Effect of capping groups at the N- and C-termini on the conformational preference of α,β-peptoids

Abstract

Peptoids (N-substituted glycines, i.e. a-peptoids) are artificial oligoamides which are closely related structurally to a-peptides with the side chains located on the amide nitrogen rather than the a-carbon (Fig. 1). A major advantage of a-peptoids is their ease of synthesis, particularly by the so-called ‘submonomer method’. A further benefit is the vast potential for diversity as the side chains on the amide nitrogens are introduced by primary amines. Therefore a-peptoids are particularly well suited for the construction of peptidomimetic libraries in the context of drug discovery as they have been shown to be resistant to proteolytic enzymes. Peptoids occupy a unique position as peptidomimetic foldamers since their backbones are deprived of free NH amides and thus have decreased capacity to form intramolecular H-bonding interactions. Although unnatural, a peptoid residue is structurally related to a proline as the coupling of residues gives tertiary amide bonds which can populate cis and trans conformations. These features confer greater flexibility to oligopeptoids but interestingly they maintain the propensity to form ordered secondary structures. a-Peptoids containing aromatic or aliphatic a-chiral side chains can fold into stable helical structures. For example, homo-peptoids with (S)-1-cyclohexylethyl or (S)-1-naphthylethyl side chains (s1npe) were reported to adopt, both in the solid