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Anion transporters and biological systems

Anion transporters and biological systems
Anion transporters and biological systems
In this Account, we discuss the development of new lipid bilayer anion transporters based on the structure of anionophoric natural products (the prodigiosins) and purely synthetic supramolecular systems. We have studied the interaction of these compounds with human cancer cell lines, and, in general, the most active anion transporter compounds possess the greatest anti-cancer properties.

Initially, we describe the anion transport properties of synthetic molecules that are based on the structure of the family of natural products known as the prodiginines. Obatoclax, for example, is a prodiginine derivative with an indole ring that is currently in clinical trials for use as an anti-cancer drug. The anion transport properties of the compounds were correlated with their toxicity toward small cell human lung cancer GLC4 cells. We studied related compounds with enamine moieties, tambjamines, that serve as active transporters. These molecules and others in this series could depolarize acidic compartments within GLC4 cells and trigger apoptosis. In a study of the variation of lipophilicity of a series of these compounds, we observed that, as log P increases, the anion transport efficiency reaches a peak and then decreases.

In addition, we discuss the anion transport properties of series of synthetic supramolecular anion receptor species. We synthesized trisureas and thioureas based on the tren backbone, and found that the thiourea compounds effectively transport anions. Fluorination of the pendant phenyl groups in this series of compounds greatly enhances the transport properties. Similar to our earlier results, the most active anion transporters reduced the viability of human cancer cell lines by depolarizing acidic compartments in GLC4 cells and triggering apoptosis.

In an attempt to produce simpler transporters that obey Lipinski’s Rule of Five, we synthesized simpler systems containing a single urea or thiourea group. Once again the thiourea systems, and in particular a thiourea with a pendant indole group, transported anions efficiently. A series of related compounds containing a pendant trifluoromethyl group showed enhanced transport and significant anticancer properties.

Researchers still need to determine of the exact mechanism of how these compounds depolarize acidic organelles within cancer cells. However, this work shows that these transporters based upon both natural products and purely synthetic supramolecular systems transport anions, depolarize acidic compartments within cancer cells and trigger apoptosis.
0001-4842
130403084748005
Gale, Philip A.
c840b7e9-6847-4843-91af-fa0f8563d943
Pérez-Tomás, Ricardo
65d20fa5-9cc1-4a21-b7f9-56a6ec287eb7
Quesada, Roberto
c7db6299-4eb5-490d-9e6b-be4b9fbc8ca9
Gale, Philip A.
c840b7e9-6847-4843-91af-fa0f8563d943
Pérez-Tomás, Ricardo
65d20fa5-9cc1-4a21-b7f9-56a6ec287eb7
Quesada, Roberto
c7db6299-4eb5-490d-9e6b-be4b9fbc8ca9

Gale, Philip A., Pérez-Tomás, Ricardo and Quesada, Roberto (2013) Anion transporters and biological systems. Accounts of Chemical Research, 130403084748005. (doi:10.1021/ar400019p).

Record type: Article

Abstract

In this Account, we discuss the development of new lipid bilayer anion transporters based on the structure of anionophoric natural products (the prodigiosins) and purely synthetic supramolecular systems. We have studied the interaction of these compounds with human cancer cell lines, and, in general, the most active anion transporter compounds possess the greatest anti-cancer properties.

Initially, we describe the anion transport properties of synthetic molecules that are based on the structure of the family of natural products known as the prodiginines. Obatoclax, for example, is a prodiginine derivative with an indole ring that is currently in clinical trials for use as an anti-cancer drug. The anion transport properties of the compounds were correlated with their toxicity toward small cell human lung cancer GLC4 cells. We studied related compounds with enamine moieties, tambjamines, that serve as active transporters. These molecules and others in this series could depolarize acidic compartments within GLC4 cells and trigger apoptosis. In a study of the variation of lipophilicity of a series of these compounds, we observed that, as log P increases, the anion transport efficiency reaches a peak and then decreases.

In addition, we discuss the anion transport properties of series of synthetic supramolecular anion receptor species. We synthesized trisureas and thioureas based on the tren backbone, and found that the thiourea compounds effectively transport anions. Fluorination of the pendant phenyl groups in this series of compounds greatly enhances the transport properties. Similar to our earlier results, the most active anion transporters reduced the viability of human cancer cell lines by depolarizing acidic compartments in GLC4 cells and triggering apoptosis.

In an attempt to produce simpler transporters that obey Lipinski’s Rule of Five, we synthesized simpler systems containing a single urea or thiourea group. Once again the thiourea systems, and in particular a thiourea with a pendant indole group, transported anions efficiently. A series of related compounds containing a pendant trifluoromethyl group showed enhanced transport and significant anticancer properties.

Researchers still need to determine of the exact mechanism of how these compounds depolarize acidic organelles within cancer cells. However, this work shows that these transporters based upon both natural products and purely synthetic supramolecular systems transport anions, depolarize acidic compartments within cancer cells and trigger apoptosis.

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More information

e-pub ahead of print date: 3 April 2013
Organisations: Organic Chemistry: Synthesis, Catalysis and Flow

Identifiers

Local EPrints ID: 350878
URI: http://eprints.soton.ac.uk/id/eprint/350878
ISSN: 0001-4842
PURE UUID: fa8b6e0c-ea2f-4fe6-aa60-d3459cc02f0b
ORCID for Philip A. Gale: ORCID iD orcid.org/0000-0001-9751-4910

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Date deposited: 09 Apr 2013 14:05
Last modified: 15 Mar 2024 03:06

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Contributors

Author: Philip A. Gale ORCID iD
Author: Ricardo Pérez-Tomás
Author: Roberto Quesada

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