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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.

Top: Synthesis of 50a and 50b and the X-ray crystal structure of 50b. Bottom: Schematic view of the ion channel formed by 50b in a lipid bilayer and for the blocking of the channel by SDS. Copyright 2017, Wiley-VCH.

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.

Structures of metal–organic complexes 51 and 52.



References associated with 1.D.208 family:

Davis, J.T., P.A. Gale, and R. Quesada. (2020). Advances in anion transport and supramolecular medicinal chemistry. Chem Soc Rev. [Epub: Ahead of Print] 32692794
Haynes, C.J.E., J. Zhu, C. Chimerel, S. Hernández-Ainsa, I.A. Riddell, T.K. Ronson, U.F. Keyser, and J.R. Nitschke. (2017). Blockable Zn L Ion Channels through Subcomponent Self-Assembly. Angew Chem Int Ed Engl 56: 15388-15392. 29024266
Jung, M., H. Kim, K. Baek, and K. Kim. (2008). Synthetic ion channel based on metal-organic polyhedra. Angew Chem Int Ed Engl 47: 5755-5757. 18576447
Kempf, J. and A.R. Schmitzer. (2017). Metal-Organic Synthetic Transporters (MOST): Efficient Chloride and Antibiotic Transmembrane Transporters. Chemistry 23: 6441-6451. 28252814