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, a new supramolecular host class with a pedigree in salt tolerance and ultra-high binding affinity towards multiple drug classes. The parent sulfo-pillar[6]arene (sP6) 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 mono-directional (A1sP6) or bi-directional (A1A2sP6) extension of the hydrophobic cavity. This new functionality enables more non-covalent interactions and strong affinity towards 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 reversing their action during emergencies is paramount. We show that the new hosts have ultra-high affinity to-wards dabigatran (Kd = 27 nM, A1A2sP6) in salty solutions. Their increased functionality resulted in a 6- and 2.5-fold in-crease in affinity towards betrixaban (Kd = 230 nM, A1A2sP6) and edoxaban (Kd = 800 nM, A1sP6), relative to the unfunctionalized sulfo-pillar[6]arene.