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Synthetic prodiginine obatoclax (GX15-070) and related analogues: anion binding, transmembrane transport, and cytotoxicity properties

Synthetic prodiginine obatoclax (GX15-070) and related analogues: anion binding, transmembrane transport, and cytotoxicity properties
Synthetic prodiginine obatoclax (GX15-070) and related analogues: anion binding, transmembrane transport, and cytotoxicity properties
Synthetic prodiginine obatoclax shows promise as a potential anticancer drug. This compound promotes apoptosis of cancer cells, although the mechanism of action is unclear. To date, only the inhibition of BCL-2 proteins has been proposed as a mechanism of action. To gain insight into other possible modes of action, we have studied the anion-binding properties of obatoclax and related analogues in solution, in the solid state, and by means of density functional theory calculations. These compounds are well suited to interact with anions such as chloride and bicarbonate. The anion-transport properties of the compounds synthesized were assayed in model phospholipid liposomes by using a chloride-selective-electrode technique and 13C?NMR spectroscopy. The results demonstrated that these compounds are efficient anion exchangers that promote chloride, bicarbonate, and nitrate transport through lipid bilayers at very low concentrations. In vitro studies on small-cell lung carcinoma cell line GLC4 showed that active ionophores are able to discharge pH gradients in living cells and the cytotoxicity of these compounds correlates well with ionophoric activity
antitumor agents, cytotoxicity, ionophores, liposomes, supramolecular chemistry
0947-6539
14074-14083
Díaz de Greñu, Borja
2d890adc-0511-4279-8235-f7fefe96f86a
Hernández, Paulina Iglesias
bbfea59b-25dd-4cb9-b102-0377c8008d3d
Espona, Margarita
e7b22690-379e-4f30-bc5e-99c05ab9d1ae
Quiñonero, David
207e83c3-af9e-41c5-88b9-c6b2bb61e11c
Light, Mark E.
cf57314e-6856-491b-a8d2-2dffc452e161
Torroba, Tomás
46c4486a-d3a4-493b-b972-112c546d3d7c
Pérez-Tomás, Ricardo
65d20fa5-9cc1-4a21-b7f9-56a6ec287eb7
Quesada, Roberto
c7db6299-4eb5-490d-9e6b-be4b9fbc8ca9
Díaz de Greñu, Borja
2d890adc-0511-4279-8235-f7fefe96f86a
Hernández, Paulina Iglesias
bbfea59b-25dd-4cb9-b102-0377c8008d3d
Espona, Margarita
e7b22690-379e-4f30-bc5e-99c05ab9d1ae
Quiñonero, David
207e83c3-af9e-41c5-88b9-c6b2bb61e11c
Light, Mark E.
cf57314e-6856-491b-a8d2-2dffc452e161
Torroba, Tomás
46c4486a-d3a4-493b-b972-112c546d3d7c
Pérez-Tomás, Ricardo
65d20fa5-9cc1-4a21-b7f9-56a6ec287eb7
Quesada, Roberto
c7db6299-4eb5-490d-9e6b-be4b9fbc8ca9

Díaz de Greñu, Borja, Hernández, Paulina Iglesias, Espona, Margarita, Quiñonero, David, Light, Mark E., Torroba, Tomás, Pérez-Tomás, Ricardo and Quesada, Roberto (2011) Synthetic prodiginine obatoclax (GX15-070) and related analogues: anion binding, transmembrane transport, and cytotoxicity properties. Chemistry - A European Journal, 17 (50), 14074-14083. (doi:10.1002/chem.201101547).

Record type: Article

Abstract

Synthetic prodiginine obatoclax shows promise as a potential anticancer drug. This compound promotes apoptosis of cancer cells, although the mechanism of action is unclear. To date, only the inhibition of BCL-2 proteins has been proposed as a mechanism of action. To gain insight into other possible modes of action, we have studied the anion-binding properties of obatoclax and related analogues in solution, in the solid state, and by means of density functional theory calculations. These compounds are well suited to interact with anions such as chloride and bicarbonate. The anion-transport properties of the compounds synthesized were assayed in model phospholipid liposomes by using a chloride-selective-electrode technique and 13C?NMR spectroscopy. The results demonstrated that these compounds are efficient anion exchangers that promote chloride, bicarbonate, and nitrate transport through lipid bilayers at very low concentrations. In vitro studies on small-cell lung carcinoma cell line GLC4 showed that active ionophores are able to discharge pH gradients in living cells and the cytotoxicity of these compounds correlates well with ionophoric activity

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e-pub ahead of print date: 9 November 2011
Published date: 9 December 2011
Keywords: antitumor agents, cytotoxicity, ionophores, liposomes, supramolecular chemistry
Organisations: Chemistry

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Local EPrints ID: 336669
URI: http://eprints.soton.ac.uk/id/eprint/336669
ISSN: 0947-6539
PURE UUID: e658c167-34bd-4ba6-98ae-e58b1cf1a421
ORCID for Mark E. Light: ORCID iD orcid.org/0000-0002-0585-0843

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Date deposited: 02 Apr 2012 14:05
Last modified: 18 Feb 2021 16:52

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Contributors

Author: Borja Díaz de Greñu
Author: Paulina Iglesias Hernández
Author: Margarita Espona
Author: David Quiñonero
Author: Mark E. Light ORCID iD
Author: Tomás Torroba
Author: Ricardo Pérez-Tomás
Author: Roberto Quesada

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