Carbon Chain Length Modulates MDA‐MB‐231 Breast Cancer Cell Killing Mechanisms by Mitochondrially Targeted Aryl−Urea Fatty Acids. (9th January 2020)

• Record Type: Journal Article
• Authors: Murray, Michael; Roseblade, Ariane; Chen, Yongjuan; Bourget, Kirsi; Rawling, Tristan
• Is Part Of: ChemMedChem. Volume 15:Number 2(2020)
• Page Start: 247
• Page End: 255
• Publication Date: 2020-01-09
• Subjects: antitumor agents -- apoptosis -- breast cancer -- fatty acids -- lipid drugs; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201900577
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: Targeting the tumor cell mitochondrion could produce novel anticancer agents. We designed an aryl−urea fatty acid (1 g ; 16({[4‐chloro‐3‐(trifluoromethyl)phenyl]carbamoyl}amino)hexadecanoic acid) that disrupted the mitochondrion and decreased MDA‐MB‐231 breast cancer cell viability. To optimize the aryl−ureas the present study evaluated mitochondrial targeting by 1 g analogues containing alkyl chains between 10–17 carbons. Using the dye JC‐1, the C12−C17 analogues efficiently disrupted the mitochondrial membrane potential (IC50 s 3.5±1.2 to 7.6±1.1 μM) and impaired ATP production; shorter analogues were less active. 7‐Aminoactinomycin D/annexin V staining and flow cytometry showed that these agents activated the killing mechanisms of necrosis and apoptosis to varying extents (7‐aminoactinomycin D/annexin V staining ratios 4.3–6.0). Indeed, 1 g and its C17 analogue preferentially activated necrosis and apoptosis, respectively (ratios 2.1 and 16). Taken together, alkyl chain length is a determinant of mitochondrial targeting by aryl−ureas and can be varied to develop analogues that activate apoptosis or necrosis in a regulated fashion. Abstract : Pick your poison : The alkyl chain was varied in the anticancer aryl−urea fatty acid 1 g (16({[4‐chloro‐3‐(trifluoromethyl)phenyl]carbamoyl}amino)hexadecanoic acid). The C12−C17 analogues were found to efficiently impair the mitochondrial membrane potential and ATP production, whereas shorter analogues were less active. Compound 1 g and the C17 analogue also preferentially activated necrosis and apoptosis, respectively. Thus, alkyl chain length is a determinant of mitochondrial targeting by these agents and can be varied to develop analogues that activate apoptosis or necrosis in a regulated fashion.