Design, synthesis and biological evaluation of novel Brevilin A derivatives as antitumor agents.

Brevilin A (BA), a natural sesquiterpene lactone, has exhibited promising anticancer activity. However, studies on the antitumor derivatization and structure-activity relationships (SAR) of BA, as a chemical scaffold derived from Centipeda minima, remain relatively limited. To obtain derivatives with improved activity, we designed and synthesized a series of BA derivatives on the B-ring and C-ring. The antiproliferative activity was evaluated in vitro against A549, H1975, H1299, and HepG2 cell lines. SAR analysis indicated that the B-ring ester side chain plays an important role in supporting the binding of the A-ring alkylation center to target proteins, and the C-11 position of the C-ring exhibits great potential for optimizing the antitumor activity of BA scaffold. The MTT screening revealed that C-ring derivatives featuring an exocyclic alkylation center possessed superior activity. Compound c8 was selected as a representative to further examine its antitumor effects and the underlying molecular mechanisms. The cellular thermal shift assay (CETSA) demonstrated that c8 stabilized STAT3 protein, suggesting a potential interaction. Western blotting (WB) analysis showed that c8 downregulates p-STAT3 and key STAT3 downstream targets (Bcl-2 and Survivin). In vivo, c8 at a dose of 25-50 mg/kg showed significant antitumor efficacy in A549 xenografts. Notably, no obvious toxic side effects were observed at administered doses throughout the experiment.