Design and Synthesis of Combretastatin A4‐Chalcone Hybrids as Tubulin Polymerization Inhibitors

A new series of combretastatin A4‐chalcone hybrids were designed and synthesized to explore their potential as cytotoxic agents. The compounds were evaluated for cytotoxic activity, tubulin inhibition, and anti‐angiogenic properties. The designed hybrids exhibited significant cytotoxic effects across all the tested cancer cell lines. Among them, two compounds, 5d and 5o , exhibited potent cytotoxicity, with IC 50 values of 0.02 and 0.03 μM, respectively, against the prostate cancer‐3 cell line. Further biological investigations suggested that treatment with 5d and 5o induces apoptosis, as evidenced by Hoechst 33 342 staining, Rhodamine 123 staining, MitoSOX red assays, and cell migration assays. Flow cytometric analysis revealed that both compounds caused dose‐dependent G2/M phase cell cycle arrest in PC‐3 cells. Their ability to inhibit tubulin polymerization was further confirmed through immunofluorescence assays. Additionally, molecular docking studies provided insights into their interaction profiles at the molecular level. Collectively, these findings highlight 5d and 5o as promising lead molecules with potential for further development in anticancer drug discovery.