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

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 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 p-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.

N-取代甘氨酸低聚物，或称类肽（peptoids），已成为一类重要的折叠体（foldamers），可用于研究生物分子相互作用且有望用作治疗制剂。然而，先验设计构象明确的类肽仍是一项极具挑战性的难题。解决该问题亟需新的研究路径，而系统探究单个单体单元在类肽整体折叠过程中的作用，便是其中一种有效策略。本研究通过设计、合成并表征含硝基芳香族单体单元的类肽，探索了此类研究路径的可行性。为推进相关实验，我们首先合成了一种新型手性胺结构单元——(S)-1-(2-硝基苯基)乙胺（s2ne），该单元可通过标准固相类肽合成技术便捷地接入类肽链中。我们设计了一系列类肽九聚体，以此探究该相对缺电子且空间位阻较大的α-手性侧链对类肽结构的影响，具体包括类肽的螺纹环结构与螺旋结构。对类肽的圆二色谱（circular dichroism spectroscopy）检测结果显示，硝基芳香族单体对类肽二级结构具有显著调控作用。具体而言，在交替含有N-(S)-1-苯基乙基甘氨酸（Nspe）与Ns2ne单体的九聚体中，原有的螺纹环结构被破坏，主要构象转变为螺旋结构。将单个Ns2ne单体置于(Nspe)9的N端，相较于同聚九聚体(Nspe)9，会使螺纹环结构的稳定性显著下降；与之相反，将N-(S)-1-(4-硝基苯基)乙基甘氨酸（Nsnp，一种对位硝基取代单体）置于(Nspe)9的N端，则可提升螺纹环结构的稳定性。额外的实验结果表明，硝基芳香族侧链可通过调节类肽螺纹环结构中的关键分子内氢键强度，影响类肽九聚体的折叠过程。此外，Ns2ne单体的空间位阻相互作用也参与了该构象调控过程。总体而言，本研究进一步证实，即使仅在单个单体单元中改变芳香族侧链结构，也可对类肽主链的局部构象产生强烈影响。