The University of Southampton
University of Southampton Institutional Repository

Triggering apoptosis in cancer cells with an analogue of cribrostatin 6 that elevates intracellular ROS

Triggering apoptosis in cancer cells with an analogue of cribrostatin 6 that elevates intracellular ROS
Triggering apoptosis in cancer cells with an analogue of cribrostatin 6 that elevates intracellular ROS
Elevation of reactive oxygen species (ROS) is both a consequence and driver of the upregulated metabolism and proliferation of transformed cells. The resulting increase in oxidative stress is postulated to saturate the cellular antioxidant machinery{,} leaving cancer cells susceptible to agents that further elevate their intracellular oxidative stress. Several small molecules, including the marine natural product cribrostatin 6, have been demonstrated to trigger apoptosis in cancer cells by increasing intracellular ROS. Here, we report the modular synthesis of a series of cribrostatin 6 derivatives, and assessment of their activity in a number of cell lines. We establish that placing a phenyl ring on carbon 8 of cribrostatin 6 leads to increased potency, and observe a window of selectivity towards cancer cells. The mechanism of activity of this more potent analogue is assessed and demonstrated to induce apoptosis in cancer cells by increasing ROS. Our results demonstrate the potential for targeting tumors with molecules that enhance intracellular oxidative stress.
1477-0520
9322-9330
Asby, D.J.
d7bc348c-1cb5-4df1-88a5-20940c0d2b3c
Radigois, M.G.
cb23cfc8-73fc-4ce2-a09f-89ca2655156a
Wilson, D.C.
2d86e1f9-76cb-4ff0-9db8-925711b8aca2
Cuda, F.
ad509342-f3ce-4957-96aa-338007af1e41
Chai, C.L.L.
4c6c57f9-600f-41e2-8d33-a1e62c8610b4
Chen, A.
28ea8af7-c45c-4f4b-b6f0-44fc81aab4fd
Bienemann, A.S.
d0387c54-d6a4-46f4-88f0-583a582c1e17
Light, M.E.
d04ad463-ba94-4c59-ab35-a64901f32501
Harrowven, D.
bddcfab6-dbde-49df-aec2-42abbcf5d10b
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2
Asby, D.J.
d7bc348c-1cb5-4df1-88a5-20940c0d2b3c
Radigois, M.G.
cb23cfc8-73fc-4ce2-a09f-89ca2655156a
Wilson, D.C.
2d86e1f9-76cb-4ff0-9db8-925711b8aca2
Cuda, F.
ad509342-f3ce-4957-96aa-338007af1e41
Chai, C.L.L.
4c6c57f9-600f-41e2-8d33-a1e62c8610b4
Chen, A.
28ea8af7-c45c-4f4b-b6f0-44fc81aab4fd
Bienemann, A.S.
d0387c54-d6a4-46f4-88f0-583a582c1e17
Light, M.E.
d04ad463-ba94-4c59-ab35-a64901f32501
Harrowven, D.
bddcfab6-dbde-49df-aec2-42abbcf5d10b
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2

Asby, D.J., Radigois, M.G., Wilson, D.C., Cuda, F., Chai, C.L.L., Chen, A., Bienemann, A.S., Light, M.E., Harrowven, D. and Tavassoli, Ali (2016) Triggering apoptosis in cancer cells with an analogue of cribrostatin 6 that elevates intracellular ROS. Organic & Biomolecular Chemistry, 14 (39), 9322-9330. (doi:10.1039/C6OB01591C).

Record type: Article

Abstract

Elevation of reactive oxygen species (ROS) is both a consequence and driver of the upregulated metabolism and proliferation of transformed cells. The resulting increase in oxidative stress is postulated to saturate the cellular antioxidant machinery{,} leaving cancer cells susceptible to agents that further elevate their intracellular oxidative stress. Several small molecules, including the marine natural product cribrostatin 6, have been demonstrated to trigger apoptosis in cancer cells by increasing intracellular ROS. Here, we report the modular synthesis of a series of cribrostatin 6 derivatives, and assessment of their activity in a number of cell lines. We establish that placing a phenyl ring on carbon 8 of cribrostatin 6 leads to increased potency, and observe a window of selectivity towards cancer cells. The mechanism of activity of this more potent analogue is assessed and demonstrated to induce apoptosis in cancer cells by increasing ROS. Our results demonstrate the potential for targeting tumors with molecules that enhance intracellular oxidative stress.

Text
manuscript.pdf - Accepted Manuscript
Download (2MB)
Text
ESI.pdf - Other
Download (4MB)

More information

Accepted/In Press date: 7 September 2016
e-pub ahead of print date: 15 September 2016

Identifiers

Local EPrints ID: 401242
URI: https://eprints.soton.ac.uk/id/eprint/401242
ISSN: 1477-0520
PURE UUID: 187bc291-ef44-401a-a845-5a80e573e625
ORCID for D. Harrowven: ORCID iD orcid.org/0000-0001-6730-3573
ORCID for Ali Tavassoli: ORCID iD orcid.org/0000-0002-7420-5063

Catalogue record

Date deposited: 07 Oct 2016 13:54
Last modified: 14 Jul 2018 00:36

Export record

Altmetrics

Contributors

Author: D.J. Asby
Author: M.G. Radigois
Author: D.C. Wilson
Author: F. Cuda
Author: C.L.L. Chai
Author: A. Chen
Author: A.S. Bienemann
Author: M.E. Light
Author: D. Harrowven ORCID iD
Author: Ali Tavassoli ORCID iD

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of https://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×