Wilson Chelsea R, Puckett Austia O, Murray Isabella M, Oliver Allen G, Hof Fraser
Department of Chemistry, University of Victoria, 3800 Finnerty Rd., Victoria, British Columbia V8P 5C2, Canada.
Centre for Advanced Materials and Related Technology (CAMTEC), University of Victoria, 3800 Finnerty Rd., Victoria, British Columbia V8W 2Y2, Canada.
J Am Chem Soc. 2024 Oct 2;146(41):28005-13. doi: 10.1021/jacs.4c03905.
Herein, we report the synthesis of extended sulfo-pillar[6]arenes (), 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 () or bidirectional () 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 -terphenyl (). We show that these new hosts have ultrahigh affinity toward dabigatran ( = 27 nM, ) in salty solutions and that the analogue can bind betrixaban in bovine plasma with a physiologically relevant (7 μM).
在此，我们报告了扩展磺化柱[6]芳烃（）的合成，这是一类新的主体化合物，在耐盐性以及对多种药物类别具有超高结合亲和力方面具有良好的表现。母体磺化柱[6]芳烃是一种高亲和力主体，有潜力作为超分子逆转剂。然而，它缺乏核心骨架的合成多样性。新型扩展磺化柱[6]芳烃具有疏水腔的单向（）或双向（）延伸。这种新功能能够实现更多的非共价相互作用以及对客体更强的亲和力，我们使用直接口服抗凝剂（DOACs）达比加群、贝曲西班和依度沙班对此进行了验证。DOACs是临床常用的治疗药物，但在主客体化学领域的研究较少。这些药物可预防血栓形成，是超分子螯合作用的主要靶点。这种功能化还通过引入的三联苯（）为磺化柱[6]芳烃家族赋予了新的荧光特性。我们表明，这些新型主体在含盐溶液中对达比加群具有超高亲和力（ = 27 nM，），并且类似物在牛血浆中能以生理相关的（7 μM）结合贝曲西班。
