<i>o</i> ‐Terphenyl‐Based Family of Conjugated Macrocycles: Selective Recognition of Phenylalanine in Water and Interaction With Insulin

Abstract

ABSTRACT The design of supramolecular receptors for amino acids presents a fundamentally challenging yet highly promising avenue of research. Phenylalanine attracts special attention because of its multifaceted role in living organisms. Although many synthetic hosts have been explored for recognition of phenylalanine (Phe), besides cucurbiturils, there are no receptors that show selectivity for Phe over other aromatic amino acids and related aromatic neurotransmitters in water. Toward addressing this challenge, we explored pi‐conjugated water‐soluble macrocycles with hydrophobic pockets. A new family of o ‐terphenyl‐based macrocycles, TP[n] ( n = 2‐8) was synthesized using the Yamamoto reaction. Macrocycles up to the octamer, TP[2]‐TP[8], were isolated and fully characterized. X‐ray studies reveal that these macrocycles can form folded conformations stabilized by stacking interactions. TP[3] was identified as the most selective host for Phe with an affinity of 7 x 10 3 M −1 in water. The hosts, composed of 2–5 subunits were found to effectively inhibit protein aggregation according to the fluorescence assay using thioflavin T. The discovery of the new family of macrocycles paves the way for designing hosts with diverse architectures, precisely tailored geometries, and optimized binding properties capable of targeting not only individual amino acids but also entire protein surfaces.