Dibenzo-12-crown-4 group as a pore-forming enhancer for anion transport

Abstract

Dysregulation of anion transport is implicated in a range of diseases, including congenital myotonia, cystic fibrosis, and hereditary renal lithiasis. While natural anion channels exhibit highly complex and intricate structures, the development of structurally simpler artificial channels holds promise for advancing the understanding of anion transport mechanisms and offering novel therapeutic approaches. Among emerging strategies, the use of side chain–side chain interactions to construct artificial anion channels has shown significant potential, particularly through the application of flexible hydrocarbon side chains to facilitate pore formation. Building on this concept, we introduce a novel scaffold—the dibenzo-12-crown-4 group—which unexpectedly acts as a pore-forming enhancer, rather than a cation transporter. By strengthening side chain–side chain interactions, this group promotes the formation of sizable pores within lipid bilayers, selectively and efficiently transporting anions, rather than cations. Notably, channel A10 exhibits a remarkable high Cl⁻/K⁺ selectivity ratio of 17 while showcasing a distinct hierarchy in anion conductivity: ClO₄⁻ > I⁻ > NO₃⁻ > Br⁻ > Cl⁻.