NCα‐gem‐dimethylated peptoid side chains: A novel approach for structural control and peptide sequence mimetics

Abstract

The design of linear peptoid oligomers adopting well‐defined secondary structures while mimicking defined peptide primary sequences is a major challenge in the context of drug discovery. To this end, chemists have developed cis‐inducing peptoid side chains to build robust polyproline type I helices. However, the number of efficient examples remains scarce and chemical diversity accessible through the use of these side chains is limited. Herein, we introduce an array of NCα‐gem‐dimethylated peptoid residues mimicking proteinogenic amino acids. Submonomer synthesis and block‐coupling approaches were explored to access heterooligomers incorporating these novel types of side chains. NMR studies of monomer and trimer models showed that the NCα‐gem‐dimethylated groups exert complete cis control on the backbone amide conformation. Lastly, a preliminary molecular modeling study gave an insight into the preferred orientation of the substituents of the NCα‐gem‐dimethyl side chains relative to the peptoid backbone.

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

“…[34] On the other hand, sterically controlled peptoids, show little variations in K cis/trans values with change in solvent, which can be seen for tert-butyl and NC α -gem-dimethylated side chains containing peptoids 26, 33-35. [45][46][47] Although theoretical models have been proposed for folding of natural peptides, reports on designing of such model to study the solvation effect on peptoid folding are limited. [62] In a view to unravel the forces that stabilise the peptoid foldamers in the presence of a solvent, Broda and co-workers theoretically (MP2 based method) delineated the effect of a polar environment on a peptoid models 79 and 80 (Figure 16).…”

“…Recently, Shyam et al incorporated NC α -gem-dimethylated amines in peptoids. [47] Introduction of such gem-dimethylated functionalities is expected to increase the diversity of peptoid Figure 6. A) Chemical structure and crystal structure of 25.…”

Solution‐Phase Synthesis of Backbone‐Constrained Cationic Peptoid Hexamers with Antibacterial and Anti‐Biofilm Activities

“…Based on previous work, the N ‐ tert ‐butyl peptoid amides of the synthesized oligomers have a cis ‐conformation [15–16] . In previous study, NMR and computational studies have also shown that despite the absence of chirality, Nt Bu peptoid oligomers adopt preferentially the PPI‐like helical conformation thanks to a network of weak interactions such as intramolecular CO( i )⋅⋅⋅HC( i ‐n) hydrogen bonds and t Bu⋅⋅⋅ t Bu London interactions [24] .…”

“…Sterically hindered side‐chains could also favor the cis conformation of the N , N ‐disubstituted amide as observed with the naphtylethyl side‐chain [13] or with sterically hindered aliphatic groups [7,12,14] . Among the latter, the tert ‐butyl ( t Bu) [15] and NC α‐ gem ‐dimethylated [16] side‐chains totally lock the amide in the cis conformation whatever the solvent used (Figure 1c). Despite the potential of the tert ‐butyl group as cis ‐amide inducer, [17] oligomers containing this side‐chain are still rare in the literature and such peptoids exhibiting biological activities have never been reported.…”

“…Bromo acetamide 4 : [16] Compound 4 was synthesized in three steps starting from compound 1 . Compound 2 was synthesized by starting from compound 1 (2.73 g, 17.1 mmol) by application of the General Procedure B.…”