2.B.124.  THE Aryl Urea-modified Fatty Acid (AUFA) Family 

Mitochondrial uncoupling by small molecule protonophores is a promising strategy for developing novel anticancer agents. Aryl urea substituted fatty acids (aryl ureas or AUFAs) are protonophoric anticancer agents (York et al. 2024). To mediate proton transport these molecules self-assemble into membrane-permeable anionic dimers in which intermolecular hydrogen bonds between the carboxylate and aryl-urea anion receptor delocalise the negative charge across the aromatic π-system. York et al. 2024 extended the aromatic π-system by introducing a second phenyl substituent to the aryl urea scaffold and compared the proton transport mechanisms and mitochondrial uncoupling actions of these compounds to their monoaryl analogues. Incorporation of meta-linked phenyl substituents into the aryl urea scaffold enhanced proton transport in vesicles and demonstrated superior capacity to depolarise mitochondria, inhibit ATP production and reduce the viability of MDA-MB-231 breast cancer cells. In contrast, diphenyl ureas linked through a 1,4-distribution across the phenyl ring displayed diminished proton transport activity, despite both diphenyl urea isomers possessing similar binding affinities for carboxylates. Mechanistic studies suggest that inclusion of a second aryl ring changes the proton transport mechanism, presumably due to steric factors that impose higher energy penalties for dimer formation.