Design, synthesis and structure-activity relationship of 5'-prenylated chalcone derivatives inhibited the proliferation of human non-small cell lung cancer cells via inducing ferroptosis.

Chalcone-based natural products, characterized by their α, β-unsaturated carbonyl structure and prenylated A-ring, exhibit diverse pharmacological activities, including anticancer effects. Recent studies suggest that certain chalcone derivatives can induce ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation. In this study, we designed and synthesized a novel series of 5'-prenylated chalcone derivatives featuring structural modifications at the A-ring (2', 4'-hydroxyl protection with methyl, allyl, or prenyl groups) and B-ring (aromatic heterocycle substitution and electronic modulation). The anticancer activity of these compounds was evaluated against PC9, H1975, MDA-MB-231, SMMC-7721, and SGC-7901 cancer cell lines. Structure-activity relationship (SAR) analysis revealed that B-ring heterocyclic substitution significantly enhanced cytotoxicity. Among the derivatives, compound 4a exhibited potent broad-spectrum antiproliferative activity in vitro and effectively suppressed tumor growth in vivo with minimal toxicity. Mechanistic investigations demonstrated that compound 4a induces ferroptosis in human non-small cell lung cancer (NSCLC) cells by modulating the Nrf2/xCT/GPX4 signaling axis. These findings highlight the potential of 5'-prenylated chalcone derivatives as promising ferroptosis-inducing agents for anti-NSCLC therapy.