Enhancing the Mitochondrial Uptake of Phosphonium Cations by Carboxylic Acid Incorporation.
computational chemistry
membrane permeation
membrane potential
mitochondria
mitochondria-targeting
pH gradient
phosphonium
Journal
Frontiers in chemistry
ISSN: 2296-2646
Titre abrégé: Front Chem
Pays: Switzerland
ID NLM: 101627988
Informations de publication
Date de publication:
2020
2020
Historique:
received:
27
04
2020
accepted:
27
07
2020
entrez:
9
10
2020
pubmed:
10
10
2020
medline:
10
10
2020
Statut:
epublish
Résumé
There is considerable interest in developing drugs and probes targeted to mitochondria in order to understand and treat the many pathologies associated with mitochondrial dysfunction. The large membrane potential, negative inside, across the mitochondrial inner membrane enables delivery of molecules conjugated to lipophilic phosphonium cations to the organelle. Due to their combination of charge and hydrophobicity, quaternary triarylphosphonium cations rapidly cross biological membranes without the requirement for a carrier. Their extent of uptake is determined by the magnitude of the mitochondrial membrane potential, as described by the Nernst equation. To further enhance this uptake here we explored whether incorporation of a carboxylic acid into a quaternary triarylphosphonium cation would enhance its mitochondrial uptake in response to both the membrane potential and the mitochondrial pH gradient (alkaline inside). Accumulation of arylpropionic acid derivatives depended on both the membrane potential and the pH gradient. However, acetic or benzoic derivatives did not accumulate, due to their lowered pK
Identifiants
pubmed: 33033715
doi: 10.3389/fchem.2020.00783
pmc: PMC7509049
doi:
Types de publication
Journal Article
Langues
eng
Pagination
783Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 110158/Z/15/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00015/3
Pays : United Kingdom
Informations de copyright
Copyright © 2020 Pala, Senn, Caldwell, Prime, Warrington, Bright, Prag, Wilson, Murphy and Hartley.
Références
J Phys Chem B. 2011 Dec 15;115(49):14556-62
pubmed: 21875126
Free Radic Biol Med. 2015 Dec;89:668-78
pubmed: 26453920
Redox Biol. 2013;1(1):86-93
pubmed: 23667828
J Chem Theory Comput. 2010 Sep 14;6(9):2872-87
pubmed: 26616087
Free Radic Biol Med. 2015 Dec;89:883-94
pubmed: 26454075
J Chem Phys. 2010 Apr 21;132(15):154104
pubmed: 20423165
J Comput Chem. 2011 May;32(7):1456-65
pubmed: 21370243
Acc Chem Res. 2016 Sep 20;49(9):1893-902
pubmed: 27529125
J Bioenerg Biomembr. 2013 Feb;45(1-2):165-73
pubmed: 23180142
J Phys Chem B. 2009 May 7;113(18):6378-96
pubmed: 19366259
Phys Chem Chem Phys. 2006 Mar 7;8(9):1057-65
pubmed: 16633586
Trends Pharmacol Sci. 2012 Jun;33(6):341-52
pubmed: 22521106
Chem Rev. 2005 Aug;105(8):2999-3093
pubmed: 16092826
Phys Rev Lett. 2003 Oct 3;91(14):146401
pubmed: 14611541
J Am Chem Soc. 2014 Jun 11;136(23):8418-29
pubmed: 24841256
Chembiochem. 2009 Aug 17;10(12):1939-50
pubmed: 19637148
Biochim Biophys Acta. 2014 Feb;1840(2):923-30
pubmed: 23726990
European J Org Chem. 2015 Sep 1;2015(27):5919-5924
pubmed: 27065751
Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5407-12
pubmed: 12697897
Antioxid Redox Signal. 2011 Dec 15;15(12):3021-38
pubmed: 21395490
Biochem J. 2006 Nov 15;400(1):199-208
pubmed: 16948637
Bioconjug Chem. 2017 Feb 15;28(2):590-599
pubmed: 28049291
Cell. 2012 Mar 16;148(6):1145-59
pubmed: 22424226
Phys Chem Chem Phys. 2005 Sep 21;7(18):3297-305
pubmed: 16240044
Nat Rev Drug Discov. 2018 Dec;17(12):865-886
pubmed: 30393373
Nat Rev Dis Primers. 2016 Oct 20;2:16080
pubmed: 27775730
Phys Chem Chem Phys. 2019 Nov 14;21(42):23355-23363
pubmed: 31621727