Exploring the Effects of Fluoroalkyl Sidechains on Peptoid Secondary Structure

Abstract

N-substituted glycines (peptoids) are a promising class of peptidomimetic that exhibit proteolytic resistance, enhanced lipophilicity, and greater structural diversity relative to their peptide counterparts. Peptoids have shown great potential as antimicrobials owing their advantageous properties, yet the development of novel antimicrobial sequences is hindered. This is due the presence of a tertiary amide backbone, which removes the capacity for hydrogen bonding interactions and thus renders many peptoids disordered in solution. Currently, the de novo design of extended sequences is reliant on a toolbox of peptoid monomers, capable of directing the tertiary amide bond to a single isomer. This selection of monomers is currently dominated by bulky, charged, chiral and aromatic sidechains.

This work describes the development of novel, fluoroalkyl sidechains capable of inducing the cis amide bond isomer in model dipeptoid systems. A series of 1D and 2D NMR experiments were performed to calculate Kcis/trans for the library of monomers studied. Further NMR experiments evaluated the relationship between sidechain fluorination and lipophilicity. The fluorinated monomers investigated gave Kcis/trans values up to 6.22 in CD3CN and displayed an increase in lipophilicity upon higher degrees of fluorination. A selection of these new monomers were then incorporated into oligomers utilizing microwave irradiation to accelerate the solid-phase synthesis. Analysis of these extended sequences in solution gave characteristic, right-handed, alpha-helical spectra by CD spectroscopy.