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.