Tunable transmembrane chloride transport by bis-indolylureas

Haynes, Cally J. E.; Moore, Stephen; Hiscock, Jennifer R.; Marques, Igor; Costa, Paulo J.; Félix, Vı́tor; Gale, Philip A.

doi:10.1039/c2sc20041d

Cited by 59 publications

(47 citation statements)

References 64 publications

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“…4 Anion transport may be achieved by a number of strategies including self-assembled channels, 5 relay systems, 6 and mobile carriers. [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] For biological applications, carriers are probably favoured as they do not require cooperative action by several molecules and hence can function at low dose. Carriers may be positively charged, forming neutral complexes which can easily pass through membrane interiors, or may acquire positive charge through protonation.…”

Section: Introductionmentioning

confidence: 99%

Lipophilic balance – a new design principle for transmembrane anion carriers

et al. 2014

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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.

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Section: Introductionmentioning

confidence: 99%

Lipophilic balance – a new design principle for transmembrane anion carriers

et al. 2014

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“…The lipophilicity of an anion carrier is known to affect its transport activity 5,6 and calculated log P (c log P) values (the n-octanol/water partition coefficient) have been shown to be key in determining the transport activity of simple thioureas. 7 Additionally, Quesada et al have shown that for the tambjamine class of transporters, there exists an optimum log P for transport.…”

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confidence: 99%

“…Experiments were also conducted using POPC vesicles doped with cholesterol. The condensing and ordering effects of cholesterol (Chol) on the membrane are well described, 23 hence cholesterol assays have previously been used as evidence for a mobile carrier mechanism in anion transport 5,24 (as slower diffusion across a more rigid membrane is evidence that supports a mobile carrier over a channel mechanism).…”

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Anion transport across varying lipid membranes – the effect of lipophilicity

Spooner

Gale

2015

Chem. Commun.

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“…16 In other work we have shown that ortho-phenylenediamine-based bisureas are effective anion receptors. 17 We decided to explore the anion transport properties of ortho-phenylenediamine-based bisureas as promising candidates for biologically active ion transporters that may conform to the rules of thumb dened by Lipinski and others.…”

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Chloride, carboxylate and carbonate transport by ortho-phenylenediamine-based bisureas

et al. 2013

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Highly potent but structurally simple transmembrane anion transporters are reported that function at receptor to lipid ratios as low as 1 : 1 000 000. The compounds, based on the simple ortho phenylenediamine based bisurea scaffold, have been studied for their ability to facilitate chloride/ nitrate and chloride/bicarbonate antiport, and HCl symport processes using a combination of ion selective electrode and fluorescence techniques. In addition, the transmembrane transport of dicarboxylate anions (maleate and fumarate) by the compounds was examined. Molecular dynamics simulations showed that these compounds permeate the membrane more easily than other promising receptors corroborating the experimental efflux data. Moreover, cell based assays revealed that the majority of the compounds showed cytotoxicity in cancer cells, which may be linked to their ability to function as ion transporters.

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Tunable transmembrane chloride transport by bis-indolylureas

Cited by 59 publications

References 64 publications

Lipophilic balance – a new design principle for transmembrane anion carriers

Lipophilic balance – a new design principle for transmembrane anion carriers

Anion transport across varying lipid membranes – the effect of lipophilicity

Chloride, carboxylate and carbonate transport by ortho-phenylenediamine-based bisureas

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