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

Paul A. Jackson, John C. Widen, Daniel A. Harki, Kay M. Brummond

Research output: Contribution to journalArticlepeer-review

150 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)839-885
Number of pages47
JournalJournal of medicinal chemistry
Volume60
Issue number3
DOIs
StatePublished - Feb 9 2017

Bibliographical note

Funding Information:
This work was supported by the NIH (R01-GM110129 to DAH and R01-GM054161 to KMB).

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