Lipophilic balance – a new design principle for transmembrane anion carriers

Abstract

Despite extensive interest in transmembrane anion carriers (anionophores), the factors that govern activity are still only partly understood. Herein we report a study which identifies a new principle for anionophore design, that of "lipophilic balance". A series of simple thioureas with identical molecular formulae has been prepared and assayed for chloride/nitrate transport activity in synthetic vesicles. The molecules differ only in the positioning of the phenylthiourea binding unit within an 11-carbon linear chain. They are shown to possess very similar lipophilicities and anion affinities, while a test for leaching establishes that they locate almost exclusively in the vesicle membranes. Notwithstanding their close similarities, activities across the series show >5-fold variation, peaking when the phenylthiourea group is centrally located. The results suggest that transport is favoured by a balanced array of lipophilic substituents, possibly because this arrangement facilitates transfer of the complexed anion into the apolar membrane interior.

A synthetic ion transporter that disrupts autophagy and induces apoptosis by perturbing cellular chloride concentrations

“…Lipophilicity, which determines the ability of a compound to partition into the membrane, has been linked to transmembrane anion transport activity 22,27 ; however, no clear correlation 28 between lipophilicity and anion transport with these compounds could be found (Supplementary Fig. 97a).…”

Thiosquaramides: pH switchable anion transporters

“…It has often been suggested that ion transport across lipid bilayers is diminished when receptors become too lipophilic to interact with the ions at the lipid-water interphase. 12,24,41,42 In order to obtain an estimate of the lipophilicity of compounds 1–8, experimental retention times on reversed-phase HPLC 43 were determined (Table 3). It is clear that the three inactive transporters are also the receptors with the highest lipophilicity (highest retention time), suggesting that lipophilicity may also contribute to the inactivity of 4, 7 and 8 .…”

Aromatic isophthalamides aggregate in lipid bilayers: evidence for a cooperative transport mechanism

“…In a typical assay, unilamellar 1-palmitoyl-2-oleoylsn-glycero-3-phosphocholine (POPC) vesicles (200 nm diameter) were prepared containing an internal aqueous solution of sodium chloride (489 mM NaCl buffered to pH 7.2 with 5 mM sodium phosphate salts). 25 In a recent study on synthetic Tamjamine derivatives by Quesada and co-workers, it was suggested that the optimal lipophilicity range for an anion transporter is between 4.2-5. The internal and external salt solutions were kept isotonic to prevent the vesicles from rupturing.…”