β^2,3‐Cyclic Aminoxy Acids: Rigid and Ring‐Size‐Independent Building Blocks of Foldamers

Abstract

Independent of the ring size in the aliphatic side chains, peptides made up of β2,3‐cyclic aminoxy acids, novel chiral building blocks of foldamers, adopt uniform secondary structures consisting of rigid β NO turns and 1.89‐helix structures (see figure). This contrasts previous results from other groups with cyclic ring‐constrained β‐peptides.

A Short Helix Formed by Cyclic β2,3‐Aminoxy Peptides in Protic Solvents

“…Furthermore, the chemical shift of aminoxy amide NH b of 3 is about 1 ppm more downfield than that of the NH a proton, which was intermolecularly hydrogen‐bonded with the solvent methanol, though both became undetectable in buffers because of a fast exchange with water as a result of their high acidities. This result suggests that the NH b protons of 2 and 3 and the NH c proton of 3 form intramolecular hydrogen bonds while the NH a proton does not, presumably with hydrogen bonding patterns that are very similar to those observed in β 2 ‐aminoxy peptides, β 2,2 ‐aminoxy peptides, β 3 ‐aminoxy peptides, β 2,3 ‐aminoxy peptides possessing acyclic side chains, and β 2,3 ‐aminoxy peptides possessing cyclic aliphatic (non‐polar) side chains …”

“…We previously reported that peptides composed of α‐, β‐, and γ‐aminoxy acids comprise a novel class of foldamers that adopt unique and stable secondary structures, such as N−O turns and helices, in the solid state and non‐polar solutions . In particular, the hydrophobic cyclic β 2,3 ‐aminoxy peptides, employing the ring constrain strategy to enhance the conformational stability, are well folded in the solid state, non‐polar solvent chloroform, and polar solvent methanol; however, poor water solubility restricts their structural studies in water. In addition, functionalized α‐aminoxy peptides with polar side chains fold into a 1.8 8 ‐helix in methanol and acidic aqueous buffer, but the conformational stability decreases dramatically in neutral and basic aqueous buffer .…”

“…This pattern reveals that proton NH b is orientated away from the adjacent amide plane; such a conformation prevents any intramolecular hydrogen bond formation and allows the NH b group to form hydrogen bonds with solvent molecules. By contrast, compound 2 exhibited a NOE pattern that is consistent with those of β N−O turns displayed by β 2,3 ‐aminoxy peptides with cyclic aliphatic (non‐polar) side chains: strong NOEs exist between its amide protons NH b and both α (H 2 ) and β (H 1 ) protons . This distinct NOE pattern indicates that the amide proton NH b points directly toward the adjacent amide carbonyl group to form intramolecular hydrogen bonds.…”

Synthesis of L‐Lys‐Aminoxy‐Goralatide

“…α-Aminoxy peptides [22,23] affect in vivo cell penetration better than native peptides [24]. Recent studies revealed that peptides composed of aminoxy acids form hydrogen bonds between adjacent residues [2,20,24] and helical structures that consist of consecutive N-O turns [25,18].…”

Novel Fluorescent Aminoxy Acids and Aminoxy Hybrid Peptides

“…An aaminoxy acid is more rigid than the corresponding b-amino acid, 11 moreover, aminoxy amide bonds resist enzymatic degradation; this has led to the exploration of aaminoxy acids as peptidomimetics. 12 a-Aminoxy peptides have also attracted considerable interest as novel foldamers, [13][14][15] because of unusual conformations and interesting bioactivity. [16][17][18][19][20] Aminoxy peptides may exhibit strong intramolecular hydrogen bonds between adjacent residues in peptidomimetic foldamers 21,22 and could provide useful labels.…”