Unusual truncation of N-acylated peptoids under acidic conditions

Kim, Soomin; Biswas, Goutam; Park, Shin-Ae; Kim, Arim; Park, Hyun-Jung; Park, Eunsook; Kim, Jeongmi; Kwon, Yong Uk

doi:10.1039/c3ob42572j

Cited by 27 publications

(31 citation statements)

References 20 publications

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“…20,21,27 Peptoids 1−4 were synthesized by the solid-phase submonomer method 28 and acetylated at their N termini. 29 The peptoids were purified by reverse phase high performance liquid chromatography (HPLC) using a cyano column to >90% molecular purity. The synthesis methods and analytical characterization are described in detail in the SI.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Universal Relationship between Molecular Structure and Crystal Structure in Peptoid Polymers and Prevalence of the cis Backbone Conformation

et al. 2018

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Peptoid polymers are often crystalline in the solid-state as examined by X-ray scattering, but thus far, there has been no attempt to identify a common structural motif among them. In order to probe the relationship between molecular structure and crystal structure, we synthesized and analyzed a series of crystalline peptoid copolymers, systematically varying peptoid side-chain length (S) and main-chain length (N). We also examined X-ray scattering data from 18 previously reported peptoid polymers. In all peptoids, we found that the unit cell dimensions, a, b, and c, are simple functions of S and N: a (Å) = 4.55, b (Å) = [2.98]N + 0.35, and c (Å) = [1.86]S + 5.5. These relationships, which apply to both bulk crystals and self-assembled nanosheets in water, indicate that the molecules adopt extended, planar conformations. Furthermore, we performed molecular dynamics simulations (MD) of peptoid polymer lattices, which indicate that all backbone amides adopt the cis conformation. This is a surprising conclusion, because previous studies on isolated molecules indicated an energetic preference for the trans conformer. This study demonstrates that when packed into supramolecular lattices or crystals, peptoid polymers prefer to adopt a regular, extended, all-cis secondary structure.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Universal Relationship between Molecular Structure and Crystal Structure in Peptoid Polymers and Prevalence of the cis Backbone Conformation

et al. 2018

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“…These include 2-methoxyethylamine and 2-phenylethylamine, which form N -substituted diketopiperazines; 4-(2-aminoethyl)morpholine and N Im -tritylhistamine, which have a nucleophilic group that also may react with the main-chain bromoacetyl group; 2,4,6-trimethoxybenzylamine and p -guanidino-substituted α-methylbenzylamine which is unstable during TFA cleavage. Peptides and peptoids are often acetylated at the N-terminus to improve biological activity; Kim et al [ 174 ] reported that N -acetylated peptoids may spontaneously truncate under standard TFA cleavage conditions. They found that the problem could be circumvented by using a cleavage cocktail of TFA/CH 2 Cl 2 /H 2 O/TIS (50:42:5:3) for 1 h. Finally, it should be mentioned that HOBt and HOAt reduce the yield significantly when employed as additives in solid-phase submonomer synthesis [ 147 ].…”

Section: Peptidomimeticsmentioning

confidence: 99%

Advances in Development of Antimicrobial Peptidomimetics as Potential Drugs

2017

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The rapid emergence of multidrug-resistant pathogens has evolved into a global health problem as current treatment options are failing for infections caused by pan-resistant bacteria. Hence, novel antibiotics are in high demand, and for this reason antimicrobial peptides (AMPs) have attracted considerable interest, since they often show broad-spectrum activity, fast killing and high cell selectivity. However, the therapeutic potential of natural AMPs is limited by their short plasma half-life. Antimicrobial peptidomimetics mimic the structure and biological activity of AMPs, but display extended stability in the presence of biological matrices. In the present review, focus is on the developments reported in the last decade with respect to their design, synthesis, antimicrobial activity, cytotoxic side effects as well as their potential applications as anti-infective agents. Specifically, only peptidomimetics with a modular structure of residues connected via amide linkages will be discussed. These comprise the classes of α-peptoids (N-alkylated glycine oligomers), β-peptoids (N-alkylated β-alanine oligomers), β3-peptides, α/β3-peptides, α-peptide/β-peptoid hybrids, α/γ N-acylated N-aminoethylpeptides (AApeptides), and oligoacyllysines (OAKs). Such peptidomimetics are of particular interest due to their potent antimicrobial activity, versatile design, and convenient optimization via assembly by standard solid-phase procedures.

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“…N ‐Me‐peptide synthesis faces three major challenges. (1) coupling obstacles which include (a) racemization, (b) deletions of NMAA, and (c) double hit incorporation; (2) oxazolone or diketopiperazine (DKP) ring formation during coupling or in the cleavage steps, leading to fragmentations in the peptide; and (3) acetylation of the N ‐Me‐terminal, leading to the loss of Ac‐NMAA, as explained below in detail (Figure ) …”

Section: Side Reactions In N‐methylated Peptidesmentioning

confidence: 99%

“…Furthermore, N‐ Me terminal peptides capped on solid phase using an acetyl group are subjected to another side reaction during cleavage from the resin using TFA, whereas the Ac‐NMAA terminal undergoes side reaction through formation of oxazolonium intermediate moiety leading to formation of a truncated peptide (Scheme ) …”

Section: Side Reactions In N‐methylated Peptidesmentioning

confidence: 99%

N‐methylation in amino acids and peptides: Scope and limitations

et al. 2018

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Active pharmaceutical ingredients (APIs) can be divided into two types, namely chemical and biological entities. Traditionally, the former has been associated with the so-called small molecules. The revival of peptides in pharmaceutical industry results from their importance in many biological roles. However, low metabolic stability and the lack of oral availability of most peptides is the main drawback for peptide to fulfill that paradigmatic situation. In this regard, efforts are being channeled into addressing this issue by introducing restrictions into the flexible peptide backbone, mainly through N-methyl amino acids (NMAAs) or development of small cyclic peptides. In many cases, both the above restrictions are combined with the aim to enhance oral availability. The synthesis of NMAAs is complex and their introduction into the peptide chain brings additional synthetic challenges and also sometimes leads to side-reactions. Here we discuss the most efficient methods for the synthesis of NMAAs (either in solution or in solid phase) and also their introduction into peptide sequences. Special attention is also given to the detection of side reactions and the most efficient way to prevent them.

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Unusual truncation of N-acylated peptoids under acidic conditions

Cited by 27 publications

References 20 publications

Universal Relationship between Molecular Structure and Crystal Structure in Peptoid Polymers and Prevalence of the cis Backbone Conformation

Universal Relationship between Molecular Structure and Crystal Structure in Peptoid Polymers and Prevalence of the cis Backbone Conformation

Advances in Development of Antimicrobial Peptidomimetics as Potential Drugs

N‐methylation in amino acids and peptides: Scope and limitations

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