Carbon Chain Length in a Novel Anticancer Aryl-Urea Fatty Acid Modulates Mitochondrial Targeting, Reactive Oxygen
Yasmin A Elmaghrabi1, Ariane Roseblade2, Khalilur Rahman1
1Discipline of Pharmacology and Sydney Pharmacy School, Faculty of Medicine and Health, University of Sydney, Camperdown NSW, 2006, Australia.
Abstract:
The cancer cell mitochondrion could be a promising target for the development of new anticancer agents. 16-([3-chloro-5-(trifluoromethyl)-phenyl]carbamoylamino)hexadecanoic acid (2) is a novel aryl-urea fatty acid that targets the mitochondrion in MDA-MB-231 breast cancer cells and activates cell death. In the present study, the relationships between alkyl chain length in 2 analogues, mitochondrial disruption and cell killing were evaluated. The chain-contracted C13-analogue 7 c optimally disrupted the mitochondrial membrane potential (IC50 4.8±0.8 μM). In addition, annexin V-FITC/7-AAD assays demonstrated that 7 c was the most effective cell killing analogue and C11 BODIPY (581/591) assays demonstrated that 7 c was also most effective in generating reactive oxygen species in MDA-MB-231 cells. Together, carbon chain length is a key factor that determines the capacity of 2 analogues to disrupt the mitochondrial membrane, induce the production of reactive oxygen species and kill breast cancer cells. As an aryl-urea with enhanced activity and improved drug-like properties, 7 c may be a suitable lead molecule for entry into a program of development of these molecules as anticancer agents.
Insights
A novel aryl-urea fatty acid derivative, 7c, effectively targets cancer cell mitochondria, disrupting membrane potential and inducing cell death. This compound shows promise as a new anticancer agent by generating reactive oxygen species.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Mitochondria are crucial targets for novel anticancer drug development.
- Aryl-urea fatty acids represent a class of compounds with potential anticancer activity.
- Compound 2, a novel aryl-urea fatty acid, targets mitochondria in breast cancer cells.
Purpose of the Study:
- To evaluate the relationship between alkyl chain length of aryl-urea fatty acid analogues and their effects on mitochondrial disruption and cancer cell killing.
- To identify optimal analogues for further development as anticancer agents.
Main Methods:
- Synthesis and evaluation of aryl-urea fatty acid analogues with varying alkyl chain lengths.
- Assessment of mitochondrial membrane potential disruption using specific assays.
- Quantification of cancer cell death using annexin V-FITC/7-AAD staining.
- Measurement of reactive oxygen species (ROS) generation using C11 BODIPY assays.
Main Results:
- The C13-analogue, designated 7c, demonstrated optimal disruption of mitochondrial membrane potential (IC50 = 4.8 ± 0.8 μM).
- Compound 7c exhibited the most effective cancer cell killing and induced the highest levels of reactive oxygen species in MDA-MB-231 cells.
- Alkyl chain length was identified as a critical determinant for the efficacy of these analogues.
Conclusions:
- The carbon chain length of aryl-urea fatty acids significantly influences their ability to disrupt mitochondrial function, generate ROS, and induce cancer cell death.
- Compound 7c displays enhanced activity and improved drug-like properties, positioning it as a promising lead molecule for anticancer drug development.
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