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2.B.87.  The Tetra Urea Macrocycle-Anion Transporter (TUM-AT) Family

Gale and co-workers studied the anion transport properties of simple tetraurea macrocycles such as 45 (see figure below; Davis et al. 2020). Compound 45 was found to be a selective HCl co-transporter with a very low EC50 value in POPC LUVs of 0.000067% (compound to lipid molar ratio) approaching that of prodigiosin 46 (which has an EC50 value of 0.000061% under the same conditions). In fact, 45 was found to exclusively function as an HCl co-transporter and was unable to facilitate the uniport of chloride. This was due to the high affinity of the free macrocycle for the phospholipid head group, which prevented the free macrocycle diffusing across the lipid bilayer. Only when binding an anionic guest such as chloride or a deprotonated fatty acid, or when deprotonated (so lowering the affinity of the receptor for anions) could the macrocycle traverse the bilayer resulting in exclusive HCl cotransport under the conditions used in the assay (Wu et al. 2019).

HCl cotransporters: tetraurea macrocycle 45 and the natural product prodigiosin 46.

References associated with 2.B.87 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
Wu, X., J.R. Small, A. Cataldo, A.M. Withecombe, P. Turner, and P.A. Gale. (2019). Voltage-Switchable HCl Transport Enabled by Lipid Headgroup-Transporter Interactions. Angew Chem Int Ed Engl 58: 15142-15147. 31400024