Strategies to Control the Cis‐Trans Isomerization of Peptoid Amide Bonds

Abstract

Peptoids are oligomers of N‐substituted glycine units. They structurally resemble peptides but, unlike natural peptides, the side chains of peptoids are present on the amide nitrogen atoms instead of the α‐carbons. The N‐substitution improves cell‐permeability of peptoids and enhance their proteolytic stability over natural peptides. Therefore, peptoids are ideal peptidomimetic candidates for drug discovery, especially for intracellular targets. Unfortunately, most peptoid ligands discovered so far possess moderate affinity towards their biological targets. The moderate affinity of peptoids for biomacromolecules is linked to their conformational flexibility, which causes substantial entropic loss during the peptoid‐biomacromolecule binding process. The conformational flexibility of peptoids is caused by the lack of backbone chirality, absence of hydrogen bond donors (NH) in their backbone to form CO⋅⋅⋅HN hydrogen bonds and the facile cis‐trans isomerization of their tertiary amide bonds. In recent years, many investigators have shown that the incorporation of specific side chains with unique steric and stereoelectronic features can favourably shift the cis‐trans equilibria of peptoids towards one of the two isomeric forms. Such strategies are helpful to design homogenous peptoid oligomers having well defined secondary structures. Herein, we discuss the strategies developed over the years to control the cis‐trans isomerization of peptoid amide bonds.

Various Strategies to Control the Conformation of Peptoids

“…1B). All these findings are recapitulated in a recent review by Kalita et al [2]. Here we report on our results with the following two sterically demanding aliphatic side chains, tert-butyl (tBu) and (S)-1tert-butyl(ethyl) (s1tbe), which our group has introduced to the peptoid "tool box" to induce cisamides.…”

Guidelines for designing peptoid structures: Insights from the Peptoid Data Bank

“…[ 51 ] Other side chain types, including N‐aryl, [ 52 ] N‐hydroxy [ 53 ] N‐alkoxy, [ 54 ] and N‐imino (or N‐alkylamino) [ 55 ] side chains, have been shown to strongly favor a trans ‐amide bond. For a thorough review of strategies to control isomerization of the amide bond, see Kalita et al [ 18 ] These general chemical properties that allow a side chain to restrict its backbone from four to two or even one conformation are an advantage of peptoids and lend themselves to the distinct design strategies we will describe below.…”

First series of N-alkylamino peptoid homooligomers: solution phase synthesis and conformational investigation

“…Thus, adoption of well-defined secondary structures requires fine control of backbone amide isomerism. Considerable efforts have been made to regulate the conformation of peptoids through steric and electronic interactions involving peptoid amides and nearby side chains [17,18]. For example, N-substituted monomers bearing benzylic-type Nα-chiral groups including the phenylethyl [19][20][21], naphthylethyl [17,[22][23][24], and triazolium groups [25][26][27], alkyl ammonium [28], tert-butyl/α,α-gem-dimethyl [29], or fluorinated groups [30] will preferentially form cis-amides (Figure 1A).…”