Highly Active Halogen Bonding and Chalcogen Bonding Chloride Transporters with Non-Protonophoric Activity.

Laura E Bickerton,Matthew J Langton,Fernanda Duarte,Paul D Beer,Andrew Docker,Heike Kuhn,Alistair J Sterling

doi:10.1002/chem.202101681

Laura E Bickerton, Matthew J Langton + Show 5 more

Open Access

https://doi.org/10.1002/chem.202101681

Copy DOI

Abstract

Synthetic anion transporters show much promise as potential anti‐cancer agents and therapeutics for diseases associated with mis‐regulation of protein anion channels. In such applications high activity and anion selectivity are crucial to overcome competing proton or hydroxide transport which dissipates cellular pH gradients. Here, highly active bidentate halogen bonding and chalcogen bonding anion carriers based on electron deficient iodo‐ and telluromethyl−triazole derivatives are reported. Anion transport experiments in lipid bilayer vesicles reveal record nanomolar chloride transport activity for the bidentate halogen bonding anion carrier, and remarkably high chloride over proton/hydroxide selectivity for the chalcogen bonding anionophore. Computational studies provide further insight into the role of sigma‐hole mediated anion recognition and desolvation at the membrane interface. Comparison with hydrogen bonding analogues demonstrates the importance of employing sigma‐hole donor motifs in synthetic anionophores for achieving both high transport activity and selectivity.

Highlights

Nature is capable of exquisitely selective and highly efficient transmembrane ion transport using membrane-spanning protein ion channels and pumps
We reported that simple acyclic, monodentate iodotriazole derivatives are potent anion transporters, outperforming the archetypal XB donors iodoperfluorobenzene 4 and iodoperfluorohexane 5.[18]. Analysis of the anion transport data and computational studies revealed that multiple triazole XB donors were required per anion to effectively mediate transmembrane anion transport
We report novel bidentate halogen bonding and chalcogen bonding iodo- and telluromethyl-triazole derivatives that act as highly active anionophores

Summary

Introduction

Nature is capable of exquisitely selective and highly efficient transmembrane ion transport using membrane-spanning protein ion channels and pumps. High selectivity for chloride over proton/hydroxide (ClÀ > H+/OHÀ ) is desirable because transmembrane pH gradients are essential for cellular function.[24] Unintended dissipation of pH gradients by anionophores, such as those developed as therapies for channelopathies,[25] may lead to toxicity Many anionophores, such as those based on the naturally occurring H+/ClÀ symporter prodigiosin,[26,27] are known to neutralise acidic organelles and uncouple ATPase proton pumps, and are studied as potential anti-cancer therapeutics.[28,29,30] Beyond applications in medicine, non-protonophoric chloride transporters may find utility as an anion equivalent to the potassium transporter valinomycin, which does not mediate H+ /OHÀ transport and finds numerous applications in physiological research.[31] Recently, Gale, Davis and co-workers highlighted that a key challenge to overcome in order to develop a highly selective ClÀ > H+/OHÀ transporter, is that employing acidic hydrogen bond donors – which are necessary to afford strong anion binding and high transport activity – will significantly suppress or completely nullify chloride selectivity.[32] Common hydrogen bonding anionophores based on simple thiourea and squaramide derivatives exhibit little to no ClÀ > H+/OHÀ selectivity. The alkyne precursors were subjected to CuAAC reactions with azido-pentafluorobenzene in the presence of catalytic [Cu(MeCN)4]PF6 and Cu(I) stabilising ligand tris(benzyltriazolyl) amine (TBTA), affording the bidentate and monodentate anionophores in yields ranging from 46–87 % (Scheme 1C, see the Supporting Information for further synthetic details and characterisation data)

Results and Discussion

Conclusion

Conflict of Interest