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Function-Oriented and Modular (+/?)-cis-Pseudoguaianolide Synthesis: Discovery of New Nrf2 Activators and NF-κB Inhibitors |
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| Authors: | Dr Fabien Emmetiere Dr Ranjala Ratnayake Henry A M Schares Katherine F M Jones Emily Bevan–Smith Prof Hendrik Luesch Prof Daniel A Harki Prof Alexander J Grenning |
| Institution: | 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: | enyne metathesis modular synthesis NF-κB inhibitors Nrf2 activators pseudoguaianolides |