Design, Synthesis, and Biological Evaluation of Esculetin-Furoxan-DEAC Ternary Hybrids for Anti-Triple Negative Breast Cancer

Twelve new hybrid compounds of Esculetin with nitric oxide (NO) donors and/or mitochondrial targeting groups were designed, synthesized, and evaluated for their anti-tumor activity and mechanism in vitro and in vivo. Notably, the most potent compound A11 exhibited nanomolar antiproliferative activity on triple-negative breast Cancer (TNBC) MDA-MB-231 cells (IC₅₀ = 8 nM) with a strikingly selective inhibitory effect. The mechanism of A11 involves targeting MDA-MB-231 cells' mitochondria, releasing a high NO concentration, and increasing the expression of Cyclophilin D (CypD), leading to increased Reactive Oxygen Species (ROS) and triggering Cancer cell Apoptosis. Additionally, A11 could arrest the cell cycle at the G2/M phase to achieve anti-tumor effects. Moreover, A11 demonstrated a superior TNBC inhibition rate and diminished toxicity relative to doxorubicin (DOX) in vivo. In summary, A11 serves as a noteworthy contender for TNBC treatment with high potency and minimal toxicity.