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

Chemistry. 2021 Mar 22;27(17):5564-5571. doi: 10.1002/chem.202100038. Epub 2021 Feb 26.

Authors

Fabien Emmetiere¹, Ranjala Ratnayake², Henry A M Schares³, Katherine F M Jones⁴, Emily Bevan-Smith¹, Hendrik Luesch², Daniel A Harki^{3

4}, Alexander J Grenning¹

Affiliations

¹ Department of Chemistry, University of Florida, PO Box 117200, Gainesville, FL, 32608, USA.
² Department of Medicinal Chemistry and Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, Gainesville, FL, 32610, USA.
³ Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, 55455, USA.
⁴ Department of Chemistry, University of Minnesota, Minneapolis, MN, 55455, USA.

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.

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

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