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Protonophoric and mitochondrial uncoupling activity of aryl-carbamate substituted fatty acids.

Hugo I MacDermott-OpeskinCallum ClarkeXin WuAriane RosebladeEdward YorkEthan PacchiniRitik RoyCharles G CranfieldPhilip A GaleMegan L O'MaraMichael MurrayTristan Rawling
Published in: Organic & biomolecular chemistry (2022)
Aryl-urea substituted fatty acids are protonophores and mitochondrial uncouplers that utilise a urea-based synthetic anion transport moiety to carry out the protonophoric cycle. Herein we show that replacement of the urea group with carbamate, a functional group not previously reported to possess anion transport activity, produces analogues that retain the activity of their urea counterparts. Thus, the aryl-carbamate substituted fatty acids uncouple oxidative phosphorylation and inhibit ATP production by collapsing the mitochondrial proton gradient. Proton transport proceeds via self-assembly of the deprotonated aryl-carbamates into membrane permeable dimeric species, formed by intermolecular binding of the carboxylate group to the carbamate moiety. These results highlight the anion transport capacity of the carbamate functional group.
Keyphrases
  • fatty acid
  • molecular docking
  • oxidative stress
  • ionic liquid
  • nitric oxide