Cited by 588Chemical Reaction MechanismsSulfur Compounds in BiologySynthesis and Reactivity of Sulfur-Containing Compounds

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

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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Crossref · 10.1021/acs.jmedchem.6b00788

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  1. [199]Ayers P Yang W Bartolot ti LJ Chemical Reactivity Theory: A Density Functional View 2009 1 255 267 CRC Press Boca Raton, FL

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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
Published
2016-12-20
Volume
60
Issue
3
Pages
839-885
ISSN
  • 0022-2623 (ISSN-L)
  • 1520-4804
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
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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