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Development of a library of thiophene‐based drug‐like Lego molecules: Evaluation of their anion binding, transport properties, and cytotoxicity

Development of a library of thiophene‐based drug‐like Lego molecules: Evaluation of their anion binding, transport properties, and cytotoxicity
Development of a library of thiophene‐based drug‐like Lego molecules: Evaluation of their anion binding, transport properties, and cytotoxicity
The anion‐binding and transport properties of an extensive library of thiophene‐based molecules are reported. Seventeen bis‐urea positional isomers, with different binding conformations and lipophilicities, have been synthesized by appending α‐ or β‐thiophene or α‐, β‐, or γ‐benzo[b]thiophene moieties to an ortho‐phenylenediamine central core, yielding six subsets of positional isomers. Through 1H NMR, X‐ray crystallography, molecular modelling, and anion efflux studies, it is demonstrated that the most active transporters adopt a pre‐organized binding conformation capable of promoting the recognition of chloride, using urea and C−H binding groups in a cooperative fashion. Additional large unilamellar vesicle‐based assays, carried out under electroneutral and electrogenic conditions, together with N‐methyl‐d‐glucamine chloride assays, have indicated that anion efflux occurs mainly through an H+/Cl− symport mechanism. On the other hand, the most efficient anion transporter displays cytotoxicity against tumor cell lines, while having no effects on a cystic fibrosis cell line.
anion transport, cytotoxicity, efflux studies, molecular modelling, thiophene-based molecules
0947-6539
888-889
Vieira, Paulo
869870b2-d3df-4dfb-8c43-34f28579c80b
Miranda, Margarida Q.
f4ae5b90-cc88-40da-9e53-a5742fa745f6
Marques, Igor
97cbc26e-6d94-43e6-a934-1d69dad8de06
Carvalho, Sílvia
4125da5d-db90-46db-9db3-014b28b142e1
Chen, Li‐jun
03469049-e359-4022-91c1-b4389fad6d97
Howe, Ethan N. W.
ddb73eed-ad54-4f23-86ee-5e719747c7ed
Zhen, Carl
bc227cd4-7120-49a7-829c-c70901bd8600
Leung, Claudia Y.
06ed3388-c56d-4dd9-839b-5543261d59c7
Spooner, Michael J.
bb6ca5e3-f485-4025-900f-8945fd47f461
Morgado, Bárbara
0e12ec54-02b2-411f-867c-abda453860ea
Cruz E Silva, Odete A. B.
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Moiteiro, Cristina
518f2554-bb6c-4838-8c5d-591354cead7c
Gale, Philip A.
c840b7e9-6847-4843-91af-fa0f8563d943
Félix, Vítor
b4098ac2-b86b-48f3-af11-c767e24fac6e
Vieira, Paulo
869870b2-d3df-4dfb-8c43-34f28579c80b
Miranda, Margarida Q.
f4ae5b90-cc88-40da-9e53-a5742fa745f6
Marques, Igor
97cbc26e-6d94-43e6-a934-1d69dad8de06
Carvalho, Sílvia
4125da5d-db90-46db-9db3-014b28b142e1
Chen, Li‐jun
03469049-e359-4022-91c1-b4389fad6d97
Howe, Ethan N. W.
ddb73eed-ad54-4f23-86ee-5e719747c7ed
Zhen, Carl
bc227cd4-7120-49a7-829c-c70901bd8600
Leung, Claudia Y.
06ed3388-c56d-4dd9-839b-5543261d59c7
Spooner, Michael J.
bb6ca5e3-f485-4025-900f-8945fd47f461
Morgado, Bárbara
0e12ec54-02b2-411f-867c-abda453860ea
Cruz E Silva, Odete A. B.
55d55c16-ff74-43b3-bbb9-b001d9f694cc
Moiteiro, Cristina
518f2554-bb6c-4838-8c5d-591354cead7c
Gale, Philip A.
c840b7e9-6847-4843-91af-fa0f8563d943
Félix, Vítor
b4098ac2-b86b-48f3-af11-c767e24fac6e

Vieira, Paulo, Miranda, Margarida Q., Marques, Igor, Carvalho, Sílvia, Chen, Li‐jun, Howe, Ethan N. W., Zhen, Carl, Leung, Claudia Y., Spooner, Michael J., Morgado, Bárbara, Cruz E Silva, Odete A. B., Moiteiro, Cristina, Gale, Philip A. and Félix, Vítor (2020) Development of a library of thiophene‐based drug‐like Lego molecules: Evaluation of their anion binding, transport properties, and cytotoxicity. Chemistry - A European Journal, 26 (4), 888-889. (doi:10.1002/chem.201904255).

Record type: Article

Abstract

The anion‐binding and transport properties of an extensive library of thiophene‐based molecules are reported. Seventeen bis‐urea positional isomers, with different binding conformations and lipophilicities, have been synthesized by appending α‐ or β‐thiophene or α‐, β‐, or γ‐benzo[b]thiophene moieties to an ortho‐phenylenediamine central core, yielding six subsets of positional isomers. Through 1H NMR, X‐ray crystallography, molecular modelling, and anion efflux studies, it is demonstrated that the most active transporters adopt a pre‐organized binding conformation capable of promoting the recognition of chloride, using urea and C−H binding groups in a cooperative fashion. Additional large unilamellar vesicle‐based assays, carried out under electroneutral and electrogenic conditions, together with N‐methyl‐d‐glucamine chloride assays, have indicated that anion efflux occurs mainly through an H+/Cl− symport mechanism. On the other hand, the most efficient anion transporter displays cytotoxicity against tumor cell lines, while having no effects on a cystic fibrosis cell line.

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e-pub ahead of print date: 7 November 2019
Published date: 16 January 2020
Keywords: anion transport, cytotoxicity, efflux studies, molecular modelling, thiophene-based molecules

Identifiers

Local EPrints ID: 437376
URI: http://eprints.soton.ac.uk/id/eprint/437376
ISSN: 0947-6539
PURE UUID: 2bc32720-3059-497b-923d-ecb813979b28
ORCID for Philip A. Gale: ORCID iD orcid.org/0000-0001-9751-4910

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Date deposited: 29 Jan 2020 17:30
Last modified: 15 Sep 2021 01:44

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Contributors

Author: Paulo Vieira
Author: Margarida Q. Miranda
Author: Igor Marques
Author: Sílvia Carvalho
Author: Li‐jun Chen
Author: Ethan N. W. Howe
Author: Carl Zhen
Author: Claudia Y. Leung
Author: Michael J. Spooner
Author: Bárbara Morgado
Author: Odete A. B. Cruz E Silva
Author: Cristina Moiteiro
Author: Philip A. Gale ORCID iD
Author: Vítor Félix

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