Previous experiments have revealed that curcumin exerts potential antitumor effect by inducing apoptosis and ferroptosis of tumor cells. However, its low solubility and bioavailability, as well as fast metabolism limit its clinical use. The structural modification of curcumin is beneficial for the discovery of potential candidate drugs for cancer treatment. Here, three new series of curcumin derivatives including 25 compounds were synthesized at active sites on benzene ring and β-diketone moiety. Further antiproliferative activities against five cancer cell lines (Hela, A549, HepG2, MCF-7 and HT-29) in vitro showed that compound 4a-4e displayed remarkable anti-tumor effect against A549, HepG2, MCF-7 and HT-29. Of them, compound 4d is particularly prominent against MCF-7, with IC