The <i>tert</i>-Butyl Side Chain: A Powerful Means to Lock Peptoid Amide Bonds in the Cis Conformation

Roy, Olivier; Caumes, Cécile; Esvan, Yannick J.; Didierjean, Claude; Faure, Sophie; Taillefumier, Claude

doi:10.1021/ol400820y

Cited by 95 publications

(110 citation statements)

References 36 publications

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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.…”

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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Section: Peptoidsmentioning

confidence: 99%

β-Peptoid Foldamers at Last

2015

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“…[2] By placing ab ulky unit, such as a tert-butyl group,onthe nitrogen atom of asecondary amide,t he activation barrier for the isomerization of 1 is lowered and the equilibrium regarding the two original substituents is shifted towards the cis rotamer (Scheme 1). [5] As tronger influence on the conformational distribution was observed for the pyridinium-and triazolium-substituted amides 2 and 3. [6,7] These effects are explained by n!p* Aryl interactions between the carbonyl oxygen and an antibinding orbital of the adjacent electron-deficient aromatic ring system.…”

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confidence: 92%

Switching and Conformational Fixation of Amides Through Proximate Positive Charges

2015

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“…However, given their tertiary amide backbone, peptoids lack the capacity to form hydrogen bonds so that their secondary structures are dominated by relatively weak interactions. Considerable efforts have been devoted to try and understand the relationships between a peptoid primary sequence and its folded structure 6, 7, 8, 9, 10. The cis / trans isomerization of the tertiary amide bond is the major cause of conformational heterogeneity in peptoid oligomers.…”

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confidence: 99%

“…However, it is not possible to use the aforementioned NCIs to stabilize the cis ‐amide conformation of alkyl peptoid monomers, and thus the design of stable peptoid helices remains dominated by the use of chiral aromatic residues (e.g., 1 and 2 ) 9. Recently, Faure, Taillefumier, and co‐workers exploited steric effects in the design of a non‐chiral t Bu alkyl monomer that has a clear cis ‐amide preference ( Nt Bu, 3 ) 10. Whereas 3 offers a route to control peptoid structure that avoids the use of aromatic building blocks, the design of non‐chiral but stable cis ‐amide alkyl monomers is an area that is still highly underdeveloped.…”

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confidence: 99%

Stabilising Peptoid Helices Using Non‐Chiral Fluoroalkyl Monomers

et al. 2018

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Stability towards protease degradation combined with modular synthesis has made peptoids of considerable interest in the fields of chemical biology, medicine, and biomaterials. Given their tertiary amide backbone, peptoids lack the capacity to hydrogen‐bond, and as such, controlling secondary structure can be challenging. The incorporation of bulky, charged, or chiral aromatic monomers can be used to control conformation but such building blocks limit applications in many areas. Through NMR and X‐ray analysis we demonstrate that non‐chiral neutral fluoroalkyl monomers can be used to influence the Kcis/trans equilibria of peptoid amide bonds in model systems. The cis‐isomer preference displayed is highly unprecedented given that neither chirality nor charge is used to control the peptoid amide conformation. The application of our fluoroalkyl monomers in the design of a series of linear peptoid oligomers that exhibit stable helical structures is also reported.

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The tert-Butyl Side Chain: A Powerful Means to Lock Peptoid Amide Bonds in the Cis Conformation

Cited by 95 publications

References 36 publications

β-Peptoid Foldamers at Last

β-Peptoid Foldamers at Last

Switching and Conformational Fixation of Amides Through Proximate Positive Charges

Stabilising Peptoid Helices Using Non‐Chiral Fluoroalkyl Monomers

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