A Novel Piperine Derivative, NOHJ, Exerts Antibreast Cancer Effects by Inhibiting MDM2

Objective: To design and synthesize a novel piperine derivative with enhanced antitumor efficacy compared to the natural compound piperine. Methods: Compound NOHJ was synthesized via the condensation of (E)-3-(4,5-dimethoxy-2-nitrophenyl)acrylic acid with 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline. Its antitumor activity was evaluated using both in vitro and in vivo models. Potential molecular targets of NOHJ were identified through molecular docking, Western blotting, and immunofluorescence assays. Results and Discussion: NOHJ exhibited significant antitumor activity and demonstrated greater efficacy than piperine in inhibiting cell adhesion, migration, invasion, and colony formation in MDA-MB-231 and MCF-7 breast cancer cell lines. Additionally, NOHJ effectively suppressed tumor growth in vivo and inhibited angiogenesis in the chick embryo chorioallantoic membrane (CAM) assay. Mechanistic studies revealed that NOHJ treatment upregulated the expression of p53 and p21, while downregulating CDK1 and CCNB1, indicating cell cycle disruption. Conclusions: NOHJ exerts its antibreast cancer effects by targeting and inhibiting MDM2, stabilizing p53, and modulating key regulators of the cell cycle, ultimately leading to G₂/M phase arrest and apoptosis. These findings suggest that NOHJ is a promising therapeutic candidate for breast cancer.