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1.D.209.  The Pyridine-2,6-Dicarboxamide (PDA) Unit in a Macrocycle (PDA-MC-ACh) Family

 Chen et al. 2018 designed a unimolecular anion channel by combining three known motifs in the arena of synthetic channels (see figure below) Pyridine-2,6-dicarboxamide (PDA) units, embedded in a macrocycle (Yamnitz et al. 2010), were attached to lipophilic rods (Sisson et al. 2006). The authors hypothesized that PDA rings on phenylene ethylene oligomers (OPE 53n) would stack on an edge of the rod and provide a pipeline for anion transport. OPE 533, estimated to be 3.3 nm long, was the top anion transporter (EC50 = 0.36 μM in EYPC LUVs); it is selective for Cl and functions via H+/Cl co-transport. The linear relationship between kobs for anion transport and concentration of OPE 533 suggested it functions as a unimolecular transporter (Davis et al. 2020). Voltage-clamp experiments were consistent with single channels, showing open lifetimes of seconds, and a large conductance of 0.6 nS was reported for OPE 533. Drawbacks associated with multi-step synthesis of OPE 53 may be outweighed by the pre-organisation of ion binding sites along a membrane-spanning rod.

OPE 53. Schematic showing how OPE 53 (n = 3) enables ion flow across a membrane.  Copyright 2018, Royal Society of Chemistry.


References associated with 1.D.209 family:

Chen, S., , Y. Zhao, , C. Bao, , Y. Zhou, , C. Wang, , Q. Lin, , and L. Zhu,. (2018). A well-defined unimolecular channel facilitates chloride transport. Chem Commun (Camb) 54: 1249-1252. 29340374
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
Sisson, A.L., M.R. Shah, S. Bhosale, and S. Matile. (2006). Synthetic ion channels and pores (2004-2005). Chem Soc Rev 35: 1269-1286. 17225888
Yamnitz, C.R., S. Negin, I.A. Carasel, R.K. Winter, and G.W. Gokel. (2010). Dianilides of dipicolinic acid function as synthetic chloride channels. Chem Commun (Camb) 46: 2838-2840. 20369200