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

Research paper by Paul A PA Jackson, Henry A M HAM Schares, Katherine F M KFM Jones, John C JC Widen, Daniel P DP Dempe, Francois F Grillet, Matthew E ME Cuellar, Michael A MA Walters, Daniel A DA Harki, Kay M KM Brummond

Indexed on: 20 Nov '20Published on: 18 Nov '20Published in: Journal of Medicinal Chemistry


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.