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 language | English (US) |
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Pages (from-to) | 839-885 |
Number of pages | 47 |
Journal | Journal of medicinal chemistry |
Volume | 60 |
Issue number | 3 |
DOIs | |
State | Published - Feb 9 2017 |
Bibliographical note
Funding Information:This work was supported by the NIH (R01-GM110129 to DAH and R01-GM054161 to KMB).
Publisher Copyright:
© 2016 American Chemical Society.