Design, Synthesis and Biological Evaluation of Chalcone Acetamide Derivatives against Triple Negative Breast Cancer

Breast Cancer (BC) incidence rates increased (0.5%) annually in recent decades with moderate mortality. Triple-negative breast cancer (TNBC) poses molecularly diversified tumor aggressiveness, heterogeneous illness, recurrence, and high risk of metastasis. TNBC patients have poor prognosis due to later-stage diagnosis and fewer treatment options than other subtypes. Chalcones are chemical scaffolds found in natural products, especially in plants, considered diverse and structurally privileged in medicinal chemistry for drug development. Herein, we designed and synthesized novel acetamide derivatives of chalcone to evaluate against TNBC, and characterized them using 1H NMR, 13C NMR, HRMS and IR spectroscopic methods. The derivatives were screened against human cancer cells for their cytotoxicity using SRB assay. Among the derivatives, 8h with the pyrrolidine group exhibited better cell growth inhibitor activity against both TNBC (MDA-MB-231 and MDA-MB-468) cells. SRB, Colony formation and fluorescent dye-based screening assays demonstrated that 8h significantly inhibited MDA-MB-231 cell proliferation. Furthermore, 8h promoted apoptosis via upregulation of the cellular reactive oxygen species (ROS) levels and loss of mitochondrial membrane potential. 8h increased the pro-apoptotic proteins (Bax and caspase-3) and Bax/Bcl-2 ratio, inhibiting the anti-apoptotic (Bcl-2) protein levels in TNBC cells. The above results suggest that 8h can promote cellular death through apoptotic mechanisms in TNBC cells, and this hypothesis confirms that chalcones can be designed with potential cytotoxicity against TNBC.