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Elucidating cylindrospermopsin toxicity via synthetic analogues: An in vitro approach

Elucidating cylindrospermopsin toxicity via synthetic analogues: An in vitro approach
Elucidating cylindrospermopsin toxicity via synthetic analogues: An in vitro approach
Cylindrospermopsin (CYN) is an alkaloid biosynthesized by selected cyanobacteria, the cyto- and genotoxic properties of which have been studied extensively by in vitro and in vivo experimental models. Various studies have separately established the role of uracil, guanidine and hydroxyl groups in CYNinduced toxicity. In the present study, we have prepared five synthetic analogues that all possess a uracil group but had variations in the other functionality found in CYN.We compared the in vitro toxicity of these analogues in common carp hepatocytes by assessing oxidative stress markers, DNA fragmentation and apoptosis. All the analogues tested induced generation of reactive oxygen species, lipid peroxidation (LPO) and DNA fragmentation. However, the greatest increase in LPO and increase in caspase-3 activity, an apoptosis marker, was demonstrated by an analogue containing guanidine, hydroxyl and uracil functionalities similar to those found in CYN but lacking the complex tricyclic structure of CYN.We also report a crystal structure of an analogue lacking the hydroxyl group found in CYN which does not show intramolecular H-bonding interactions between the guanidine and the uracil functionalities. The observations made in this work supports the hypothesis that CYN toxicity is a result of an interplay between both of the uracil, hydroxyl and guanidine functional groups.
cylindrospermopsin, cyanobacteria, mechanism of action, hepatocytes, Oxidative stress, DNA damage
0045-6535
139-147
Evans, Daniel M.
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Hughes, Jack
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Jones, Leigh F.
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Murphy, Patrick J.
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Falfushynska, Halina
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Horyn, Oksana
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Sokolova, Inna M.
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Christensen, Jeppe
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Coles, Simon J.
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Rzymski, Piotr
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Evans, Daniel M.
22675d60-6c15-44b9-b6ce-4e8b6b9d49ef
Hughes, Jack
0ac4ccb6-e64c-4e32-8282-82cd2d787c1b
Jones, Leigh F.
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Murphy, Patrick J.
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Falfushynska, Halina
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Horyn, Oksana
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Sokolova, Inna M.
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Christensen, Jeppe
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Coles, Simon J.
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Rzymski, Piotr
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Evans, Daniel M., Hughes, Jack, Jones, Leigh F., Murphy, Patrick J., Falfushynska, Halina, Horyn, Oksana, Sokolova, Inna M., Christensen, Jeppe, Coles, Simon J. and Rzymski, Piotr (2019) Elucidating cylindrospermopsin toxicity via synthetic analogues: An in vitro approach. Chemosphere, 234, 139-147. (doi:10.1016/j.chemosphere.2019.06.021).

Record type: Article

Abstract

Cylindrospermopsin (CYN) is an alkaloid biosynthesized by selected cyanobacteria, the cyto- and genotoxic properties of which have been studied extensively by in vitro and in vivo experimental models. Various studies have separately established the role of uracil, guanidine and hydroxyl groups in CYNinduced toxicity. In the present study, we have prepared five synthetic analogues that all possess a uracil group but had variations in the other functionality found in CYN.We compared the in vitro toxicity of these analogues in common carp hepatocytes by assessing oxidative stress markers, DNA fragmentation and apoptosis. All the analogues tested induced generation of reactive oxygen species, lipid peroxidation (LPO) and DNA fragmentation. However, the greatest increase in LPO and increase in caspase-3 activity, an apoptosis marker, was demonstrated by an analogue containing guanidine, hydroxyl and uracil functionalities similar to those found in CYN but lacking the complex tricyclic structure of CYN.We also report a crystal structure of an analogue lacking the hydroxyl group found in CYN which does not show intramolecular H-bonding interactions between the guanidine and the uracil functionalities. The observations made in this work supports the hypothesis that CYN toxicity is a result of an interplay between both of the uracil, hydroxyl and guanidine functional groups.

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More information

Accepted/In Press date: 3 June 2019
e-pub ahead of print date: 10 June 2019
Published date: November 2019
Keywords: cylindrospermopsin, cyanobacteria, mechanism of action, hepatocytes, Oxidative stress, DNA damage

Identifiers

Local EPrints ID: 433567
URI: https://eprints.soton.ac.uk/id/eprint/433567
ISSN: 0045-6535
PURE UUID: f943650a-b8c8-4dd1-874c-5e2a741667be
ORCID for Simon J. Coles: ORCID iD orcid.org/0000-0001-8414-9272

Catalogue record

Date deposited: 27 Aug 2019 16:30
Last modified: 28 Aug 2019 00:36

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Contributors

Author: Daniel M. Evans
Author: Jack Hughes
Author: Leigh F. Jones
Author: Patrick J. Murphy
Author: Halina Falfushynska
Author: Oksana Horyn
Author: Inna M. Sokolova
Author: Jeppe Christensen
Author: Simon J. Coles ORCID iD
Author: Piotr Rzymski

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