Towards predictable transmembrane transport: QSAR analysis of anion binding and transport

Nathalie Busschaert,Isabelle L Kirby,Louise E Karagiannidis,Marco Wenzel,Stephen J Moore,G John Langley,Mark E Light,Julie Herniman,Neil J Wells,Paulo J Costa,Samuel J Bradberry,Jennifer R Hiscock,Vítor Félix,Peter N Horton,Jeremy G Frey,Igor Marques,Cally J E Haynes,Philip A Gale

doi:10.1039/c3sc51023a

Nathalie Busschaert, Isabelle L Kirby + Show 16 more

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https://doi.org/10.1039/c3sc51023a

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Abstract

The transport of anions across biological membranes by small molecules is a growing research field due to the potential therapeutic benefits of these compounds. However, little is known about the exact mechanism by which these drug-like molecules work and which molecular features make a good transporter. An extended series of 1-hexyl-3-phenylthioureas were synthesized, fully characterized (NMR, mass spectrometry, IR and single crystal diffraction) and their anion binding and anion transport properties were assessed using 1H NMR titration techniques and a variety of vesicle-based experiments. Quantitative structure–activity relationship (QSAR) analysis revealed that the anion binding abilities of the mono-thioureas are dominated by the (hydrogen bond) acidity of the thiourea NH function. Furthermore, mathematical models show that the experimental transmembrane anion transport ability is mainly dependent on the lipophilicity of the transporter (partitioning into the membrane), but smaller contributions of molecular size (diffusion) and hydrogen bond acidity (anion binding) were also present. Finally, we provide the first step towards predictable anion transport by employing the QSAR equations to estimate the transmembrane transport ability of four new compounds.

Highlights

The development of new transport systems for anionic species is attracting signi cant attention.1–5 The synthesis of new compounds capable of mediating the lipid bilayer transport of anions has generated compounds that can form membrane spanning channels,6–8 relay systems that can ‘hand’ anions across a membrane,9 and anionophores that coordinate anions and encapsulate them in a lipophilic coat that allows the complex to diffuse through the hydrophobic interior of the bilayer.10–13 There are potential future applications of these compounds in treating diseases caused by malfunctioning anion transport proteins in cell membranes (such as cystic brosis),14 or in perturbing pH gradients within cancer cells leading to apoptosis.15–18 Our interest in this latter approach led us to develop anion transporters that initially contained multiple hydrogen bond donors that were based on some of the most effective anion receptor motifs known, such as tris(2aminoethyl)amine (tren).19,20 in order for these species to be eventually applied in vivo we decided to move away from the types of compound traditionally used as receptors and instead develop simpler transporters that have lower molecular masses, lower numbers of hydrogen bond donors and acceptors and lower log P values (octanol–water partitioning coefficient) in order to optimize the chances that these compounds possess acceptable ADME properties (absorption, diffusion, metabolism and excretion), i.e. are more ‘drug-like’.21 By doing this we discovered that very simple small molecules such as thioureas,22,23 cyanoguanidines24 and squaramides25 are capable of effective transmembrane transport of chloride and bicarbonate
In this paper we have reported the rst attempt for a quantitative structure–activity relationship (QSAR) analysis of supramolecular anion binding and anion transport activity by simple 1-hexyl-3-phenylthioureas
It was shown that the binding constants obtained through 1H NMR titrations with chloride, bicarbonate and phosphate correlate well with the Hammett constant of the substituent in the para-position, suggesting that anion binding by simple mono-thioureas is almost exclusively governed by hydrogen bond donor acidity

Summary

Introduction

The development of new transport systems for anionic species is attracting signi cant attention.1–5 The synthesis of new compounds capable of mediating the lipid bilayer transport of anions has generated compounds that can form membrane spanning channels,6–8 relay systems that can ‘hand’ anions across a membrane,9 and anionophores that coordinate anions and encapsulate them in a lipophilic coat that allows the complex to diffuse through the hydrophobic interior of the bilayer.10–13 There are potential future applications of these compounds in treating diseases caused by malfunctioning anion transport proteins in cell membranes (such as cystic brosis),14 or in perturbing pH gradients within cancer cells leading to apoptosis.15–18 Our interest in this latter approach led us to develop anion transporters that initially contained multiple hydrogen bond donors that were based on some of the most effective anion receptor motifs known, such as tris(2aminoethyl)amine (tren).19,20 in order for these species to be eventually applied in vivo we decided to move away from the types of compound traditionally used as receptors and instead develop simpler transporters that have lower molecular masses, lower numbers of hydrogen bond donors and acceptors and lower log P values (octanol–water partitioning coefficient) in order to optimize the chances that these compounds possess acceptable ADME properties (absorption, diffusion, metabolism and excretion), i.e. are more ‘drug-like’.21 By doing this we discovered that very simple small molecules such as thioureas,22,23 cyanoguanidines24 and squaramides25 are capable of effective transmembrane transport of chloride and bicarbonate. Edge Article effect of lipophilicity by increasing the length of an alkyl chain.27 these previous reports link the anion transport ability to molecular properties such as anion binding in a non-quantitative manner.

Results

Conclusion