Preclinical evaluation of a fluorinated bifendate derivative in triple-negative breast cancer: integrated in vitro and in vivo evidence of antitumor activity

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited therapeutic options and poor clinical outcomes. Bifendate (DDB), a clinically used hepatoprotective agent, has shown modest antitumor activity. This study evaluated the antitumor activity of a fluorinated bifendate derivative (F-α-DDB-derivative) in TNBC models. MDA-MB-468 cells were treated with DDB or F-α-DDB-derivative to assess cell viability, migration, apoptosis, and Ki-67 expression. Antitumor efficacy and preliminary safety were further evaluated in a nude mouse xenograft model. F-α-DDB-derivative reduced cell viability in a concentration-dependent manner and showed greater potency than DDB, with a 24 h IC₅₀ of 25.06 µg/mL versus 105.00 µg/mL for DDB. At 25 µg/mL, F-α-DDB-derivative significantly inhibited migration compared with the control group, reduced Ki-67 expression, increased apoptosis, and showed stronger antitumor activity than DDB in most evaluated assays. In vivo, intraperitoneal administration of F-α-DDB-derivative (20 mg/kg, every other day for 14 days) significantly suppressed tumor growth and reduced final tumor weight compared with both the control and DDB groups. No significant abnormalities in body weight or serum biochemical markers were observed under the tested conditions. Fluorination enhanced the antitumor activity of DDB in TNBC models. F-α-DDB-derivative represents a promising fluorinated lead compound for further preclinical investigation. F-α-DDB-derivative, generated by fluorination-based optimization of bifendate, showed enhanced antitumor activity in triple-negative breast cancer models by suppressing malignant phenotypes in vitro and inhibiting xenograft growth with a favorable preliminary safety profile.