent mixture combining water and tetrahydrofuran (2:8, vol/vol) instead of DMSO . The building block approach was applied by Shuey et al to prepare long, up to 18 residues, oligomers .…”

Section: Resultsmentioning

confidence: 99%

Hybrid analogues of SFTI‐1 modified in P₁ position by β‐ and γ‐amino acids and N‐substituted β‐alanines

Dębowski

Łukajtis²,

Filipowicz³

et al. 2013

Biopolymers

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A series of compounds containing either non-proteinogenic β-/γ-amino acids or N-substituted β-alanine residues (β-peptoid units) in P1 specificity position were synthesized based on the structure of sunflower trypsin inhibitor 1 (SFTI-1). The compounds were synthesized on a solid support; the N-substituted β-alanines (βNhlys and βNhphe) were introduced into a peptidomimetic chain via a two-step approach using acryloyl chloride and an appropriate primary amine. The inhibitory activities were characterized in vitro against bovine α-chymotrypsin or bovine β-trypsin. Three analogues displayed activity comparable to fully proteinogenic counterparts-monocyclic SFTI-1 and [Phe(5)]SFTI-1. Moreover, all active peptidomimetics were resistant toward proteolytic degradation, even after 24-h incubation at room temperature.

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Synthesis and Circular Dichroism Spectroscopic Investigations of Oligomeric β-Peptoids with α-Chiral Side Chains

Cited by 46 publications

References 29 publications

α‐Aminoxy Peptoids: A Unique Peptoid Backbone with a Preference for cis‐Amide Bonds

α‐Aminoxy Peptoids: A Unique Peptoid Backbone with a Preference for cis‐Amide Bonds

β-Peptoid Foldamers at Last

Hybrid analogues of SFTI‐1 modified in P₁ position by β‐ and γ‐amino acids and N‐substituted β‐alanines

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Synthesis and Circular Dichroism Spectroscopic Investigations of Oligomeric β-Peptoids with α-Chiral Side Chains

Cited by 46 publications

References 29 publications

α‐Aminoxy Peptoids: A Unique Peptoid Backbone with a Preference for cis‐Amide Bonds

α‐Aminoxy Peptoids: A Unique Peptoid Backbone with a Preference for cis‐Amide Bonds

β-Peptoid Foldamers at Last

Hybrid analogues of SFTI‐1 modified in P1 position by β‐ and γ‐amino acids and N‐substituted β‐alanines

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Hybrid analogues of SFTI‐1 modified in P₁ position by β‐ and γ‐amino acids and N‐substituted β‐alanines