Thioimidate Bond Formation between Cardiac Troponin C and Nitrile-containing Compounds.
Journal
ACS medicinal chemistry letters
ISSN: 1948-5875
Titre abrégé: ACS Med Chem Lett
Pays: United States
ID NLM: 101521073
Informations de publication
Date de publication:
13 Jun 2019
13 Jun 2019
Historique:
received:
12
04
2019
accepted:
15
05
2019
entrez:
20
5
2020
pubmed:
20
5
2020
medline:
20
5
2020
Statut:
epublish
Résumé
We have investigated the mechanism and reactivity of covalent bond formation between cysteine-84 of the regulatory domain of cardiac troponin C and compounds containing a nitrile moiety similar to the calcium sensitizer levosimendan. The results of modifications to the levosimendan framework ranged from a large increase in covalent bond formation to complete inactivity. We present the biological activity of one of the most potent compounds. Limitations, including compound solubility and degradation at acidic pH, have prevented thorough investigation of the potential of these compounds. Our studies reveal the efficacious nature of the malononitrile moiety in targeting cNTnC and its potential in future cardiotonic drug design.
Identifiants
pubmed: 32426091
doi: 10.1021/acsmedchemlett.9b00168
pmc: PMC7227049
doi:
Types de publication
Journal Article
Langues
eng
Pagination
1007-1012Subventions
Organisme : British Heart Foundation
ID : PG/17/65/33215
Pays : United Kingdom
Informations de copyright
Copyright © 2019 American Chemical Society.
Déclaration de conflit d'intérêts
The authors declare no competing financial interest.
Références
Bioorg Med Chem Lett. 2007 Feb 15;17(4):998-1002
pubmed: 17157022
J Clin Pharm Ther. 2013 Oct;38(5):341-9
pubmed: 23594161
Eur Biophys J. 2002 Jul;31(4):245-56
pubmed: 12122471
ACS Med Chem Lett. 2014 Feb 24;5(5):501-5
pubmed: 24900869
Cardiovasc Drug Rev. 2005 Spring;23(1):71-98
pubmed: 15867949
J Muscle Res Cell Motil. 2004;25(7):559-79
pubmed: 15711886
Biochemistry. 2016 Nov 1;55(43):6032-6045
pubmed: 27673371
J Mol Cell Cardiol. 2016 Dec;101:134-144
pubmed: 27825981
Nat Chem Biol. 2012 Apr 01;8(5):471-6
pubmed: 22466421
Int J Cardiol. 2016 Jan 15;203:543-8
pubmed: 26580334
J Mol Cell Cardiol. 2000 Mar;32(3):479-91
pubmed: 10731446
Biochemistry. 2018 Apr 17;57(15):2256-2265
pubmed: 29558109
Bioorg Med Chem Lett. 2009 Feb 15;19(4):1136-8
pubmed: 19168354
J Clin Med Res. 2014 Apr;6(2):75-85
pubmed: 24578748
Basic Clin Pharmacol Toxicol. 2006 Jan;98(1):74-8
pubmed: 16433895
J Biol Chem. 2001 Mar 23;276(12):9337-43
pubmed: 11113122
Org Biomol Chem. 2012 Aug 14;10(30):5764-8
pubmed: 22336919
J Mol Cell Cardiol. 2010 Dec;49(6):1031-41
pubmed: 20801130
J Cardiovasc Pharmacol. 2014 Sep;64(3):199-208
pubmed: 24785346
J Mol Cell Cardiol. 2016 Mar;92:174-84
pubmed: 26853943
Physiol Rev. 2000 Apr;80(2):853-924
pubmed: 10747208
J Biochem. 1991 Apr;109(4):499-502
pubmed: 1869503
Circulation. 2006 Jan 17;113(2):305-15
pubmed: 16418450
J Med Chem. 2010 Nov 25;53(22):7902-17
pubmed: 20804202