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

Hugo MacDermott-Opeskin; Callum Clarke; Xin Wu; Ariane Roseblade; Edward York; Ethan Pacchini; Ritik Roy; Charles Cranfield; Philip A. Gale; Megan L. O'Mara; Michael Murray; Tristan Rawling

doi:10.1039/D2OB02049A

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

Hugo MacDermott-Opeskin,

‡^a Callum Clarke,‡^b Xin Wu,

^cd Ariane Roseblade,^b Edward York,^b Ethan Pacchini,^b Ritik Roy,^b Charles Cranfield,

^e Philip A. Gale,

^cf Megan L. O'Mara,

^ag Michael Murray^h and Tristan Rawling

*^b

Author affiliations

* Corresponding authors

^a Research School of Chemistry, College of Science, The Australian National University, Canberra, ACT, Australia

^b School of Mathematical and Physical Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia
E-mail: Tristan.Rawling@uts.edu.au
Tel: +61-2-9514-7956

^c School of Chemistry, The University of Sydney, NSW, Australia

^d School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD 4072, Australia

^e School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia

^f The University of Sydney Nano Institute (SydneyNano), The University of Sydney, NSW, Australia

^g Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia

^h Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, NSW 2006, Australia

Abstract

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.

Organic & Biomolecular Chemistry

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

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

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