Carboxylate Analogues of Aryl‐Urea‐Substituted Fatty Acids That Target the Mitochondria in MDA‐MB‐231 Breast Cancer Cells to Promote Cell Death. (23rd April 2018)

• Record Type: Journal Article
• Authors: Koolaji, Nooshin; Rawling, Tristan; Bourget, Kirsi; Murray, Michael
• Is Part Of: ChemMedChem. Volume 13:Number 10(2018)
• Page Start: 1036
• Page End: 1043
• Publication Date: 2018-04-23
• Subjects: antitumor agents -- apoptosis -- breast cancer -- fatty acids -- lipid drugs; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201800018
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: 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 compound1 analogues. The present study evaluated the role of the carboxylic acid group on the anticancer activity of1 . Bioisosteric replacement of the carboxylate in1 maintained activity. Thus, like1, the sulfonic acid analogue1‐SA and the oxo‐thiadiazole analogue1‐OT were also found to target the mitochondrion and to activate cell killing capacity. The hydroxamic acid analogue1‐HA also killed MDA‐MB‐231 cells, but its onset of action was slower than that of1‐SA and1‐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 agent1 is an important determinant of the kinetics and efficacy of anticancer cell activities of compound1 analogues. Further development of carboxylate‐modified analogues of aryl‐urea fatty acids as potential anticancer agents could now be warranted. Abstract : Three potent in vitro antagonists of the NK2 receptor, which emerged from in‐house capped dipeptide libraries, were elaborated to produce a panel of compounds endowed with significant antagonist activity in our animal model after intravenous administration. An NMR conformational analysis was done on selected molecules.