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Peptide macrocycles are useful tools in chemical biology and for the development of therapeutic compounds. Compared to their linear counterparts, cyclic peptides are more resistant to proteases and their increased conformational rigidity makes them tighter-binding to a given macromolecule [1,2]. However, the relatively high polarity of the secondary amide bonds through the cyclic peptide backbone often results in poor cellular uptake. Since many therapeutic targets are found inside cells, drugs often need to cross multiple hydrophobic membranes to reach their site of action. To cross a membrane, a molecule must first break its interactions with water to go into the hydrophobic media. In many bioactive cyclic peptides, some amide bonds undergo intramolecular hydrogen bonding (IHB), thus internalizing the polarity [3,4]. Other amide bonds are free to interact with water and bring an energetic cost to cross the membrane in a passive way. N-Methylation of free amide bonds (not involved in IHB) is a promising approach to improve cellular uptake [5,6]. Another approach is to use peptoid residues (N-substituted glycines) to replace and mimic peptide bonds. Compared to peptides, the side chains migration to the backbone nitrogens increases proteolytic resistance and decreases the global polarity [7,8]. However, the replacement of the chiral C to CH2 and the display of tertiary amide bonds lead to a lost in conformational definition as N-alkylglycine oligomers are more flexible. Considerable efforts have been achieved to rigidify peptoids, by incorporating rigid monomers that induce dihedral angle preferences. Amongst these monomers, N-arylglycine was reported to significantly rigidify linear and cyclic peptoids [9]. Kirshenbaum and coworkers have shown that electronic repulsion is occurring between the amide bond oxygen and the aromatic ring, inducing a strong energetic preference for the trans-amide bond [9]. With the aim of developing macrocyclic scaffolds that could mimic the functional and conformational space found in peptide structures, we were interested in studying the relationships between the incorporation of rigid N-aryl monomers into cyclic peptoids, the induced conformations and their effects on cellular uptake.

Towards the Development of Cell Permeable Macrocyclic Scaffolds: Probing the Structural Requirements for Enhancing Cellular Uptake