Synthesis and biological evaluation of novel gemcitabine-dexamethasone hybrid as potent antitumor agents against esophageal cancer.

Esophageal cancer remains a lethal malignancy with poor prognosis, and gemcitabine therapy is often limited by drug resistance and adverse effects. To overcome these limitations, we designed and synthesized a series of gemcitabine-dexamethasone conjugates (GD1-GD3) via a succinate linker. Among them, GD1 (N4-linked) exhibited the most potent antitumor activity and was selected for mechanistic evaluation. GD1 induced DNA damage, triggered S-phase cell cycle arrest, and suppressed EGFR/MAPK signaling in esophageal squamous cell carcinoma cells. In xenograft mouse models, oral GD1 achieved dose-dependent tumor growth inhibition (up to 86.96%) without observable adverse effects. Collectively, these findings established GD1 as a promising hybrid molecule with a distinct mechanism of action against esophageal cancer.