Chalcones Tethered with Pyridylmethyloxy Tail: Unlocking New Pathways in MDM2-p53 Targeted Cancer Treatment

The MDM2-p53 pathway has emerged as a pivotal target in cancer research and therapeutic development. Inhibition of MDM2 results in the stabilization and activation of p53, thereby inducing cell cycle arrest and apoptosis in cancer cells that retain wild type p53. Targeting the regulatory mechanisms that govern p53 functionality, especially its interaction with MDM2, represents a promising approach for the development of novel anticancer therapies. This study focused on the design, synthesis, structural characterization, and biological evaluation of a new series of chalcone-based derivatives incorporating a pyridyl moiety, that aimed at disrupting the MDM2-p53 interaction to exert antiproliferative effects. The synthesized compounds underwent comprehensive in vitro evaluation, including cytotoxicity assays, enzyme-linked immunosorbent assays (ELISA), and flow cytometry-based cell cycle analysis, to assess their biological efficacy. Compound 4b demonstrated potent cytotoxicity in MCF7 (breast cancer) and HepG2 (liver cancer) cell lines, with IC50 values of 0.16 μM and 0.17 μM, respectively. Compound 2d showed moderate activity, particularly against MCF7 cells, with an IC50 of 0.21 μM. Additionally, both compounds 4b and 2d significantly reduced MDM2 expression by 47% and 36%, respectively, at 10 μM, leading to a corresponding increase in p53 levels by approximately 1.5- and 1.3-fold, respectively, thereby enhancing its tumor-suppressive activity compared to untreated control. Furthermore, compounds 2d and 4b, exhibiting significant biological activity, were evaluated for their effects on cell cycle progression. Both compounds induced a notable depletion in the S phase, suggesting an impact on DNA replication. These results indicate that compound 4b holds substantial promise for further development as an effective anticancer agent, owing to its potent cytotoxicity across various cancer cell lines and its ability to inhibit MDM2.