PMID- 35854216
OWN - NLM
STAT- MEDLINE
DCOM- 20220822
LR  - 20221208
IS  - 1554-8937 (Electronic)
IS  - 1554-8929 (Linking)
VI  - 17
IP  - 8
DP  - 2022 Aug 19
TI  - Structure-Activity Relationship and Mechanistic Studies of Bisaryl Urea 
      Anticancer Agents Indicate Mitochondrial Uncoupling by a Fatty Acid-Activated 
      Mechanism.
PG  - 2065-2073
LID - 10.1021/acschembio.1c00807 [doi]
AB  - Targeting the cancer cell mitochondrion is a promising approach for developing 
      novel anticancer agents. The experimental anticancer agent 
      N,N'-bis(3,5-dichlorophenyl)urea (SR4) induces apoptotic cell death in several 
      cancer cell lines by uncoupling mitochondrial oxidative phosphorylation (OxPhos) 
      using a protein-free mechanism. However, the precise mechanism by which SR4 
      depolarizes mitochondria is unclear because SR4 lacks an acidic functional group 
      typically found in protein-independent uncouplers. Recently, it was shown that 
      structurally related thioureas can facilitate proton transport across lipid 
      bilayers by a fatty acid-activated mechanism, in which the fatty acid acts as the 
      site of protonation/deprotonation and the thiourea acts as an anion transporter 
      that shuttles deprotonated fatty acids across the phospholipid bilayer to enable 
      proton leak. In this paper, we show that SR4-mediated proton transport is 
      enhanced by the presence of free fatty acids in the lipid bilayer, indicating 
      that SR4 uncouples mitochondria through the fatty acid-activated mechanism. This 
      mechanistic insight was used to develop a library of substituted bisaryl ureas 
      for structure-activity relationship studies and subsequent cell testing. It was 
      found that lipophilic electron-withdrawing groups on bisaryl ureas enhanced 
      electrogenic proton transport via the fatty acid-activated mechanism and had the 
      capacity to depolarize mitochondria and reduce the viability of MDA-MB-231 breast 
      cancer cells. The most active compound in the series reduced cell viability with 
      greater potency than SR4 and was more effective at inhibiting adenosine 
      triphosphate production.
FAU - York, Edward
AU  - York E
AD  - School of Mathematical and Physical Sciences, Faculty of Science, University of 
      Technology Sydney, Sydney, NSW 2007, Australia.
FAU - McNaughton, Daniel A
AU  - McNaughton DA
AD  - School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
FAU - Roseblade, Ariane
AU  - Roseblade A
AD  - School of Mathematical and Physical Sciences, Faculty of Science, University of 
      Technology Sydney, Sydney, NSW 2007, Australia.
FAU - Cranfield, Charles G
AU  - Cranfield CG
AUID- ORCID: 0000-0003-3608-5440
AD  - School of Life Sciences, Faculty of Science, University of Technology Sydney, 
      Sydney, NSW 2007, Australia.
FAU - Gale, Philip A
AU  - Gale PA
AD  - School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
AD  - The University of Sydney Nano Institute (SydneyNano), The University of Sydney, 
      Sydney, NSW 2006, Australia.
FAU - Rawling, Tristan
AU  - Rawling T
AUID- ORCID: 0000-0002-6624-6586
AD  - School of Mathematical and Physical Sciences, Faculty of Science, University of 
      Technology Sydney, Sydney, NSW 2007, Australia.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220719
PL  - United States
TA  - ACS Chem Biol
JT  - ACS chemical biology
JID - 101282906
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Fatty Acids)
RN  - 0 (Mitochondrial Proteins)
RN  - 0 (Protons)
RN  - 8W8T17847W (Urea)
SB  - IM
MH  - *Antineoplastic Agents/metabolism/pharmacology
MH  - *Fatty Acids/metabolism
MH  - Mitochondria/metabolism
MH  - Mitochondrial Proteins/metabolism
MH  - Protons
MH  - Structure-Activity Relationship
MH  - Urea/metabolism/pharmacology
EDAT- 2022/07/20 06:00
MHDA- 2022/08/23 06:00
CRDT- 2022/07/19 23:39
PHST- 2022/07/20 06:00 [pubmed]
PHST- 2022/08/23 06:00 [medline]
PHST- 2022/07/19 23:39 [entrez]
AID - 10.1021/acschembio.1c00807 [doi]
PST - ppublish
SO  - ACS Chem Biol. 2022 Aug 19;17(8):2065-2073. doi: 10.1021/acschembio.1c00807. Epub 
      2022 Jul 19.