Design, Synthesis, and Biological Evaluation of Esculetin–Furoxan–DEAC Ternary Hybrids for Anti-Triple Negative Breast Cancer
Mingju Wen, Jianbo Sun, Yang Miao, Xueling Zhang, Yue Wang, Wen Zhou, Yuning Shi, Yu‐Jing Huang, Na Li, Li Chen
Abstract
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 (IC 50 = 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.