Design and conformational analysis of peptoids containing N‐hydroxy amides reveals a unique sheet‐like secondary structure

Abstract

N-hydroxy amides can be found in many naturally occurring and synthetic compounds and are known to act as both strong proton donors and chelators of metal cations. We have initiated studies of peptoids, or N-substituted glycines, that contain N-hydroxy amide side chains to investigate the potential effects of these functional groups on peptoid backbone amide rotamer equilibria and local conformations. We reasoned that the propensity of these functional groups to participate in hydrogen bonding could be exploited to enforce intramolecular or intermolecular interactions that yield new peptoid structures. Here, we report the design, synthesis, and detailed conformational analysis of a series of model N-hydroxy peptoids. These peptoids were readily synthesized, and their structures were analyzed in solution by 1D and 2D NMR and in the solidstate by X-ray crystallography. The N-hydroxy amides were found to strongly favor trans conformations with respect to the peptoid backbone in chloroform. More notably, unique sheetlike structures held together via intermolecular hydrogen bonds were observed in the X-ray crystal structures of an N-hydroxy amide peptoid dimer, which to our knowledge represent the first structure of this type reported for peptoids. These results suggest that the N-hydroxy amide can be utilized to control both local backbone geometries and longer-range intermolecular interactions in peptoids, and represents a new functional group in the peptoid design toolbox.

A Peptoid Ribbon Secondary Structure

“…As expected, in CD 3 CN at 24 °C, the K cis / trans values for the N s1npe residues in 2 and 2 ′ were 8.7 and 10.2, respectively, while the K cis / trans values for the N ph residues were 0.1 and 0.05, respectively. We note that the overall amide K cis / trans for homodimers of N s1npe and N ph in CD 3 CN were previously shown to be 10.8 [8e] and < 0.1, [9b] respectively, suggesting that their presence in heterodimers 2 and 2 ′ did not impact the other residue’s rotameric preference. The cis - or trans -amide preferences of the N s1npe and N ph residues in 2 and 2 ′ were also maintained in a variety of solvents (CDCl 3 (Table 1); C 6 D 6 , CD 3 OD, DMSO- d 6 , and 1:1 CD 3 CN/D 2 O; see Table S-1).…”

“…Our laboratory 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 α-chiral aromatic ( S )-1-(1-naphthyl)ethyl ( s1npe ) group (Figure 1), which strongly favors cis -amide bonds ( cis:trans > 6.3:1) in peptoid model systems.…”

“…One such side chain is the α-chiral aromatic ( S )-1-(1-naphthyl)ethyl ( s1npe ) group (Figure 1), which strongly favors cis -amide bonds ( cis:trans > 6.3:1) in peptoid model systems. [9c] Moreover, N s1npe homooligomers adopt polyproline type I (PPI)-like peptoid helices that exclusively contain cis -amides in the peptoid main chain. [8e] In turn, we found that the trans -amide peptoid rotamer is strongly enforced by N -aryl side chains ( e.g.…”

“…, N ph, 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 now represent 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”.…”

“…Two dipeptoids, 2 and 2 ′ (Table 1), were synthesized by standard solution phase methods (see Supp. Info. for full synthetic details), [9a, 12] , purified, and evaluated by NMR spectroscopy. Each peptoid was capped at the N-terminus with an acetyl group (ac) and at the C-terminus as a dimethyl amide (dma) to (1) mimic the chemical environment of an extended peptoid chain at both termini, and (2) facilitate conformational analysis by 1 H- 1 H nuclear Overhauser effect spectroscopy (NOESY).…”