Synthesis of Guaianolide Analogues with a Tunable α-Methylene−γ-lactam Electrophile and Correlating Bioactivity with Thiol Reactivity

Abstract

α-Methylene−γ-lactones are present in ∼3% of known natural products, and compounds comprising this motif display a range of biological activities. However, this reactive lactone limits informed structure−activity relationships for these bioactive molecules. Herein, we describe chemically tuning the electrophilicity of the α-methylene−γ-lactone by replacement with an α-methylene−γ-lactam. Guaianolide analogues having α-methylene−γ-lactams are synthesized using the allenic Pauson−Khand reaction. Substitution of the lactam nitrogen with electronically different groups affords diverse thiol reactivity. Cellular NF-κB inhibition assays for these lactams were benchmarked against parthenolide and a synthetic α-methylene−γ-lactone showing a positive correlation between thiol reactivity and bioactivity. Cytotoxicity assays show good correlation at the outer limits of thiol reactivity but less so for compounds with intermediate reactivity. A La assay to detect reactive molecules by nuclear magnetic resonance and mass spectrometry peptide sequencing assays with the La antigen protein demonstrate that lactam analogues with muted nonspecific thiol reactivities constitute a better electrophile for rational chemical probe and therapeutic molecule design.

Anticancer Targets and Signaling Pathways Activated by Britannin and Related Pseudoguaianolide Sesquiterpene Lactones

“…In this case, the chemical nature of the group on the lactam nitrogen greatly impacted the reactivity of the α-methylene-γ-lactams toward a model thiol compound (cysteamine). α-Methylene-γ-lactam guaianolides maintaining an inhibitory activity toward NFκB were identified, but there is positive correlation between the thiol reactivity of the compounds and their NFκB inhibitory activity [145]. Another option consists of removing the exomethylene unit, replacing it with a less-or non-reactive group.…”

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

“…[20] Other sesquiterpene lactones (pseudoguaianolide, guaianolides,a nd beyond) and semisynthetic analogues have also shown promising biological activities. [30][31][32][33][34][35][36] As such, the (pseudo)guaianolide family and their analogues have been implicated as leads in drug development. While the majority of medicinal chemistry and drug discoverye fforts re- lated to (pseudo)guaianolides involves isolation and/or semisynthesis, [37] there are numerous total syntheses(pseudoguaianolides [12][13][14][15] and guaianolides [38][39][40][41][42][43][44][45] )m ethods/approaches, [36,[46][47][48][49][50][51] and de novo analogue syntheses.…”

“…[30][31][32][33][34][35][36] As such, the (pseudo)guaianolide family and their analogues have been implicated as leads in drug development. While the majority of medicinal chemistry and drug discoverye fforts re- lated to (pseudo)guaianolides involves isolation and/or semisynthesis, [37] there are numerous total syntheses(pseudoguaianolides [12][13][14][15] and guaianolides [38][39][40][41][42][43][44][45] )m ethods/approaches, [36,[46][47][48][49][50][51] and de novo analogue syntheses. [52,53] For drug discovery purposes, it would be ideal to have am odularr oute to pseudoguaianolide-analogues that retains the structural complexityo f the natural product family,c an tempert he reactivity of the Michael acceptors, [36] and allows for significant diversification aroundt he scaffold.…”

“…While the majority of medicinal chemistry and drug discoverye fforts re- lated to (pseudo)guaianolides involves isolation and/or semisynthesis, [37] there are numerous total syntheses(pseudoguaianolides [12][13][14][15] and guaianolides [38][39][40][41][42][43][44][45] )m ethods/approaches, [36,[46][47][48][49][50][51] and de novo analogue syntheses. [52,53] For drug discovery purposes, it would be ideal to have am odularr oute to pseudoguaianolide-analogues that retains the structural complexityo f the natural product family,c an tempert he reactivity of the Michael acceptors, [36] and allows for significant diversification aroundt he scaffold. [54] With these goals in mind, we sought to develop af unction-oriented synthetic route [54] to structurally complexp seudoguaianolidec hemical space whereby the lactone-ringi sc leaved and a" functional group" ("FG") is installed at the C-1 position (Figure 2B).…”

“…Of direct relevance to this report, helenalin has been shown to activate Nrf2 [20] . Other sesquiterpene lactones (pseudoguaianolide, guaianolides, and beyond) and semisynthetic analogues have also shown promising biological activities [30–36] . As such, the (pseudo)guaianolide family and their analogues have been implicated as leads in drug development.…”