Kinetics and thermodynamics of reversible thiol additions to mono- and diactivated Michael acceptors: implications for the design of drugs that bind covalently to cysteines

Krenske, Elizabeth H., Petter, Russell C. and Houk, K. N. (2016) Kinetics and thermodynamics of reversible thiol additions to mono- and diactivated Michael acceptors: implications for the design of drugs that bind covalently to cysteines. Journal of Organic Chemistry, 81 23: 11726-11733. doi:10.1021/acs.joc.6b02188


Author Krenske, Elizabeth H.
Petter, Russell C.
Houk, K. N.
Title Kinetics and thermodynamics of reversible thiol additions to mono- and diactivated Michael acceptors: implications for the design of drugs that bind covalently to cysteines
Journal name Journal of Organic Chemistry   Check publisher's open access policy
ISSN 1520-6904
0022-3263
Publication date 2016-12-02
Year available 2016
Sub-type Article (original research)
DOI 10.1021/acs.joc.6b02188
Open Access Status Not yet assessed
Volume 81
Issue 23
Start page 11726
End page 11733
Total pages 8
Place of publication Washington, DC, United States
Publisher American Chemical Society
Language eng
Subject 1605 Organic Chemistry
Abstract Additions of cysteine thiols to Michael acceptors underpin the mechanism of action of several covalent drugs (e.g., afatinib, osimertinib, ibrutinib, neratinib, and CC-292). Reversible Michael acceptors have been reported in which an additional electron-withdrawing group was added at the α-carbon of a Michael acceptor. We have performed density functional theory calculations to determine why thiol additions to these Michael acceptors are reversible. The α-EWG group stabilizes the anionic transition state and intermediate of the Michael addition, but less intuitively, it destabilizes the neutral adduct. This makes the reverse reaction (elimination) both faster and more thermodynamically favorable. For thiol addition to be reversible, the Michael acceptor must also contain a suitable substituent on the β-carbon, such as an aryl or branched alkyl group. Computations explain how these structural elements contribute to reversibility and the ability to tune the binding affinities and the residence times of covalent inhibitors.
Formatted abstract
Additions of cysteine thiols to Michael acceptors underpin the mechanism of action of several covalent drugs (e.g., afatinib, osimertinib, ibrutinib, neratinib, and CC-292). Reversible Michael acceptors have been reported in which an additional electron-withdrawing group was added at the α-carbon of a Michael acceptor. We have performed density functional theory calculations to determine why thiol additions to these Michael acceptors are reversible. The α-EWG group stabilizes the anionic transition state and intermediate of the Michael addition, but less intuitively, it destabilizes the neutral adduct. This makes the reverse reaction (elimination) both faster and more thermodynamically favorable. For thiol addition to be reversible, the Michael acceptor must also contain a suitable substituent on the β-carbon, such as an aryl or branched alkyl group. Computations explain how these structural elements contribute to reversibility and the ability to tune the binding affinities and the residence times of covalent inhibitors.
Keyword Chemistry, Organic
Chemistry
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID FT120100632
CHE-0548209
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: School of Chemical Engineering Publications
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