Catechols as Membrane Anion Transporters

Abstract

Compounds that transport ions across cell membranes may function as sensors, signal transducers, or antimicrobials. Synthetic transporters may also help us understand how natural systems move ions across hydrophobic barriers. 1 There is an interest in identifying compounds that transport anions, especially Cl -, across lipid membranes. 2 Reports that catechol 1 binds Cl -in organic solvents prompted us to use this group to form new anion transporters. 3,4 While bacterial siderophores and synthetic analogues use catecholates to move Fe 3+ across membranes, 5 this paper is the first report, to our knowledge, of catechols facilitating transmembrane transport of anions.We report that bis-catechol 3 is an anion transporter whose activity depends on the catechol's substitution and amphiphilicity. We also describe a liposomal assay that allows one to readily measure anion transport selectivity. This assay shows that transport facilitated by 3 follows the Hofmeister sequence, 6 wherein anions that are easier to dehydrate are made more permeable to the membrane by this bis-catechol.ESI-MS analysis showed that a dimer, 1 2 •Cl -, was the major complex formed when TBA + Cl -was mixed with excess catechol (1) ( Figure S2). Based on this finding we attached two catechols, as either 2,3-dihydroxy or 3,4-dihydroxy benzoates, to a TREN scaffold. 7 An alkyl amide group was linked to TREN's third position. Syntheses of analogues 2-7 in Chart 1 are described in the Supporting Information (SI). The membrane transport activity of these amphiphiles was first evaluated using an assay with the pH-sensitive HPTS dye. 8 EYPC liposomes filled with NaNO 3 and HPTS were suspended in a buffer containing Na 2 SO 4 as an external electrolyte. Fluorescence measurements monitored changes in intravesicular pH after adding analogues 2-7. Figure 1a indicates that intravesicular alkalinization occurred upon addition of 2-5. Because sulfate is poorly membrane permeable, the increase in intravesicular pH is likely caused by ligand-facilitated NO 3 -efflux coupled with cotransport or diffusion of H + out of the liposome.Analogues 2-5 showed major differences in their ion transport activity ( Figure 1). Bis-catechol 3, with a medium-length alkyl chain, was the most active of the 2,3-catechols, indicating that transport activity depends on the compound's ability to partition into the membrane. Compound 5 with the longer C17 chain likely aggregates in water, limiting its partitioning into the liposomes. Compound 2, with the shortest chain, was the least active analogue. Presumably, the most active analogue 3 does not aggregate too much in water and is hydrophobic enough to partition into liposomes. The bis-catechol's alkyl chain length was not the only structural determinant for transport function. Figure 1b/c shows that the catechol's substitution pattern is also crucial for ion transport. Both 2,3-O-methyl analogue 6 and 3,4-substituted catechol 7 were inactive, indicating that 2,3-OH diols are essential for membrane transport activity. Simple changes i...

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