3-Deoxy-4-sulfonamido-butein derivatives promote cell cycle arrest and apoptosis by inhibiting EGFR/JAK2/STAT3 signaling in A549 lung cancer cells

Butein, a naturally occurring chalcone, exhibits diverse pharmacological potential but suffers from limited Anticancer efficacy. To address this limitation and improve drug-likeness, we designed and synthesized a novel series of 3-deoxy-4-sulfonamido-butein derivatives. The synthesized compounds were evaluated for their antiproliferative activities against human non-small cell lung Cancer (NSCLC) cells, including A549, H1299, and H1975 lines. Among them, compounds 8o (MRC-B-016) and 8p (MRC-B-018), characterized by electron-donating dialkylamino substituents, demonstrated profoundly enhanced growth inhibition compared to the parent compound without significant cytotoxicity in WI-38 normal lung cells. Mechanistic investigations revealed that 8o (MRC-B-016) and 8p (MRC-B-018) effectively induced G2/M cell cycle arrest and apoptotic cell death. Furthermore, these lead candidates operated through a convergent dual-targeting mechanism by directly inhibiting epidermal growth factor receptor (EGFR) tyrosine kinase activity while concurrently suppressing the downstream JAK2/STAT3 signaling axis. Molecular docking simulations corroborated these biological outcomes, displaying highly favorable binding interactions within both the EGFR kinase and STAT3 SH2 domains. Notably, these derivatives successfully suppressed oncogenic activation and colony formation even in gefitinib-resistant NSCLC models. Collectively, this study identifies sulfonamide-modified butein derivatives, particularly 8o (MRC-B-016) and 8p (MRC-B-018), as promising dual-targeting agents. Future research will focus on expanding the structure-activity relationship and conducting comprehensive in vivo evaluations to advance these chemotypes toward clinical translation for treatment-resistant lung Cancer.