Benzoylurea Oligomers: Synthetic Foldamers That Mimic Extended α Helices

Abstract

Not‐so‐short and curlies: A new benzoylurea‐based foldamer scaffold favors a linear conformation governed by intramolecular hydrogen bonding (see picture, left). The functional groups R are in a staggered arrangement analogous to an α helix. Iterative synthesis and diversification of the functional groups leads to structures with lengths similar to those of naturally occurring α helices (right).

Synthesis and screening of small-molecule α-helix mimetic libraries targeting protein–protein interactions

“…This solid-phase method led to rapid synthesis of various O-alkylated oligoamide structures including longer oligomers (e.g., hexamers) by assembling the monomer building blocks. Such longer oligomers are well suited when targeting extended a-helices, such as transmembrane proteins as demonstrated by Hamilton [28,58]. Ahn and Lee have also described an efficient solid-phase synthesis of tris O-alkylated oligoamides in high purity (83-99%) [40].…”

Oligophenylenaminones as Scaffolds for α-Helix Mimicry

“…These oligobenzoylureas have been shown to adopt conformationally biased structures that are able to project peptidomimetic side chains with the distance and angular projection similar to an R-helix 19,20 and furthermore are able to successfully mimic R-helical protein function in a biological environment. 18 The success of the benzoylureas prompted us to pursue other R-helix mimics of this type.…”

Bcl-2 Family Proteins as Therapeutic Targets

“…More recently benzoylureas (8) have been proposed as an -helical mimetic scaffold (Fig. 5) [71][72][73]. This backbone has been used to develop compounds that bind to pro-survival Bcl-2 family proteins in the low micromolar range [71].…”