A potent fluorescent transmembrane HCl transporter perturbs cellular pH and promotes cancer cell death.

Fares, M; Wu, X; McNaughton, DA; Gilchrist, AM; Lewis, W; Keller, PA; Arias-Betancur, A; Fontova, P; Pérez-Tomás, R; Gale, PA

A potent fluorescent transmembrane HCl transporter perturbs cellular pH and promotes cancer cell death.

Fares, M Wu, X McNaughton, DA Gilchrist, AM Lewis, W Keller, PA Arias-Betancur, A Fontova, P Pérez-Tomás, R Gale, PA

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Publisher:: Royal Society of Chemistry (RSC)
Publication Type:: Journal Article
Citation:: Org Biomol Chem, 2023, 21, (12), pp. 2509-2515
Issue Date:: 2023-03-22

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Field	Value	Language
dc.contributor.author	Fares, M
dc.contributor.author	Wu, X
dc.contributor.author	McNaughton, DA
dc.contributor.author	Gilchrist, AM
dc.contributor.author	Lewis, W
dc.contributor.author	Keller, PA
dc.contributor.author	Arias-Betancur, A
dc.contributor.author	Fontova, P
dc.contributor.author	Pérez-Tomás, R
dc.contributor.author	Gale, PA
dc.date.accessioned	2023-09-27T04:46:02Z
dc.date.available	2023-09-27T04:46:02Z
dc.date.issued	2023-03-22
dc.identifier.citation	Org Biomol Chem, 2023, 21, (12), pp. 2509-2515
dc.identifier.issn	1477-0520
dc.identifier.issn	1477-0539
dc.identifier.uri	http://hdl.handle.net/10453/172324
dc.description.abstract	A series of fluorescent coumarin bis-ureas 1-4 have been synthesised, and their anion transport properties studied. The compounds function as highly potent HCl co-transport agents in lipid bilayer membranes. Single crystal X-ray diffraction of compound 1 showed antiparallel stacking of the coumarin rings, stabilised by hydrogen bonds. Binding studies, using 1H-NMR titration, showed moderate chloride binding in DMSO-d6/0.5% with 1 : 1 binding mode (for transporter 1) and 1 : 2 binding mode (host: guest, for transporters 2-4). We examined the cytotoxicity of compounds 1-4 against three cancer cell lines, lung adenocarcinoma (A549), colon adenocarcinoma (SW620) and breast adenocarcinoma (MCF-7). The most lipophilic transporter, 4 showed a cytotoxic effect against all three cancer cell lines. Cellular fluorescence studies showed compound 4 crossed the plasma membrane and localised in the cytoplasm after a short time. Interestingly, compound 4, lacking any lysosome targeting groups, was co-localised with LysoTracker Red at 4 and 8 h in the lysosome. Cellular anion transport of compound 4 was assessed by measuring intracellular pH and showed a decrease in cellular pH, which may be due to the capacity of transporter 4 to co-transport HCl across biological membranes, as evidenced by the liposomal studies.
dc.format	Electronic
dc.language	eng
dc.publisher	Royal Society of Chemistry (RSC)
dc.relation	http://purl.org/au-research/grants/arc/DP200100453
dc.relation.ispartof	Org Biomol Chem
dc.relation.isbasedon	10.1039/d3ob00128h
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry
dc.subject.classification	Organic Chemistry
dc.subject.classification	3404 Medicinal and biomolecular chemistry
dc.subject.classification	3405 Organic chemistry
dc.subject.mesh	Humans
dc.subject.mesh	Adenocarcinoma
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Colonic Neoplasms
dc.subject.mesh	Cell Death
dc.subject.mesh	Antineoplastic Agents
dc.subject.mesh	Anions
dc.subject.mesh	Coumarins
dc.subject.mesh	Hydrogen-Ion Concentration
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Humans
dc.subject.mesh	Adenocarcinoma
dc.subject.mesh	Colonic Neoplasms
dc.subject.mesh	Anions
dc.subject.mesh	Coumarins
dc.subject.mesh	Antineoplastic Agents
dc.subject.mesh	Cell Death
dc.subject.mesh	Hydrogen-Ion Concentration
dc.subject.mesh	Humans
dc.subject.mesh	Adenocarcinoma
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Colonic Neoplasms
dc.subject.mesh	Cell Death
dc.subject.mesh	Antineoplastic Agents
dc.subject.mesh	Anions
dc.subject.mesh	Coumarins
dc.subject.mesh	Hydrogen-Ion Concentration
dc.title	A potent fluorescent transmembrane HCl transporter perturbs cellular pH and promotes cancer cell death.
dc.type	Journal Article
utslib.citation.volume	21
utslib.location.activity	England
utslib.for	0304 Medicinal and Biomolecular Chemistry
utslib.for	0305 Organic Chemistry
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 - TKC - The Kidman Centre
utslib.copyright.status	closed_access	*
dc.date.updated	2023-09-27T04:46:00Z
pubs.issue	12
pubs.publication-status	Published online
pubs.volume	21
utslib.citation.issue	12

Abstract:

A series of fluorescent coumarin bis-ureas 1-4 have been synthesised, and their anion transport properties studied. The compounds function as highly potent HCl co-transport agents in lipid bilayer membranes. Single crystal X-ray diffraction of compound 1 showed antiparallel stacking of the coumarin rings, stabilised by hydrogen bonds. Binding studies, using 1H-NMR titration, showed moderate chloride binding in DMSO-d6/0.5% with 1 : 1 binding mode (for transporter 1) and 1 : 2 binding mode (host: guest, for transporters 2-4). We examined the cytotoxicity of compounds 1-4 against three cancer cell lines, lung adenocarcinoma (A549), colon adenocarcinoma (SW620) and breast adenocarcinoma (MCF-7). The most lipophilic transporter, 4 showed a cytotoxic effect against all three cancer cell lines. Cellular fluorescence studies showed compound 4 crossed the plasma membrane and localised in the cytoplasm after a short time. Interestingly, compound 4, lacking any lysosome targeting groups, was co-localised with LysoTracker Red at 4 and 8 h in the lysosome. Cellular anion transport of compound 4 was assessed by measuring intracellular pH and showed a decrease in cellular pH, which may be due to the capacity of transporter 4 to co-transport HCl across biological membranes, as evidenced by the liposomal studies.

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http://hdl.handle.net/10453/172324