Convenient Solution-Phase Synthesis and Conformational Studies of Novel Linear and Cyclic α,β-Alternating Peptoids

Hjelmgaard, Thomas; Faure, Sophie; Caumes, Cécile; Santis, Emiliana De; Edwards, Alison A.; Taillefumier, Claude

doi:10.1021/ol9015767

Cited by 54 publications

(35 citation statements)

References 21 publications

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“…Peptoids 1 – 13 were synthesized in solution using modified versions of previously reported procedures. 40 The crude peptoids were purified by flash silica gel column chromatography and characterized by MS to confirm their identity (See Table 1). See Supporting Information for detailed synthetic procedures and complete compound characterization, including HPLC and MS data, for peptoids 1 – 13 and their respective synthetic intermediates.…”

Section: Methodsmentioning

confidence: 99%

Extraordinarily Robust Polyproline Type I Peptoid Helices Generated via the Incorporation of α-Chiral Aromatic N-1-Naphthylethyl Side Chains

et al. 2011

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Peptoids, or oligomers of N-substituted glycines, are a class of foldamers that have shown extraordinary functional potential since their inception nearly two decades ago. However, the generation of well-defined peptoid secondary structures remains a difficult task. This challenge is due, in part, to the lack of a thorough understanding of peptoid sequence-structure relationships and consequently, an incomplete understanding of the peptoid folding process. We seek to delineate sequence-structure relationships through the systematic study of noncovalent interactions in peptoids and the design of novel amide side chains capable of such interactions. Herein, we report the synthesis and detailed structural analysis of a series of (S)-N-(1-naphthylethyl)glycine (Ns1npe) peptoid homooligomers by X-ray crystallography, NMR and circular dichroism (CD) spectroscopy. Four of these peptoids were found to adopt well-defined structures in the solid state, with dihedral angles similar to those observed in polyproline type I (PPI) peptide helices and in peptoids with α-chiral side chains. The X-ray crystal structure of a representative Ns1npe tetramer revealed an all cis-amide helix, with approximately three residues per turn, and a helical pitch of approximately 6.0 Å. 2D-NMR analysis of the length-dependent Ns1npe series showed that these peptoids have very high overall backbone amide Kcis/trans values in acetonitrile, indicative of conformationally homogeneous structures in solution. Additionally, CD spectroscopy studies of the Ns1npe homooligomers in acetonitrile and methanol revealed a striking length-dependent increase in ellipticity per amide. These Ns1npe helices represent the most robust peptoid helices to be reported, and the incorporation of (S)-N-(1-naphthylethyl)glycines provides a new approach for the generation of stable helical structure in this important class of foldamers.

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Section: Methodsmentioning

confidence: 99%

Extraordinarily Robust Polyproline Type I Peptoid Helices Generated via the Incorporation of α-Chiral Aromatic N-1-Naphthylethyl Side Chains

et al. 2011

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“…8,76.9,77.1,77.2,77.3,77.7,77.8,78.2,78.3,78.4 (4 C,4 × CH 2 C≡CH),81.2,81.4,81.6,81.7,82.5,82.6,82.8,83.0 (C,167.1,167.3,167.4,167.5,167.6,168.0,168.1,168.2,170.5,170.6,170.8,171.1,171.2 (4 C,4 × C=O). 2974,1726,1636,1456,1445,1418,1368,1287,1252,1217,1153,1098,1063,1030,993,924,845,754,731 1,32.4,32.7,32.9,33.7,33.9,34.1,34.4 (4 CH 5,32.0,…”

Section: A-tetrapeptoidmentioning

confidence: 99%

“…4 In addition, we have recently communicated our initial studies on a new family of a,b-alternating peptoids. 5 Structurally, peptoids differ from peptides in that the side chains are attached to the amide nitrogen rather than to the a-or b-carbon. The peptoid backbone is therefore achiral and does not contain any amide protons.…”

mentioning

confidence: 99%

“…Accordingly, our published methodology for iterative solution-phase synthesis of peptoids (Scheme 1) has provided improvements, in terms of cost and time, compared to earlier techniques. 5 Briefly, the peptoid residues are created in two steps by acylation of the N-terminus, followed by reaction of the acylated intermediate with an appropriate amine. By using tetrahydrofuran as the solvent for the acylation steps the formed ammonium salts precipitate, allowing for easy removal by filtration.…”

mentioning

confidence: 99%

“…The lower yield of a,bpeptoid 2, compared to that of b-peptoid 1, was anticipated since the solution-phase synthesis of a-peptoid residues proceeds less cleanly than that of b-peptoid residues. 5 Replacing triethylamine in the substitution reaction with a further two equivalents of propargylamine gave reaction mixtures that proved difficult to filter, and consequently, a slightly decreased overall yield was obtained (Table 2, entry 2). A significant improvement in the overall yield to 42% was observed when maintaining the use of triethylamine in the substitution steps, and at the …”

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confidence: 99%

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Highly Convenient Gram-Scale Solution-Phase Peptoid Synthesis and Orthogonal Side-Chain Post-Modification

