Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, WI 53706-1322, USA.
Biopolymers. 2011;96(5):604-16. doi: 10.1002/bip.21599.
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 which 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 solid-state 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 sheet-like 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.
N-羟基酰胺可以在许多天然和合成化合物中找到，并且已知它们既可以作为强质子供体，也可以作为金属阳离子的螯合剂。我们已经开始研究肽类，即含有 N-羟基酰胺侧链的 N-取代甘氨酸，以研究这些官能团对肽骨架酰胺旋转异构体平衡和局部构象的潜在影响。我们推断，这些官能团参与氢键的倾向可以被利用来强制形成新的肽类结构的分子内或分子间相互作用。在这里，我们报告了一系列模型 N-羟基肽类的设计、合成和详细的构象分析。这些肽类很容易合成，其结构通过 1D 和 2D NMR 在溶液中以及通过 X 射线晶体学在固态中进行了分析。在氯仿中，N-羟基酰胺被发现强烈有利于相对于肽骨架的反式构象。更值得注意的是，在 N-羟基酰胺肽类二聚体的 X 射线晶体结构中观察到了通过分子间氢键结合在一起的独特片状结构，据我们所知，这代表了肽类中首次报道的这种类型的结构。这些结果表明，N-羟基酰胺可以用于控制肽类中的局部骨架几何形状和长程分子间相互作用，并且代表了肽类设计工具包中的一个新的官能团。
