Cancer cell mitochondria are promising anticancer drug targets because they control cell death and are structurally and functionally different from normal cell mitochondria. We synthesized arylurea fatty acids and found that the analogue 16-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)hexadecanoic acid (13b) decreased proliferation and activated apoptosis in MDA-MB-231 breast cancer cells in vitro and in vivo. In mechanistic studies 13b emerged as the prototype of a novel class of mitochondrion-targeted agents that deplete cardiolipin and promote cancer cell death.
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Article Synopsis
- Aryl-urea substituted fatty acids function as protonophores and mitochondrial uncouplers, leveraging a synthetic anion transport system to disrupt proton gradients.
- By substituting the urea with carbamate, a newly identified functional group, the modified compounds still effectively uncouple oxidative phosphorylation and reduce ATP production.
- The study illustrates that dimeric structures formed by the interaction between carboxylate groups and carbamate enable efficient proton transport across membranes, demonstrating the anion transport potential of carbamates.
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