Alpha-aminoxy acids: new possibilities from foldamers to anion receptors and channels

Abstract

Naturally occurring peptides serve important functions as enzyme inhibitors, hormones, neurotransmitters, and immunomodulators in many physiological processes including metabolism, digestion, pain sensitivity, and the immune response. However, due to their conformational flexibility and poor bioavailability, such peptides are not generally viewed as useful therapeutic agents in clinical applications. In an effort to solve these problems, chemists have developed peptidomimetic foldamers, unnatural oligomeric molecules that fold into rigid and well-defined secondary structures mimicking the structures and biological functions of these natural peptides. We have designed peptidomimetic foldamers that give predictable, backbone-controlled secondary structures irrespective of the nature of the side chains. This Account presents our efforts to develop a novel class of peptidomimetic foldamers comprising alpha-aminoxy acids and explore their applications in the simulation of ion recognition and transport processes in living systems. Peptides constructed from alpha-aminoxy acids fold according to the following rules: (1) A strong intramolecular eight-membered-ring hydrogen bond forms between adjacent alpha-aminoxy acid residues (the alpha N-O turn). The chirality of the alpha-carbon, not the nature of the side chains, determines the conformation of this chiral N-O turn. (2) While homochiral oligomers of alpha-aminoxy acids form an extended helical structure (1.8 8 helix), heterochiral ones adopt a bent reverse turn structure. (3) In peptides of alternating alpha-amino acids and alpha-aminoxy acids, the seven-membered-ring intramolecular hydrogen bond, that is, the gamma-turn, is initiated by a succeeding alpha N-O turn. Thus, this type of peptide adopts a novel 7/8 helical structure. In investigating the potential applications of alpha-aminoxy acids, we have found that the amide NH units of alpha-aminoxy acids are more acidic than are regular amide NH groups, which makes them better hydrogen bond donors when interacting with anions. This property makes alpha-aminoxy acids ideal building blocks for the construction of anion receptors. Indeed, we have constructed both cyclic and acyclic anion receptors that have strong affinities and good (enantio-)selectivities toward chloride (Cl(-)) and chiral carboxylate ions. Taking advantage of these systems' preference for Cl(-) ions, we have also employed alpha-aminoxy acid units to construct a synthetic Cl(-) channel that can mediate the passage of Cl(-) ions across cell membranes. Continued studies of these peptidomimetic systems built from alpha-aminoxy acids should lead to a broad range of applications in chemistry, biology, medicine, and materials science.