Extended Sulfo-Pillar[6]arenes ─ a New Host Family and Its Application in the Binding of Direct Oral Anticoagulants

Herein, we report the synthesis of extended sulfo-pillar[6]arenes (sP6), a new host class with a pedigree in salt tolerance and ultrahigh binding affinity toward multiple drug classes. The parent sulfo-pillar[6]arene is a high-affinity host with the potential to act as a supramolecular reversal agent. However, it lacks synthetic diversification of the core scaffold. The new extended sulfo-pillar[6]arenes have either a monodirectional (A1sP6) or bidirectional (A1A2sP6) extension of the hydrophobic cavity. This new functionality enables more noncovalent interactions and strong affinity toward guests, which we demonstrate using the direct oral anticoagulants (DOACs) dabigatran, betrixaban, and edoxaban. DOACs are highly prescribed therapeutics that are underexplored in host–guest chemistry. These agents prevent the formation of blood clots and are prime targets for supramolecular sequestration. This functionalization also introduces new fluorescent properties to the sulfo-pillar[6]arene family via an incorporated p-terphenyl (A1A2sP6). We show that these new hosts have ultrahigh affinity toward dabigatran (Kd = 27 nM, A1A2sP6) in salty solutions and that the A1A2sP6 analogue can bind betrixaban in bovine plasma with a physiologically relevant Kd (7 μM).