Anion Recognition by a Bioactive Diureidodecalin Anionophore: Solid‐State, Solution, and Computational Studies

Abstract

Recent work has identified a bis‐(p‐nitrophenyl)ureidodecalin anion carrier as a promising candidate for biomedical applications, showing good activity for chloride transport in cells yet almost no cytotoxicity. To underpin further development of this and related compounds, a detailed structural and binding investigation is reported. Crystal structures of the transporter as five solvates confirm the diaxial positioning of urea groups while revealing a degree of conformational flexibility. Structures of complexes with Cl−, Br−, NO3 −, SO4 2− and AcO−, supported by computational studies, show how the binding site can adapt to accommodate these anions. 1H NMR binding studies revealed exceptionally high affinities for anions in DMSO, decreasing in the order SO4 2−>H2PO4 −≈HCO3 −≈AcO−≫HSO4 −>Cl−>Br−>NO3 −>I−. Analysis of the binding results suggests that selectivity is determined mainly by the H‐bond acceptor strength of different anions, but is also modulated by receptor geometry.

Anion carriers as potential treatments for cystic fibrosis: transport in cystic fibrosis cells, and additivity to channel-targeting drugs

“…However, 19 was inhibited by both CaCC inh -A01 and CFTR inh -172, possibly because the tren scaffold is more exible and accessible to small molecule inhibitors. 49 Surprisingly, CFTR inh -172 increased anion transport by 15 by a small but signicant degree. Further studies are required to understand this effect.…”

Measuring anion binding at biomembrane interfaces

“…a Gibbs energies of hydration at 25 °C, compiled by Marcus 25 . b Reported by Jurček et al 20 . c Ionic strength fixed at 0.2 M. d Reported by Tatulian 34 , using egg PC vesicles.…”

Measuring anion binding at biomembrane interfaces

“…Compared with Davis's acyclic bis-urea 2 (Fig. 1c), 10 the macrocyclic receptor has a modest 1-2 fold affinity enhancement for Cl -, Brand I -, but a significant 33-fold enhancement for NO3 -. Geometrical optimisations of the anion complexes suggest that 1 has a perfect size and shape complementary fit for NO3resulting in a perfectly flat and D3h-symmeric complex (Fig.…”