Conformational Control of Transmembrane Cl^- Transport

Abstract

Due to their biological importance, the complexation, sensing, and transport of anions are attracting increasing attention. 1,2 A variety of receptors based on the isophthalamide skeleton (e.g., 1 in Figure 1) have been studied, as these systems are easy to make and are effective anion receptors in organic solution. 3,4 Two strategies to improve the affinity and selectivity of anion receptors are to increase the acidity of hydrogen bond donors and/or to build more rigid scaffolds. The first strategy may, in some cases, result in deprotonation of the receptor by basic anions, 5 whereas the second strategy may require involved syntheses. We report here a host designed to have both enhanced hydrogen bond donor strength and conformational preorganization. Intramolecular hydrogen bonds make isophthalamide 2 a potent anion binder and an effective transmembrane transporter of Cl -.Experiment and calculations show that isophthalamides such as 1 prefer a syn-anti conformation about the 1,3-diamide unit. 6 As this conformation lacks convergent hydrogen bond donors, it is not optimal for anion binding. We reasoned that the -OH groups in 2 should form intramolecular hydrogen bonds with the amide carbonyls to stabilize the syn-syn conformation and favor the cleft needed for anion binding. 3 Compound 3 is a negative control, as its C4, C6-OMe groups should hydrogen bond with the N-H protons to stabilize the anti-anti conformation and preclude anion binding. Figure 2 shows solid-state structures for 2 and 3. 7 The majority of the molecules in the unit cell of 2 adopt a syn-syn conformation with intramolecular hydrogen bonds between the hydroxy and carbonyl groups (O‚‚‚O 2.55-2.57 Å). In this structure, two molecules of 2 in the syn-syn conformation bind the carbonyl oxygens of a third molecule of the receptor (Supporting Information). Compound 3 exists only in the anti-anti conformation. The amide and methoxy substituents are coplanar and involved in intramolecular hydrogen bonds (N‚‚‚O 2.67-2.68 Å). NMR data confirmed that these conformations for 2 and 3 also predominate in solution. In CD 3 CN, the 1 H NMR resonance for the OH protons in 2 was far downfield (δ 13.50), consistent with involvement in hydrogen bonding. Moreover, the chemical shift for the aromatic hydrogen between the amide side chains moved progressively downfield (δ 7.80, 8.18, and 8.70) in going from 2 to 1 to 3, reflecting an increasing preference for conformations wherein the hydrogen is syn to the deshielding carbonyls. The NMR signal for the N-H proton in dimethoxy 3 (δ 7.71) was shifted downfield relative to the N-H protons for 1 and 2 (δ 7.10), presumably due to involvement in intramolecular hydrogen bonds. This structural data indicated that 2 is predisposed toward a syn-syn orientation, whereas 3 favors an anti-anti orientation.Addition of Cl -, Br -, and I -anions to 1 and 2 in CD 3 CN resulted in downfield shifts of the N-H and H2 signals, whereas little change was observed for the O-H signal in 2. These data suggest that 1 and 2 bind anions wit...

Thiosquaramides: pH switchable anion transporters

“…So far, there have only been two other reports concerning switching-off anion transport by deprotonation, but these involve deprotonation of phenolic OH groups which have high p K a values and the switch consequently occurs at pHs that are not physiologically relevant (pH > 7.4). 65,66 On the other hand, the ON–OFF switch in the region pH 6–7 gives the thiosquaramide based receptors more potential in the biological arena and an investigation of the biological activity of thiosquaramides is currently ongoing in our laboratories.…”

Using small molecules to facilitate exchange of bicarbonate and chloride anions across liposomal membranes

“…This efflux is produced via an exchange mechanism with external nitrate anions, in agreement with previous studies. 16,29 Replacing nitrate by the more hydrophilic sulfate in the external medium resulted in no anion transport activity as an anion exchange mechanism is not possible due to the higher hydrophilicity of the dianionic sulfate. A subsequent assay in which a second anion (bicarbonate) was added to the external sulfate medium showed that chloride transport by compounds 1-4 was restored, clear evidence that these compounds facilitate HCO 3 -/Cl -exchange across phospholipid membranes.…”

“…We recently reported the transmembrane chloride transport activity of 4,6-dihydroxyisophthalamide 1. 16 Isophthalamides have amide NH groups that are able to form hydrogen bonds with anions. 17 In the case of 1, conformational control of the anion binding cleft by means of intramolecular hydrogen bonds between the 4,6 dihydroxy units and the neighbouring amide carbonyls resulted in an improved anion affinity in solution and in optimal activity for transmembrane transport of chloride anion.…”

Artificial Anion Transporters in Bilayer Membranes

“…Smith [75] and with J.T. Davis and R. Quesada [76] was aimed to reveal the delicate balance between ionophore conformation and its anion transport rate. In compound 14 (Fig.…”