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

Herein, we report the synthesis of extended sulfo-pillar[6]arenes\n(<b>sP6</b>), a new host class with a pedigree in salt tolerance\nand ultrahigh binding affinity toward multiple drug classes. The parent\nsulfo-pillar[6]arene is a high-affinity host with the potential to\nact as a supramolecular reversal agent. However, it lacks synthetic\ndiversification of the core scaffold. The new extended sulfo-pillar[6]arenes\nhave either a monodirectional (<b>A1sP6</b>) or bidirectional\n(<b>A1A2sP6</b>) extension of the hydrophobic cavity. This new\nfunctionality enables more noncovalent interactions and strong affinity\ntoward guests, which we demonstrate using the direct oral anticoagulants\n(DOACs) dabigatran, betrixaban, and edoxaban. DOACs are highly prescribed\ntherapeutics that are underexplored in host–guest chemistry.\nThese agents prevent the formation of blood clots and are prime targets\nfor supramolecular sequestration. This functionalization also introduces\nnew fluorescent properties to the sulfo-pillar[6]arene family via\nan incorporated <i>p</i>-terphenyl (<b>A1A2sP6</b>). We show that these new hosts have ultrahigh affinity toward dabigatran\n(<i>K</i><sub>d</sub> = 27 nM, <b>A1A2sP6</b>) in\nsalty solutions and that the <b>A1A2sP6</b> analogue can bind\nbetrixaban in bovine plasma with a physiologically relevant <i>K</i><sub>d</sub> (7 μM).