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Structure–activity relationships in tripodal transmembrane anion transporters: the effect of fluorination

Structure–activity relationships in tripodal transmembrane anion transporters: the effect of fluorination
Structure–activity relationships in tripodal transmembrane anion transporters: the effect of fluorination
A series of easy-to-make fluorinated tripodal anion transporters containing urea and thiourea groups have been prepared and their anion transport properties studied. Vesicle anion transport assays using ion-selective electrodes show that this class of compound is capable of transporting chloride through a lipid bilayer via a variety of mechanisms, including chloride/H+ cotransport and chloride/nitrate, chloride/bicarbonate, and to a lesser extent an unusual chloride/sulfate antiport process. Calculations indicate that increasing the degree of fluorination of the tripodal transmembrane transporters increases the lipophilicity of the transporter and this is shown to be the major contributing factor in the superior transport activity of the fluorinated compounds, with a maximum transport rate achieved for clog P = 8. The most active transporter 5 contained a urea functionality appended with a 3,5-bis(trifluoromethyl)phenyl group and was able to mediate transmembrane chloride transport at receptor to lipid ratios as low as 1:250000. Proton NMR titration and single crystal X-ray diffraction revealed the ability of the tripodal receptors to bind different anions with varying affinities in a 1:1 or 2:1 stoichiometry in solution and in the solid state. We also provide evidence that the most potent anion transporters are able to induce apoptosis in human cancer cells by using a selection of in vitro viability and fluorescence assays
0002-7863
14136-14148
Busschaert, Nathalie
bf307f09-0a86-4a03-afd8-4b0a59a8f72b
Wenzel, Marco
d1c2d66d-80a9-4d77-88c6-5c25fbaac546
Light, Mark E.
cf57314e-6856-491b-a8d2-2dffc452e161
Iglesias-Hernández, Paulina
c20ef208-a182-47f4-87ab-47ae17bdef90
Pérez-Tomás, Ricardo
65d20fa5-9cc1-4a21-b7f9-56a6ec287eb7
Gale, Philip A.
c840b7e9-6847-4843-91af-fa0f8563d943
Busschaert, Nathalie
bf307f09-0a86-4a03-afd8-4b0a59a8f72b
Wenzel, Marco
d1c2d66d-80a9-4d77-88c6-5c25fbaac546
Light, Mark E.
cf57314e-6856-491b-a8d2-2dffc452e161
Iglesias-Hernández, Paulina
c20ef208-a182-47f4-87ab-47ae17bdef90
Pérez-Tomás, Ricardo
65d20fa5-9cc1-4a21-b7f9-56a6ec287eb7
Gale, Philip A.
c840b7e9-6847-4843-91af-fa0f8563d943

Busschaert, Nathalie, Wenzel, Marco, Light, Mark E., Iglesias-Hernández, Paulina, Pérez-Tomás, Ricardo and Gale, Philip A. (2011) Structure–activity relationships in tripodal transmembrane anion transporters: the effect of fluorination. Journal of the American Chemical Society, 133 (35), 14136-14148. (doi:10.1021/ja205884y). (PMID:21846096)

Record type: Article

Abstract

A series of easy-to-make fluorinated tripodal anion transporters containing urea and thiourea groups have been prepared and their anion transport properties studied. Vesicle anion transport assays using ion-selective electrodes show that this class of compound is capable of transporting chloride through a lipid bilayer via a variety of mechanisms, including chloride/H+ cotransport and chloride/nitrate, chloride/bicarbonate, and to a lesser extent an unusual chloride/sulfate antiport process. Calculations indicate that increasing the degree of fluorination of the tripodal transmembrane transporters increases the lipophilicity of the transporter and this is shown to be the major contributing factor in the superior transport activity of the fluorinated compounds, with a maximum transport rate achieved for clog P = 8. The most active transporter 5 contained a urea functionality appended with a 3,5-bis(trifluoromethyl)phenyl group and was able to mediate transmembrane chloride transport at receptor to lipid ratios as low as 1:250000. Proton NMR titration and single crystal X-ray diffraction revealed the ability of the tripodal receptors to bind different anions with varying affinities in a 1:1 or 2:1 stoichiometry in solution and in the solid state. We also provide evidence that the most potent anion transporters are able to induce apoptosis in human cancer cells by using a selection of in vitro viability and fluorescence assays

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More information

e-pub ahead of print date: 16 August 2011
Published date: 7 September 2011
Organisations: Organic Chemistry: Synthesis, Catalysis and Flow

Identifiers

Local EPrints ID: 195377
URI: https://eprints.soton.ac.uk/id/eprint/195377
ISSN: 0002-7863
PURE UUID: d4d427ab-768f-4eac-a6d2-3602d312f22b
ORCID for Mark E. Light: ORCID iD orcid.org/0000-0002-0585-0843
ORCID for Philip A. Gale: ORCID iD orcid.org/0000-0001-9751-4910

Catalogue record

Date deposited: 19 Aug 2011 07:56
Last modified: 06 Jun 2018 12:54

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