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 bioacti

SUBMITTER: Jackson PA 

PROVIDER: S-EPMC8877724 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature