Alkylating the Nitrogen of an amide bond results in peptoid structures, leading to conformational restrains, like N-methylation and allows backbone derivatisation. Altering cytotoxicity, bacterial cell selectivity and receptor pharmacology through formation of peptoid derivatives has been published for Cilengitide, Piscidin 1, and MC3, MC4 and MC5 receptor agonists. Sophisticated building blocks furthermore enable the design of macrocycles through intermolecular crosslinking or backbone stabilization through intermolecular ring-closure.

With the example of Cilengitide it has been shown that the N-(4-azidobutyl) group exerts similar conformational restraints as a backbone N-Me group, but additionally it allows conjugation of a desired molecule either via click chemistry or - after azide reduction - via acylation or reductive alkylation. The introduction with simple and robust standard SPPS techniques is described.

Head-to-tail cyclization of N-substituted glycine peptoid oligomers has been shown in another example (MC4 receptor agonist) by bridging the side chains of a peptoid via Cu(I)-catalyzed azide–alkyne cycloaddition. Under dilute conditions, intramolecular side chain tethering is favored over formation of intermolecular crosslinked macrocycles.

In the case of Piscidin 1 (Pis-1), a novel cytotoxic peptide with a cationic α-helical structure, a peptoid residue-substituted derivative has been designed, in which Gly8 of Pis-1 was replaced with Nlys (Lys peptoid residue). Pis-1[NkG] had higher antibacterial activity and lower cytotoxicity against mammalian cells than Pis-1. Pis-1 has a rigid bent structure at Pro8 whereas Pis-1[NkG] existed in a dynamic equilibrium of two conformers with a flexible hinge structure at Nlys8.

The properties of N-substituted Glycine building blocks:

• Provide conformation restrains like N-Methylation
• Enable dackbone derivatisation via Click-reaction or Amine-modification via acylation or reductive amination

➔ Need standard reagents for peptide synthesis?

➔ Follow this link and you find all coupling reagents and solvents

• The Backbone N‑(4-Azidobutyl) Linker for the Preparation of Peptide Chimera; Ana I. Fernández-Llamazares, Jesús García, Jaume Adan, David Meunier, Francesc Mitjans, Jan Spengler and Fernando Albericio; Org. Lett. 2013; 15(17): 4572–4575. DOI: 10.1021/ol402150m.
• Twice tied tight: Enforcing conformational order in bicyclic peptoid oligomers; Sidonie B. L. Vollrath, Stefan Bräse and Kent Kirshenbaum; Chem. Sci. 2012; 3: 2726–2731. DOI: 10.1039/c2sc20473h.
• Peptoid-Peptide Hybrids as Potent Novel Melanocortin Receptor Ligands; John A. W. Kruijtzer, Wouter A. J. Nijenhuis, Nienke Wanders, Willem Hendrik Gispen, Rob M. J. Liskamp and Roger A. H. Adan; J. Med. Chem. 2005; 48: 4224-4230. DOI: 10.1021/jm0490033.
• Structural flexibility and the positive charges are the key factors in bacterial cell selectivity and membrane penetration of peptoid-substituted analog of Piscidin; Jin-Kyoung Kim, Sung-Ah Lee, Soyoung Shin, Jee-Young Lee, Ki-Woong Jeong, Yong Hai Nan, Yong Sun Park, Song Yub Shin, Yangmee Kim; Biochimica et Biophysica Acta 2010; 1798: 1913–1925. DOI: 10.1016/j.bbamem.2010.06.026.