Caumes¹,

Hjelmgaard²,

Remuson³

et al. 2010

Synthesis

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This paper describes the development of a highly convenient solution-phase methodology using volatile amines for the synthesis of b-, a,b-and a-tetrapeptoids, as an alternative to solid-phase technologies. Column chromatographic purifications are reduced to a minimum and the majority of the intermediates are purified by filtration and/or evaporation. The method is amenable to gram-scale synthesis of peptoids, and post-modification of a model peptoid by successive and selective ligations, using click thiol-ene coupling, and copper-catalysed azide-alkyne cycloaddition is demonstrated.There has been considerable interest in developing pseudopeptide oligomers with reduced complexity that are able to fulfill the functions of their natural peptide counterparts, without drawbacks such as low half-life and limited bioavailability. 2 Oligomers of N-substituted glycines, or a-peptoids, were developed in the early 1990s as a new type of simple peptidomimetic. They are characterised by resistance to proteases, rapid cellular uptake, a large potential for diversity and straightforward syntheses. 3 The first synthesis of oligomers of N-substituted balanines, or b-peptoids, followed later in the same decade. 4 In addition, we have recently communicated our initial studies on a new family of a,b-alternating peptoids. 5 Structurally, peptoids differ from peptides in that the side chains are attached to the amide nitrogen rather than to the a-or b-carbon. The peptoid backbone is therefore achiral and does not contain any amide protons. In spite of this, peptoids can still be driven to form secondary structures such as helices if a-chiral side chains are incorporated. 6 Peptoids have attracted significant interest and have been used in a number of important biological applications. 7The structural simplicity of the peptoids allows for their synthesis using a unique 'submonomer' protocol in which the peptoid residues are created directly on a growing chain, in an iterative manner. Highly efficient procedures have been developed for solid-phase synthesis of peptoids. However, our research project aimed at using b-and a,b-peptoids as scaffolds for multivalent ligand display 8 necessitates the development of efficient solution-phase methodologies which are able to provide large quantities of peptoids in a manner competitive with solid-phase synthesis. Accordingly, our published methodology for iterative solution-phase synthesis of peptoids (Scheme 1) has provided improvements, in terms of cost and time, compared to earlier techniques. 5Briefly, the peptoid residues are created in two steps by acylation of the N-terminus, followed by reaction of the acylated intermediate with an appropriate amine. By using tetrahydrofuran as the solvent for the acylation steps the formed ammonium salts precipitate, allowing for easy removal by filtration. Evaporation of the filtrate then furnishes the acylated intermediates in sufficiently high purity for direct use in the second step. Thus, only one chromatography operation per synthesised peptoid re...

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A Peptoid Ribbon Secondary Structure

2013

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Delineating the relationships between sequence, structure, and function in biopolymers is critical to our understanding of fundamental biochemical interactions. These relationships are equally important for the design of functional biomimetic oligomers (that is, foldamers). [1] Oligomers of N-substituted glycine, or peptoids (Figure 1 a), [2] are an important class of foldamers that have been shown to possess numerous biological functions [3] and could find use in a range of fundamental and applied contexts as bio-inspired materials. [4] Peptoids are highly attractive scaffolds for such purposes, as their non-native backbones are resistant to proteolytic degradation [5] and their straightforward, modular synthesis [6] enables the ready incorporation of a range of structurally diverse amide side chains. [7] However, the design and prediction of peptoid secondary or higher-order structure remains a major challenge, and few discrete structures have been characterized to date for acyclic peptoids. [8] This paucity of structure-function data limits the potential utility of peptoids, despite their many advantages.Structural studies of peptoids have been largely thwarted by the intrinsic conformational flexibility of the peptoid backbone itself. This backbone contains C-a methylene units, lacks hydrogen bond donating atoms, and, perhaps most notably, is linked by tertiary amides that can be isoenergetic between cis and trans amide geometries (Figure 1 b). We and others reasoned that the development of peptoid side chains capable of engendering a high degree of control over proximate main-chain amide geometries could facilitate the design of well-defined peptoid structures and expand our understanding of peptoid folding. [9] We recently designed and synthesized a range of peptoid model systems to test this hypothesis, and have identified several classes of amide side chains that favor cis or trans main-chain amides in peptoid oligomers, predominantly through steric and stereoelectronic effects. One such side chain is the a-chiral aromatic (S)-1-(1naphthyl)ethyl (s1npe) group (Figure 1), which strongly favors cis amide bonds (cis/trans > 6.3:1) in peptoid model systems. [9c] Moreover, Ns1npe homooligomers adopt polyproline type I (PPI)-like peptoid helices that contain exclusively cis amides in the peptoid main chain. [8e] In turn, we found that the trans amide peptoid rotamer is strongly enforced by Naryl side chains (for example, Nph, cis/trans < 0.05:1; Figure 1), and homooligomers of these residues have been calculated to give rise to extended, polyproline type II (PPII)like peptoid helices with all trans amides. [9b] These peptoid monomers are thus a set of building blocks with which to initiate a rational construction of new peptoid secondary structures. Herein, we report our first test of this modular design strategy for peptoids and our ensuing discovery of a new secondary structure containing an alternating sequence of aromatic residues that we designate as the "peptoid ribbon".In view of the strong rotameri...

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Convenient Solution-Phase Synthesis and Conformational Studies of Novel Linear and Cyclic α,β-Alternating Peptoids

Cited by 54 publications

References 21 publications

Extraordinarily Robust Polyproline Type I Peptoid Helices Generated via the Incorporation of α-Chiral Aromatic N-1-Naphthylethyl Side Chains

Extraordinarily Robust Polyproline Type I Peptoid Helices Generated via the Incorporation of α-Chiral Aromatic N-1-Naphthylethyl Side Chains

Highly Convenient Gram-Scale Solution-Phase Peptoid Synthesis and Orthogonal Side-Chain Post-Modification

A Peptoid Ribbon Secondary Structure

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