Cited by 618Physical Organic Chemistry and Reaction KineticsSulfur Compounds in BiologySynthesis and Reactivity of Sulfur-Containing Compounds

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Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions

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Jackson, Paul A., Widen, John C., Harki, Daniel A., Brummond, Kay M.·2017·Journal of Medicinal Chemistry

DOI 10.1021/acs.jmedchem.6b00788PMC PMC5308545

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Abstract

Although Michael acceptors display a potent and broad spectrum of bioactivity, they have largely been ignored in drug discovery because of their presumed indiscriminate reactivity. As such, a dearth of information exists relevant to the thiol reactivity of natural products and their analogues possessing this moiety. In the midst of recently approved acrylamide-containing drugs, it is clear that a good understanding of the hetero-Michael addition reaction and the relative reactivities of biological thiols with Michael acceptors under physiological conditions is needed for the design and use of these compounds as biological tools and potential therapeutics. This Perspective provides information that will contribute to this understanding, such as kinetics of thiol addition reactions, bioactivities, as well as steric and electronic factors that influence the electrophilicity and reversibility of Michael acceptors. This Perspective is focused on α,β-unsaturated carbonyls given their preponderance in bioactive natural products.

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Authors: Jackson, P. A., Widen, J. C., Harki, D. A., & Brummond, K. M.
Affiliations: University of Pittsburgh (US)
University of Minnesota (US)
Corresponding author: Harki, Daniel A.
Brummond, Kay M.
ORCID: Widen, John C.
Harki, Daniel A.
Brummond, Kay M.
Venue: Journal of Medicinal Chemistry
Publisher: American Chemical Society (ACS)
Published: 2016-12-20
Volume: 60
Issue: 3
Pages: 839-885
ISSN: 0022-2623 (ISSN-L)
1520-4804
DOI: 10.1021/acs.jmedchem.6b00788
PMC: PMC5308545
OpenAlex: W2564708666
Cited by: 588
References: 329
Citations by year: 2026: 88 · 2025: 71 · 2024: 80 · 2023: 51 · 2022: 58 · 2021: 74 · 2020: 72 · 2019: 51 · 2018: 27 · 2017: 15
FWCI: 14.54
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Journal of Medicinal Chemistry (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institute of General Medical Sciences (R01-GM054161, R01-GM110129)
Topics: Physical Sciences › Chemistry › Organic Chemistry › Physical Organic Chemistry and Reaction Kinetics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
Physical Sciences › Chemistry › Organic Chemistry › Synthesis and Reactivity of Sulfur-Containing Compounds
Keywords: α,β-unsaturated carbonyl compounds, Michael acceptors, hetero-Michael addition, thiol reactivity, acrylamide, electrophilicity, reaction kinetics, steric and electronic effects, natural products, drug design, biological activity
MeSH terms: Humans, Ketones, Sulfhydryl Compounds, Drug Design, Cell Line, Tumor, ErbB Receptors

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Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions

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