The Click Triazolium Peptoid Side Chain: A Strong <i>cis</i>-Amide Inducer Enabling Chemical Diversity

Caumes, Cécile; Roy, Olivier; Faure, Sophie; Taillefumier, Claude

doi:10.1021/ja302342h

Cited by 115 publications

(125 citation statements)

References 31 publications

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“…Compound 2 was included due to its strongly trans ‐amide bond‐inducing phenyl side chain . The α‐aminoxy peptoid 6 served as a cis ‐promoting model compound due to the cis ‐directing triazolium side chain . The model peptoid 7 containing a tert ‐butyl ester was incorporated to analyze an alternative C‐terminal cap group.…”

Section: Resultsmentioning

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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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: 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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“…72 Similarly, Huisgen azide–alkyne 1,3-dipolar cycloaddition can be used to construct an electron-deficient triazolium ring, which is a potent n →π* acceptor that enforces a cis conformation upon the tertiary amide of a peptoid. 73 This tack is complementary to tuning the ability of a carbonyl group to be an n →π* donor, which can be either enhanced with a thioamide (vide supra) 12−14,28,74−76 or selenoamide 77 or attenuated with electron-withdrawing groups. 74,78 …”

Section: Contributions To Other Polymersmentioning

confidence: 99%

The n→π* Interaction

2017

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ConspectusThe carbonyl group holds a prominent position in chemistry and biology not only because it allows diverse transformations but also because it supports key intermolecular interactions, including hydrogen bonding. More recently, carbonyl groups have been found to interact with a variety of nucleophiles, including other carbonyl groups, in what we have termed an n→π* interaction. In an n→π* interaction, a nucleophile donates lone-pair (n) electron density into the empty π* orbital of a nearby carbonyl group. Mixing of these orbitals releases energy, resulting in an attractive interaction. Hints of such interactions were evident in small-molecule crystal structures as early as the 1970s, but not until 2001 was the role of such interactions articulated clearly.These non-covalent interactions were first discovered during investigations into the thermostability of the proline-rich protein collagen, which achieves a robust structure despite a relatively low potential for hydrogen bonding. It was found that by modulating the distance between two carbonyl groups in the peptide backbone, one could alter the conformational preferences of a peptide bond to proline. Specifically, only the trans conformation of a peptide bond to proline allows for an attractive interaction with an adjacent carbonyl group, so when one increases the proximity of the two carbonyl groups, one enhances their interaction and promotes the trans conformation of the peptide bond, which increases the thermostability of collagen.More recently, attention has been paid to the nature of these interactions. Some have argued that rather than resulting from electron donation, carbonyl interactions are a particular example of dipolar interactions that are well-approximated by classical mechanics. However, experimental evidence has demonstrated otherwise. Numerous examples now exist where an increase in the dipole moment of a carbonyl group decreases the strength of its interactions with other carbonyl groups, demonstrating unequivocally that a dipolar mechanism is insufficient to describe these interactions. Rather, these interactions have important quantum-mechanical character that can be evaluated through careful experimental analysis and judicious use of computation.Although individual n→π* interactions are relatively weak (∼0.3–0.7 kcal/mol), the ubiquity of carbonyl groups across chemistry and biology gives the n→π* interaction broad impact. In particular, the n→π* interaction is likely to play an important role in dictating protein structure. Indeed, bioinformatics analysis suggests that approximately one-third of residues in folded proteins satisfy the geometric requirements to engage in an n→π* interaction, which is likely to be of particular importance for the α-helix. Other carbonyl-dense polymeric materials like polyesters and peptoids are also influenced by n→π* interactions, as are a variety of small molecules, some with particular medicinal importance. Research will continue to identify molecules whose conformation and activity are affect...

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“…Especially, the cisamide conformation can be predominantely populated by choosing sterically bulky side chains, such as N-1-(1-naphthyl)-ethyl 13 or tert-butyl, 16 or side chains containing positively charged groups, such as pyridinium 13 or triazolium. 15 Control of the trans-amide conformation can also be accomplished with N-aryl side chains. 14 The n → π* interaction between adjacent amide carbonyls in the backbone has also been suggested as a putative stabilizing noncovalent interaction in peptoids.…”

Section: Peptoidsmentioning

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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The Click Triazolium Peptoid Side Chain: A Strong cis-Amide Inducer Enabling Chemical Diversity

Cited by 115 publications

References 31 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

The n→π* Interaction

β-Peptoid Foldamers at Last

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