Natural products are an important source for developing anti-cancer agents. Previously, we identified the anti-cancer flavonoid protoapigenone from (Gaud.) and synthesized its derivative, WYC-0209, with improved anti-cancer properties. In this study, to further optimize this protoapigenone derivative for better therapeutic efficacy, various functional groups were introduced onto its naphthalene ring, and their anti-cancer properties were evaluated. A total of eighteen WYC-0209 derivatives were synthesized, among which the derivative containing two units of the isopentyl-substituted side chain exhibited superior cytotoxicity against cancer cells and was named WYC-241. Further investigation in A549 lung cancer cells showed that WYC-241 significantly inhibited colony formation (proliferation) and suppressed cell migration (mobility). Additionally, WYC-241 induced both necrosis and apoptosis, potentially through a substantial increase in intracellular reactive oxygen species (ROS) levels and inhibition of the PI3K/AKT pathway. studies showed that weekly intravenous (i.v.) injection of WYC-241 significantly suppressed tumor growth in mice. ADMET analysis further indicated that WYC-241 possesses drug-like properties. Collectively, this study suggests that WYC-241 is a promising candidate for further development as a novel anti-cancer therapy and provides a foundation for future drug design and optimization.