Thioimidate Bond Formation between Cardiac Troponin C and Nitrile-containing Compounds

Brittney A. Klein; Ian M. Robertson; Béla Reiz; Thomas Kampourakis; Liang Li; Brian D. Sykes

doi:10.1021/acsmedchemlett.9b00168

Thioimidate Bond Formation between Cardiac Troponin C and Nitrile-containing Compounds

Brittney A. Klein, Ian M. Robertson, Béla Reiz, Thomas Kampourakis, Liang Li, Brian D. Sykes

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	1007-1012
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	10
Issue number	6
DOIs	https://doi.org/10.1021/acsmedchemlett.9b00168
State	Published - Jun 13 2019

Bibliographical note

Publisher Copyright:
© 2019 American Chemical Society.

Keywords

Cardiac troponin C
levosimendan
malononitrile
reversible thioimidate bond formation

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/acsmedchemlett.9b00168

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abstract = "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.",

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AU - Klein, Brittney A.

AU - Robertson, Ian M.

AU - Reiz, Béla

AU - Kampourakis, Thomas

AU - Li, Liang

AU - Sykes, Brian D.

PY - 2019/6/13

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AB - 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.

KW - Cardiac troponin C

KW - levosimendan

KW - malononitrile

KW - reversible thioimidate bond formation

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Thioimidate Bond Formation between Cardiac Troponin C and Nitrile-containing Compounds

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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