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

Towards predictable transmembrane transport: QSAR analysis of anion binding and anion transport
Towards predictable transmembrane transport: QSAR analysis of anion binding and anion transport
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.
1478-6524
3036-3045
Gale, Philip A.
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Busschaert, Nathalie
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Bradberry, Samuel J.
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Wenzel, Marco
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Haynes, Cally
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Hiscock, Jennifer R.
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Kirby, Isabelle
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Karagiannidis, Louise E.
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Moore, Stephen J.
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Wells, Neil
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Herniman, Julie
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Langley, John
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Horton, Peter
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Light, Mark E.
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Marques, Igor
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Costa, Paulo Jorge
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Felix, Vitor
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Frey, J.G.
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Gale, Philip A.
c840b7e9-6847-4843-91af-fa0f8563d943
Busschaert, Nathalie
bf307f09-0a86-4a03-afd8-4b0a59a8f72b
Bradberry, Samuel J.
7660c1c5-1351-44a6-8e58-238845020311
Wenzel, Marco
d1c2d66d-80a9-4d77-88c6-5c25fbaac546
Haynes, Cally
c56ceaa2-ca95-4ef6-bcce-c5cb825c2ca0
Hiscock, Jennifer R.
99a8a34c-a869-48e2-b713-1e69e4741032
Kirby, Isabelle
5839d488-f346-4741-b757-9ecf30777938
Karagiannidis, Louise E.
625706f1-9870-43dd-9ee1-b981c60562b4
Moore, Stephen J.
34bf8d61-0e01-4e6c-95e9-3e2cad590a1b
Wells, Neil
0eed4c15-38c4-49dd-aee0-dc7e0b908c90
Herniman, Julie
530b1a36-1386-4602-8df7-defa6eb3512b
Langley, John
7ac80d61-b91d-4261-ad17-255f94ea21ea
Horton, Peter
154c8930-bfc3-495b-ad4a-8a278d5da3a5
Light, Mark E.
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Marques, Igor
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Costa, Paulo Jorge
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Felix, Vitor
2d812f44-51b9-4359-9f8b-0e644342c0fe
Frey, J.G.
ba60c559-c4af-44f1-87e6-ce69819bf23f

Gale, Philip A., Busschaert, Nathalie, Bradberry, Samuel J., Wenzel, Marco, Haynes, Cally, Hiscock, Jennifer R., Kirby, Isabelle, Karagiannidis, Louise E., Moore, Stephen J., Wells, Neil, Herniman, Julie, Langley, John, Horton, Peter, Light, Mark E., Marques, Igor, Costa, Paulo Jorge, Felix, Vitor and Frey, J.G. (2013) Towards predictable transmembrane transport: QSAR analysis of anion binding and anion transport. Chemical Science, 4 (8), 3036-3045. (doi:10.1039/C3SC51023A).

Record type: Article

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.

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Published date: 8 May 2013
Organisations: Characterisation and Analytics, Chemistry, Faculty of Natural and Environmental Sciences, Organic Chemistry: Synthesis, Catalysis and Flow

Identifiers

Local EPrints ID: 352306
URI: http://eprints.soton.ac.uk/id/eprint/352306
ISSN: 1478-6524
PURE UUID: 2bb54509-5293-4dfb-9093-9c738694e922
ORCID for Philip A. Gale: ORCID iD orcid.org/0000-0001-9751-4910
ORCID for Julie Herniman: ORCID iD orcid.org/0000-0003-4834-1093
ORCID for John Langley: ORCID iD orcid.org/0000-0002-8323-7235
ORCID for Peter Horton: ORCID iD orcid.org/0000-0001-8886-2016
ORCID for Mark E. Light: ORCID iD orcid.org/0000-0002-0585-0843
ORCID for J.G. Frey: ORCID iD orcid.org/0000-0003-0842-4302

Catalogue record

Date deposited: 09 May 2013 10:59
Last modified: 18 Feb 2021 16:55

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Contributors

Author: Philip A. Gale ORCID iD
Author: Nathalie Busschaert
Author: Samuel J. Bradberry
Author: Marco Wenzel
Author: Cally Haynes
Author: Jennifer R. Hiscock
Author: Isabelle Kirby
Author: Louise E. Karagiannidis
Author: Stephen J. Moore
Author: Neil Wells
Author: Julie Herniman ORCID iD
Author: John Langley ORCID iD
Author: Peter Horton ORCID iD
Author: Mark E. Light ORCID iD
Author: Igor Marques
Author: Paulo Jorge Costa
Author: Vitor Felix
Author: J.G. Frey ORCID iD

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