Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions
Open accessAbstract
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.
- 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
- 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 · 2015: 1
- 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 › Chemical Reaction Mechanisms
- 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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