Ugi Reaction of Natural Amino Acids: A General Route toward Facile Synthesis of Polypeptoids for Bioapplications

Abstract

Polypeptoids represent a significant class of synthetic analogues of natural polypeptides with potential biomimetic applications in materials, catalysis, and pharmaceuticals, but their simple and general synthesis still remains a key challenge. Herein, we demonstrate that Ugi reaction of natural amino acids leads to structurally diverse polypeptoids, including γand δ-, as well as poly(ε-peptoid)s, under mild conditions (open to air, room temperature, and catalyst free). Moreover, this strategy also offers manifold opportunities to introduce functional groups such as fluorescent and clickable alkenes groups into polypeptoids. Such poly(ε-peptoid)s not only exhibit good biocompatibility and antibacterial activity, but perform very effectively as a drugdelivery system. The bacterial inhibition rate of poly(ε-peptoid) was up to 88.8% at concentration of 20 μg mL −1 in comparison to 61.8% of the poly(ε-lysine) control. Overall, this study offers us a general methodology toward facile preparation of polypeptoids for bioapplications.

Polypeptoids synthesis based on Ugi reaction: Advances and perspectives

“…Tao et al . initially approached the synthesis of structurally diverse polypeptoids through Ugi reaction of amino acids . The first attempt was made using α‐amino acids (such as glycine, alanine, etc.)…”

“…A, Synthesis and self‐assembly of amphiphilic polypeptoids. B, Synthesis of fluorescent polypeptoid via Ugi reaction Source : Reproduced with permission from Zhang et al ., 2016, American Chemical Society …”

“…Tao et al . described that the introduction of supplementary carbons between the amino and acid groups would hinder the formation of cyclic intermediate . Obviously, the longer distance between the reactive groups in dipeptides would also disfavor the intramolecular cyclization.…”

“…in 1992, scientists have explored the synthetic, conformational, and application‐oriented aspects of the “peptoid landscape” . Polypeptoids, including α‐, β‐, γ‐, and poly(ε‐peptoid)s, are structural mimics of polypeptides (Figure ) . Because side chains are appended to the amide nitrogen, polypeptoids lack main‐chain chirality, and do not have extensive intermolecular and intramolecular hydrogen bondings .…”

“…Inspired by this unresolved challenge, Ugi reaction was introduced into polypeptoids chemistry . The Ugi reaction is a four‐component reaction between acid, amine, isocyanide, and aldehyde (Figure ) .…”