Design, Synthesis, and Antiproliferative Evaluation of C3/C12-Modified Panaxadiol Derivatives Against Gastric Cancer...

Panaxadiol (PD) is a bioactive dammarane triterpenoid with limited antiproliferative potency, and systematic optimization of its C3 and C12 positions remains underexplored. Here, a stepwise, site-differentiated strategy was established by combining selective C3 esterification with late-stage C12 diversification through a chloroacetyl-piperazine linker, affording 23 PD derivatives and enabling complementary C3/C12 structure-activity analysis. Antiproliferative screening in AGS gastric cancer cells identified compounds 6, 11, and 17 as the most active analogues, with IC₅₀ values of 8.41, 5.08, and 6.78 μM, respectively, all outperforming 5-fluorouracil under identical conditions. Compound 6 provided a relatively favorable balance between low-micromolar activity and preservation of non-malignant GES-1 cells within a defined concentration range and was therefore selected for mechanistic investigation. Transcriptomic profiling identified 298 differentially expressed genes associated with cellular stress, cytokine signaling, epithelial growth regulation, and extracellular remodeling, whereas metabolomic analysis revealed marked perturbation of glycerophospholipid, choline, polyunsaturated fatty acid, and glutathione metabolism. Integrated analysis highlighted membrane-lipid remodeling, redox dysregulation, and ferroptosis-related processes as central features of the response. These findings establish a modular platform for PD optimization and identify compound 6 as a promising lead for further anti-gastric cancer development.