Synthesis and Characterization of Nitroaromatic Peptoids: Fine Tuning Peptoid Secondary Structure through Monomer Position and Functionality

Abstract

N-substituted glycine oligomers, or peptoids, have emerged as an important class of foldamers for the study of biomolecular interactions and for potential use as therapeutic agents. However, the design of peptoids with well-defined conformations a priori remains a formidable challenge. New approaches are required to address this problem, and the systematic study of the role of individual monomer units in the global peptoid folding process represents one strategy. Here, we report our efforts toward this approach through the design, synthesis, and characterization of peptoids containing nitroaromatic monomer units. This work required the synthesis of a new chiral amine building block, (S)-1-(2-nitrophenyl)ethanamine (s2ne), which could be readily installed into peptoids using standard solid-phase peptoid synthesis techniques. We designed a series of peptoid nonamers that allowed us to probe the effects of this relatively electron-deficient and sterically encumbered α-chiral side chain on peptoid structure, namely, the peptoid threaded loop and helix. Circular dichroism (CD) spectroscopy of the peptoids revealed that the nitroaromatic monomer has a significant effect on peptoid secondary structure. Specifically, the threaded loop structure was disrupted in a nonamer containing alternating N-(S)-1-phenylethylglycine (Nspe) and Ns2ne monomers, and the major conformation was helical instead. Indeed, placement of a single Ns2ne at the N-terminal position of (Nspe)9 resulted in a destabilized form of the threaded loop structure relative to the homononamer (Nspe)9. Conversely, we observed that incorporation of N-(S)-1-(4-nitrophenyl)ethylglycine (Nsnp, a para-nitro monomer) at the N-terminal position stabilized the threaded loop structure relative to (Nspe)9. Additional experiments revealed that nitroaromatic side chains can influence peptoid nonamer folding by modulating the strength of key intramolecular hydrogen bonds in the peptoid threaded loop structure. Steric interactions were also implicated for the Ns2ne monomer. Overall, this study provides further evidence that aromatic side chain structure, even if perturbed in a single monomer unit, can strongly influence local peptoid backbone conformation.

New Strategies for the Design of Folded Peptoids Revealed by a Survey of Noncovalent Interactions in Model Systems

“…37,39 Analysis of related, small model systems suggested that these structural perturbations arise in part from an interaction between a lone pair of the proximal amide oxygen and a π* orbital of the electron-deficient aromatic ring, that is, an n→π* Ar interaction (also referred to as an lp-π interaction). 40, 41 This type of interaction has been loosely defined by a carbonyl oxygen-to-ring centroid distance between 2.8 and 3.8 Å, and a dihedral angle between the aryl plane and the carbonyl plane (X 2 C=O) of 90° or less.…”

Construction of Peptoids with AllTrans-Amide Backbones and Peptoid Reverse Turns via the Tactical Incorporation ofN-Aryl Side Chains Capable of Hydrogen Bonding

“…32 Therefore, the installation of side chains that are capable of predictably influencing the rotational preferences of the φ and ψ dihedral angles, in addition to the ω dihedral angle, may serve as a general tactic for reducing overall conformational flexibility in polypeptoids. To address these challenges, our group is studying the mechanisms of peptoid folding by probing the effects of various side chain-to-backbone and backbone-to-backbone noncovalent interactions on ω , φ , and ψ dihedral angles in model peptoid systems 30–31,33–34 We have focused our efforts on monomers that are straightforward to synthesize and install using established peptoid synthesis techniques, thereby enabling their facile incorporation into polypeptoids. Using this fundamental approach, we seek to contribute to a more complete understanding of peptoid sequence-structure relationships, and facilitate the future rational design of peptoids with novel secondary and higher-order structures.…”

Structural Modeling and Conformational Analysis of Aromatic Polypeptoid Models Confined to Different Environmental Conditions

“…Due to the hydrophobic nature of peptoids compared to the corresponding amino acids they are difficult to crystallize and their structural studies have mainly been carried out by circular dichroism-a low resolution technique and NMR spectroscopy [23,[26][27][28][29][30][31]. Also, crystallographic studies are mostly on cyclic peptoids and there are only a few studies on linear peptoids [32][33][34][35][36]. The amide bond geometry has been reported as cis in N- (1-cyclohexylyethyl) glycine pentamers (in this study DMSO was used as a solvent at the coupling stage and crystals grown from methanol) and trans with N-aryl & N-hydroxyl achiral sidechains (here DMF was the solvent at the coupling stage and crystals grown from CH 2 Cl 2 /n-hexane) [32][33][34][35][36][37].…”

“…Also, crystallographic studies are mostly on cyclic peptoids and there are only a few studies on linear peptoids [32][33][34][35][36]. The amide bond geometry has been reported as cis in N- (1-cyclohexylyethyl) glycine pentamers (in this study DMSO was used as a solvent at the coupling stage and crystals grown from methanol) and trans with N-aryl & N-hydroxyl achiral sidechains (here DMF was the solvent at the coupling stage and crystals grown from CH 2 Cl 2 /n-hexane) [32][33][34][35][36][37]. It may also be mentioned that in poly N-methylated α-peptides the amide bond geometry has also been shown to be trans by crystallographic results [28,29].…”

“…It may also be mentioned that in poly N-methylated α-peptides the amide bond geometry has also been shown to be trans by crystallographic results [28,29]. A careful analysis of literature leads to an interesting observation that when peptoids were synthesized using dimethyl formamide (DMF) [31,32,[34][35][36][37], or dimethyl sulphoxide (DMSO) [25,26,27] as solvents during the coupling reactions; the results obtained on amide bond geometry are at variance including crystallographic studies and hence the adopted structures. This implies that the nature of amide bond geometry is influenced by the solvents being used during peptoid synthesis at the coupling stage.…”