Aryl-urea fatty acids that activate the p38 MAP kinase and down-regulate multiple cyclins decrease the viability of MDA-MB-231 breast cancer cells

Carbon Chain Length Modulates MDA‐MB‐231 Breast Cancer Cell Killing Mechanisms by Mitochondrially Targeted Aryl−Urea Fatty Acids

“…Through structure‐activity relationship studies we have identified two pharmacophoric groups in the aryl−urea fatty acid drug scaffold. Effective agents contained a terminal aryl system with strongly electron‐withdrawing substituents . In addition, the carboxylate functionality is required for activity and can be replaced with bioisosteric hydroxamic acid, sulfonic acid or oxathiazole groups, but not by non‐bioisosteric amide or ester functionalities .…”

“…Effective agents contained a terminal aryl system with strongly electron-withdrawing substituents. [18,19] In addition, the carboxylate functionality is required for activity and can be replaced with bioisosteric hydroxamic acid, sulfonic acid or oxathiazole groups, but not by non-bioisosteric amide or ester functionalities. [20] The present study evaluated the importance of the alkyl chain length in the activity of 1 g by preparing and testing analogues with chains that varied from 10 to 17 carbons.…”

“…1 g is a promising new lead compound for anticancer drug development, but its optimization requires information on the structural requirements for activity. Structure‐activity relationship studies have identified two pharmacophoric groups in the drug scaffold: the aryl system substituted with strongly electron‐withdrawing substituents, and the carboxylate group that can be replaced with bioisosteric hydroxamic acid, oxo‐thiadiazole or sulfonate moieties . In 1 g these two pharmacophores are linked together by a saturated 16 carbon alkyl chain.…”

Aryl urea substituted fatty acids: a new class of protonophoric mitochondrial uncoupler that utilises a synthetic anion transporter

“…These ndings are consistent with our previous nding that only aryl-ureas with strongly electronwithdrawing groups in the meta-and para-positions promoted mitochondrial dysfunction. 13,14 Analogues 3, 4, and 5 were also inactive. These analogues possess the hydrophilic substituents (negative p total values), indicating that substituent lipophilicity is also critical to activity.…”

“…Aryl ureas capable of disrupting energy production in breast cancer cells possess strong electron withdrawing substituents (s total > 0.66) in the meta-and para-positions of the aryl ring. 13,14 In this study a series of aryl-ureas was prepared bearing electron withdrawing aryl-substituents of varying polarity, determined from the hydrophobicity constants (p total , see Table 1), to assess the inuence of substituent lipophilicity on activity. The compounds were synthesised in 2 steps using N,N-carbonyldiimidazole (CDI) chemistry to form the substituted aryl urea moieties (see Scheme S1 in ESI †).…”