1.D.54 The potassium-selective Hexyl-Benzoureido-15-Crown-5-Ether Channel (HBEC) Family

Artificial ion-channels of H-bonded hexyl-benzoureido-15-crown-5-ether are selective for K⁺ over Na⁺. K⁺-channel conductance arises from the formation of oligomeric cooperative channels, resulting in cation-induced membrane polarization and enhanced transport rates. These channels are selectively responsive to the presence of K⁺ cations, even in the presence of a large excess of Na⁺ (Gilles and Barboiu 2015).

Self-assembled alkyl-ureido-benzo-15-crown-5-ethers are selective ionophores for K⁺ cations, which are preferred to Na⁺ cations. The transport mechanism is determined by the optimal coordination rather than classical dimensional compatibility between the crown ether hole and the cation diameter. Li et al. 2018 demonstrated that systematic changes of the structure lead to unexpected modifications in the cation-transport activity and suffice to produce adaptive selection. They showed that the main contribution to performance arises from optimal constraints on the conformational freedom, which are determined by the binding macrocycles, the nature of the hydrogen-bonding groups, and the hydrophobic tails. Simple changes to the flexible 15-crown-5-ether lead to selective carriers for Na⁺. Hydrophobic stabilization of the channels through mutual interactions between lipids and variable hydrophobic tails appears to be an important cause of increased activity. However, restricted translocation is achieved when constrained hydrogen-bonded macrocyclic relays are less dynamic in a pore superstructure (Li et al. 2018). 

A suite of buckyball-based molecular balls (MBs), enabling transmembrane ion transport selectivity have been designed (Li et al. 2020). The modularly tunable MBm-Cn (m = 4-7; n = 6-12) structures consist of a C60-fullerene core, flexible alkyl linkers Cn (i.e., C6 for the n-C6H12 group), and peripherally aligned benzo-3m-crown-m ethers (i.e., m = 4 for benzo-12-crown-4) as ion-transporting units. Screening a matrix of 16 such MBs, combinatorially derived from four different crown units and four different Cn linkers, revealed that their transport selectivities resemble the intrinsic ion binding affinity of the respective benzo-crown units, making custom design of transport selectivity possible. Specifically, MB4s, containing benzo-12-crown-4 units, are Li⁺-selective for transmembrane ion transport while excluding all other monovalent alkali-metal ions. Likewise, the most Na⁺ selective MB5-C8 and K⁺ selective MB6-C8 show high Na⁺/K⁺ and K⁺/Na⁺ selectivity values of 13.7 and 7.8, respectively. For selectivity to Rb⁺ and Cs⁺, the most active MB7-C8 displays high transport efficiencies, with an EC50(Rb⁺) value of 105 nM (0.11 mol %) and an EC50(Cs⁺) value of 77 nM (0.079 mol %) (Li et al. 2020).