Structure-Activity Relationship and Mechanistic Studies of Bisaryl Urea Anticancer Agents Indicate Mitochondrial Uncoupling by a Fatty Acid-Activated Mechanism.
- Publisher:
- American Chemical Society
- Publication Type:
- Journal Article
- Citation:
- ACS Chemical Biology, 2022, 17, (8), pp. 2065-2073
- Issue Date:
- 2022-08-19
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Field | Value | Language |
---|---|---|
dc.contributor.author | York, E | |
dc.contributor.author | McNaughton, DA | |
dc.contributor.author |
Roseblade, A |
|
dc.contributor.author | Cranfield, CG | |
dc.contributor.author | Gale, PA | |
dc.contributor.author |
Rawling, T |
|
dc.date.accessioned | 2022-12-13T02:29:32Z | |
dc.date.available | 2022-12-13T02:29:32Z | |
dc.date.issued | 2022-08-19 | |
dc.identifier.citation | ACS Chemical Biology, 2022, 17, (8), pp. 2065-2073 | |
dc.identifier.issn | 1554-8929 | |
dc.identifier.issn | 1554-8937 | |
dc.identifier.uri | http://hdl.handle.net/10453/164343 | |
dc.description.abstract | Targeting the cancer cell mitochondrion is a promising approach for developing novel anticancer agents. The experimental anticancer agent N,N'-bis(3,5-dichlorophenyl)urea (SR4) induces apoptotic cell death in several cancer cell lines by uncoupling mitochondrial oxidative phosphorylation (OxPhos) using a protein-free mechanism. However, the precise mechanism by which SR4 depolarizes mitochondria is unclear because SR4 lacks an acidic functional group typically found in protein-independent uncouplers. Recently, it was shown that structurally related thioureas can facilitate proton transport across lipid bilayers by a fatty acid-activated mechanism, in which the fatty acid acts as the site of protonation/deprotonation and the thiourea acts as an anion transporter that shuttles deprotonated fatty acids across the phospholipid bilayer to enable proton leak. In this paper, we show that SR4-mediated proton transport is enhanced by the presence of free fatty acids in the lipid bilayer, indicating that SR4 uncouples mitochondria through the fatty acid-activated mechanism. This mechanistic insight was used to develop a library of substituted bisaryl ureas for structure-activity relationship studies and subsequent cell testing. It was found that lipophilic electron-withdrawing groups on bisaryl ureas enhanced electrogenic proton transport via the fatty acid-activated mechanism and had the capacity to depolarize mitochondria and reduce the viability of MDA-MB-231 breast cancer cells. The most active compound in the series reduced cell viability with greater potency than SR4 and was more effective at inhibiting adenosine triphosphate production. | |
dc.format | Print-Electronic | |
dc.language | eng | |
dc.publisher | American Chemical Society | |
dc.relation | http://purl.org/au-research/grants/arc/DP200100453 | |
dc.relation.ispartof | ACS Chemical Biology | |
dc.relation.isbasedon | 10.1021/acschembio.1c00807 | |
dc.rights | info:eu-repo/semantics/openAccess | |
dc.rights.uri | This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Chemical Biology, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see [insert ACS Articles on Request author-directed link to Published Work, see https://pubs.acs.org/doi/10.1021/acschembio.1c00807 | |
dc.subject | 03 Chemical Sciences, 06 Biological Sciences | |
dc.subject.classification | Organic Chemistry | |
dc.subject.mesh | Antineoplastic Agents | |
dc.subject.mesh | Fatty Acids | |
dc.subject.mesh | Mitochondria | |
dc.subject.mesh | Mitochondrial Proteins | |
dc.subject.mesh | Protons | |
dc.subject.mesh | Structure-Activity Relationship | |
dc.subject.mesh | Urea | |
dc.subject.mesh | Antineoplastic Agents | |
dc.subject.mesh | Fatty Acids | |
dc.subject.mesh | Mitochondria | |
dc.subject.mesh | Mitochondrial Proteins | |
dc.subject.mesh | Protons | |
dc.subject.mesh | Structure-Activity Relationship | |
dc.subject.mesh | Urea | |
dc.subject.mesh | Mitochondria | |
dc.subject.mesh | Protons | |
dc.subject.mesh | Urea | |
dc.subject.mesh | Fatty Acids | |
dc.subject.mesh | Mitochondrial Proteins | |
dc.subject.mesh | Antineoplastic Agents | |
dc.subject.mesh | Structure-Activity Relationship | |
dc.title | Structure-Activity Relationship and Mechanistic Studies of Bisaryl Urea Anticancer Agents Indicate Mitochondrial Uncoupling by a Fatty Acid-Activated Mechanism. | |
dc.type | Journal Article | |
utslib.citation.volume | 17 | |
utslib.location.activity | United States | |
utslib.for | 03 Chemical Sciences | |
utslib.for | 06 Biological Sciences | |
pubs.organisational-group | /University of Technology Sydney | |
pubs.organisational-group | /University of Technology Sydney/Faculty of Science | |
pubs.organisational-group | /University of Technology Sydney/Strength - CHT - Health Technologies | |
pubs.organisational-group | /University of Technology Sydney/Faculty of Science/School of Life Sciences | |
pubs.organisational-group | /University of Technology Sydney/Faculty of Science/School of Mathematical and Physical Sciences | |
pubs.organisational-group | /University of Technology Sydney/Strength - IBMD - Initiative for Biomedical Devices | |
pubs.organisational-group | /University of Technology Sydney/Centre for Health Technologies (CHT) | |
utslib.copyright.status | open_access | * |
pubs.consider-herdc | false | |
dc.date.updated | 2022-12-13T02:29:30Z | |
pubs.issue | 8 | |
pubs.publication-status | Published | |
pubs.volume | 17 | |
utslib.citation.issue | 8 |
Abstract:
Targeting the cancer cell mitochondrion is a promising approach for developing novel anticancer agents. The experimental anticancer agent N,N'-bis(3,5-dichlorophenyl)urea (SR4) induces apoptotic cell death in several cancer cell lines by uncoupling mitochondrial oxidative phosphorylation (OxPhos) using a protein-free mechanism. However, the precise mechanism by which SR4 depolarizes mitochondria is unclear because SR4 lacks an acidic functional group typically found in protein-independent uncouplers. Recently, it was shown that structurally related thioureas can facilitate proton transport across lipid bilayers by a fatty acid-activated mechanism, in which the fatty acid acts as the site of protonation/deprotonation and the thiourea acts as an anion transporter that shuttles deprotonated fatty acids across the phospholipid bilayer to enable proton leak. In this paper, we show that SR4-mediated proton transport is enhanced by the presence of free fatty acids in the lipid bilayer, indicating that SR4 uncouples mitochondria through the fatty acid-activated mechanism. This mechanistic insight was used to develop a library of substituted bisaryl ureas for structure-activity relationship studies and subsequent cell testing. It was found that lipophilic electron-withdrawing groups on bisaryl ureas enhanced electrogenic proton transport via the fatty acid-activated mechanism and had the capacity to depolarize mitochondria and reduce the viability of MDA-MB-231 breast cancer cells. The most active compound in the series reduced cell viability with greater potency than SR4 and was more effective at inhibiting adenosine triphosphate production.
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