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

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.