Function-Oriented and Modular (+/−)-cis-Pseudoguaianolide Synthesis: Discovery of New Nrf2 Activators and NF-κB Inhibitors

Fabien Emmetiere; Ranjala Ratnayake; Henry A.M. Schares; Katherine F.M. Jones; Emily Bevan–Smith; Hendrik Luesch; Daniel A. Harki; Alexander J. Grenning

doi:10.1002/chem.202100038

Function-Oriented and Modular (+/−)-cis-Pseudoguaianolide Synthesis: Discovery of New Nrf2 Activators and NF-κB Inhibitors

Fabien Emmetiere, Ranjala Ratnayake, Henry A.M. Schares, Katherine F.M. Jones, Emily Bevan–Smith, Hendrik Luesch, Daniel A. Harki, Alexander J. Grenning

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Described herein is a function-oriented synthesis route and biological evaluation of pseudoguaianolide analogues. The 10-step synthetic route developed retains the topological complexity of the natural product, installs functional handles for late-stage diversification, and forges the key bioactive Michael acceptors early in the synthesis. The analogues were found to be low-micromolar Nrf2 activators and micromolar NF-κB inhibitors and dependent on the local environment of the Michael acceptor moieties.

Original language	English (US)
Pages (from-to)	5564-5571
Number of pages	8
Journal	Chemistry - A European Journal
Volume	27
Issue number	17
DOIs	https://doi.org/10.1002/chem.202100038
State	Published - Mar 22 2021

Bibliographical note

Funding Information:
This material is based upon work supported by National Science Foundation Grant 1844443. The authors thank the College of Liberal Arts and Sciences and the Department of Chemistry at the University of Florida for start‐up funds and the Mass Spectrometry Research and Education Center and its funding source (National Institutes of Health S10 OD021758‐01A1). DAH gratefully acknowledges the National Institutes of Health (R01‐GM110129). KFMJ thanks the National Science Foundation Graduate Research Fellowship Program. We also acknowledge National Institutes of Health grant R01CA172310 (HL) and R50CA211487 (RR) and the Debbie and Sylvia DeSantis Chair professorship (HL) for partial support and A. Dinkova‐Kostova for the isogenic MEF cells.

Publisher Copyright:
© 2021 Wiley-VCH GmbH

Keywords

NF-κB inhibitors
Nrf2 activators
enyne metathesis
modular synthesis
pseudoguaianolides

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10.1002/chem.202100038

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abstract = "Described herein is a function-oriented synthesis route and biological evaluation of pseudoguaianolide analogues. The 10-step synthetic route developed retains the topological complexity of the natural product, installs functional handles for late-stage diversification, and forges the key bioactive Michael acceptors early in the synthesis. The analogues were found to be low-micromolar Nrf2 activators and micromolar NF-κB inhibitors and dependent on the local environment of the Michael acceptor moieties.",

keywords = "NF-κB inhibitors, Nrf2 activators, enyne metathesis, modular synthesis, pseudoguaianolides",

author = "Fabien Emmetiere and Ranjala Ratnayake and Schares, {Henry A.M.} and Jones, {Katherine F.M.} and Emily Bevan–Smith and Hendrik Luesch and Harki, {Daniel A.} and Grenning, {Alexander J.}",

note = "Funding Information: This material is based upon work supported by National Science Foundation Grant 1844443. The authors thank the College of Liberal Arts and Sciences and the Department of Chemistry at the University of Florida for start‐up funds and the Mass Spectrometry Research and Education Center and its funding source (National Institutes of Health S10 OD021758‐01A1). DAH gratefully acknowledges the National Institutes of Health (R01‐GM110129). KFMJ thanks the National Science Foundation Graduate Research Fellowship Program. We also acknowledge National Institutes of Health grant R01CA172310 (HL) and R50CA211487 (RR) and the Debbie and Sylvia DeSantis Chair professorship (HL) for partial support and A. Dinkova‐Kostova for the isogenic MEF cells. Publisher Copyright: {\textcopyright} 2021 Wiley-VCH GmbH",

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AU - Emmetiere, Fabien

AU - Ratnayake, Ranjala

AU - Schares, Henry A.M.

AU - Jones, Katherine F.M.

AU - Bevan–Smith, Emily

AU - Luesch, Hendrik

AU - Harki, Daniel A.

AU - Grenning, Alexander J.

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Y1 - 2021/3/22

N2 - Described herein is a function-oriented synthesis route and biological evaluation of pseudoguaianolide analogues. The 10-step synthetic route developed retains the topological complexity of the natural product, installs functional handles for late-stage diversification, and forges the key bioactive Michael acceptors early in the synthesis. The analogues were found to be low-micromolar Nrf2 activators and micromolar NF-κB inhibitors and dependent on the local environment of the Michael acceptor moieties.

AB - Described herein is a function-oriented synthesis route and biological evaluation of pseudoguaianolide analogues. The 10-step synthetic route developed retains the topological complexity of the natural product, installs functional handles for late-stage diversification, and forges the key bioactive Michael acceptors early in the synthesis. The analogues were found to be low-micromolar Nrf2 activators and micromolar NF-κB inhibitors and dependent on the local environment of the Michael acceptor moieties.

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KW - Nrf2 activators

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KW - modular synthesis

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Function-Oriented and Modular (+/−)-cis-Pseudoguaianolide Synthesis: Discovery of New Nrf2 Activators and NF-κB Inhibitors

Abstract

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