1.D.208. The Metal-Organic Complex-Anion Channel (MOC-ACh) Family
Although there are examples of metal–organic complexes (MOC) as cation-selective channels (Jung et al. 2008), Nitschke, Keyser and colleagues described the first MOC to form an anion-selective channel in lipid membranes (see figure shown below; Haynes et al. 2017). Using a self-assembly strategy, these investigators prepared an open-ended container 50a that is 4 nm long with a pore diameter of 2.3 Å, large enough to accommodate halide anions. A crystal structure of the parent assembly 50b (R = CH3) showed a D5-symmetric prism with an open channel.
This MOC 50b has anions bound in 3 ways: (i) 5 perchlorates are fixed on the perimeter; (ii) a bromide, anchored by 10 C–H⋯anion interactions, sits in the centre; and (iii) sulfonates plug both portals. By attaching alkyl chains, the authors prepared 50a with a lipophilic surface that enables the MOC to insert into the lipid bilayer. Complementary experiments, in liposomes and in planar bilayers, showed that 50a is a halide-selective channel and that adding an amphiphilic anion can block the channel and turn off conduction (Davis et al. 2020).
Experiments in POPC vesicles revealed that 50a catalysed selective transport of spherical halides. Fluorescence quenching of lucigenin established that 50a enables Cl−/NO3− exchange. Assays with HPTS showed that the MOC promoted transport of halide anions, with an EC50 = 50 μM for Cl−. Cations did not impact ion exchange, consistent with 50a being anion-selective. The authors uncovered two other features about anion transport catalyzed by 50a: (1) the selectivity of I− > Br− > Cl− correlates with ease of anion dehydration and (2) larger ClO4−, NO3−, pTsO− anions were poorly transported. The authors proposed that the smaller, partially hydrated, halides can access the channel but larger anions can’t.
Kempf and Schmitzer 2017 reported MOC-promoted transmembrane transport of chloride and tetracycline (see the figure below). Using an ion-selective electrode to measure chloride efflux from EYPC liposomes, they found that addition of PdCl2 to a solution of pyridyl 51 increased chloride efflux 2-fold (Davis et al. 2020). The authors concluded that the active MOC is generated by self-assembly in the membrane. Molecular models of complexes of Pd2+@51, and transport experiments in cholesterol-containing liposomes supported the proposal that these MOCs might form ion channels. A mixture of PdCl2, ligand 52 and tetracycline lowered the sensitivity of resistant bacteria to the drug 60-fold. The authors suggested that a porous channel made by MOC 52 enables tetracycline to cross the bacterial membrane.