Carboxylate Analogues of Aryl-Urea-Substituted Fatty Acids That Target the Mitochondria in MDA-MB-231 Breast Cancer Cells to Promote Cell Death

Koolaji, N; Rawling, T; Bourget, K; Murray, M

Carboxylate Analogues of Aryl-Urea-Substituted Fatty Acids That Target the Mitochondria in MDA-MB-231 Breast Cancer Cells to Promote Cell Death

Koolaji, N Rawling, T

Bourget, K Murray, M

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Publication Type:: Journal Article
Citation:: ChemMedChem, 2018, 13 (10), pp. 1036 - 1043
Issue Date:: 2018-05-23

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Field	Value	Language
dc.contributor.author	Koolaji, N	en_US
dc.contributor.author	Rawling, T https://orcid.org/0000-0002-6624-6586	en_US
dc.contributor.author	Bourget, K	en_US
dc.contributor.author	Murray, M	en_US
dc.date.issued	2018-05-23	en_US
dc.identifier.citation	ChemMedChem, 2018, 13 (10), pp. 1036 - 1043	en_US
dc.identifier.issn	1860-7179	en_US
dc.identifier.uri	http://hdl.handle.net/10453/125416
dc.description.abstract	© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Selective targeting of the tumor cell mitochondrion is a viable approach for the development of anticancer agents because the organelle is functionally different from the mitochondria of normal cells. We recently developed a novel aryl-urea fatty acid, 16({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)hexadecanoic acid (1) that was found to disrupt mitochondria and to activate apoptosis in MDA-MB-231 breast cancer cells. However, there is currently little information on the structural requirements for the activity of compound 1 analogues. The present study evaluated the role of the carboxylic acid group on the anticancer activity of 1. Bioisosteric replacement of the carboxylate in 1 maintained activity. Thus, like 1, the sulfonic acid analogue 1-SA and the oxo-thiadiazole analogue 1-OT were also found to target the mitochondrion and to activate cell killing capacity. The hydroxamic acid analogue 1-HA also killed MDA-MB-231 cells, but its onset of action was slower than that of 1-SA and 1-OT. In contrast, replacement of the carboxylate with non-bioisosteric amido and methylamido groups produced analogues that minimally altered mitochondrial function and showed little capacity to decrease tumor cell viability. These findings suggest that the carboxylate moiety in the novel mitochondrially targeted agent 1 is an important determinant of the kinetics and efficacy of anticancer cell activities of compound 1 analogues. Further development of carboxylate-modified analogues of aryl-urea fatty acids as potential anticancer agents could now be warranted.	en_US
dc.relation	http://purl.org/au-research/grants/nhmrc/GNT1087248
dc.relation.ispartof	ChemMedChem	en_US
dc.relation.isbasedon	10.1002/cmdc.201800018	en_US
dc.subject.classification	Medicinal & Biomolecular Chemistry	en_US
dc.subject.mesh	Cell Line, Tumor	en_US
dc.subject.mesh	Mitochondria	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Breast Neoplasms	en_US
dc.subject.mesh	Carboxylic Acids	en_US
dc.subject.mesh	Fatty Acids	en_US
dc.subject.mesh	Antineoplastic Agents	en_US
dc.subject.mesh	Drug Delivery Systems	en_US
dc.subject.mesh	Apoptosis	en_US
dc.subject.mesh	Cell Survival	en_US
dc.subject.mesh	Female	en_US
dc.subject.mesh	Drug Discovery	en_US
dc.title	Carboxylate Analogues of Aryl-Urea-Substituted Fatty Acids That Target the Mitochondria in MDA-MB-231 Breast Cancer Cells to Promote Cell Death	en_US
dc.type	Journal Article
utslib.citation.volume	10	en_US
utslib.citation.volume	13	en_US
utslib.for	0304 Medicinal and Biomolecular Chemistry	en_US
utslib.for	0305 Organic Chemistry	en_US
utslib.for	1115 Pharmacology and Pharmaceutical Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Mathematical and Physical Sciences
utslib.copyright.status	open_access
pubs.issue	10	en_US
pubs.publication-status	Published	en_US
pubs.volume	13	en_US

Abstract:

© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Selective targeting of the tumor cell mitochondrion is a viable approach for the development of anticancer agents because the organelle is functionally different from the mitochondria of normal cells. We recently developed a novel aryl-urea fatty acid, 16({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)hexadecanoic acid (1) that was found to disrupt mitochondria and to activate apoptosis in MDA-MB-231 breast cancer cells. However, there is currently little information on the structural requirements for the activity of compound 1 analogues. The present study evaluated the role of the carboxylic acid group on the anticancer activity of 1. Bioisosteric replacement of the carboxylate in 1 maintained activity. Thus, like 1, the sulfonic acid analogue 1-SA and the oxo-thiadiazole analogue 1-OT were also found to target the mitochondrion and to activate cell killing capacity. The hydroxamic acid analogue 1-HA also killed MDA-MB-231 cells, but its onset of action was slower than that of 1-SA and 1-OT. In contrast, replacement of the carboxylate with non-bioisosteric amido and methylamido groups produced analogues that minimally altered mitochondrial function and showed little capacity to decrease tumor cell viability. These findings suggest that the carboxylate moiety in the novel mitochondrially targeted agent 1 is an important determinant of the kinetics and efficacy of anticancer cell activities of compound 1 analogues. Further development of carboxylate-modified analogues of aryl-urea fatty acids as potential anticancer agents could now be warranted.

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http://hdl.handle.net/10453/125416