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

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.

Therapeutic potential of esculetin in various cancer types (Review)

“…Esc has shown notable anticancer properties against CRC cells, as evidenced by its ability to inhibit cell proliferation, induce apoptosis, arrest the cell cycle in the G 1 phase, reduce metastatic potential and decrease reactive oxygen species (ROS) production ( 15 – 17 ). Furthermore, in Esc-treated cell lines such as HCT116, HT-29 and DLD-1, inhibition of proliferation in these cell lines in a dose- and time-dependent manner was consistently observed ( 9 – 14 ). Choi et al ( 16 ) reported that Esc selectively targets cancer cells, sparing normal colonic epithelial cells.…”

“…In addition, in colorectal cancer, the IC 50 for 48 h in HT-29 cells was 55 µM ( 13 ), and the IC 50 for 24 h in HCT116 cells was 100 µM ( 13 ). Furthermore, the IC 50 of the designed compound in breast cancer, Esc-NO-DEAC ternary hybrid A11, was 8 nM for 48 h in MDA-MB-231 cells ( 14 ). Table I shows the different IC 50 values for Esc treatment in various cell lines.…”

“…Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer-related mortality in women worldwide ( 7 , 30 ). The results of two studies showed that Esc and Esc-Furoxan-DEAC ternary hybrids could induce mitochondrial apoptosis through the calcium and ROS accumulation pathways, respectively, thus promoting the apoptosis of breast cancer cells ( 14 , 31 ). In a study by Chang et al ( 31 ), the first to explore the effects of Esc on Ca 2+ in ZR-75-1 human breast cancer cells, Esc was found to induce a dose-dependent Ca 2+ increase in these cells.…”

“…A total of 12 new hybrid Esc compounds have been synthesized, which involved the integration of a furoxan-based NO donor and/or a mitochondria-targeting group onto the 6,7-dihydroxy structure of Esc ( 14 ). In vitro findings demonstrated that Esc-Furoxan-DEAC ternary hybrids can induce MDA-MB-231 cell apoptosis and halt mitosis at the G 2 /M phase, with its effectiveness varying in relation to the dose.…”

“…In vitro findings demonstrated that Esc-Furoxan-DEAC ternary hybrids can induce MDA-MB-231 cell apoptosis and halt mitosis at the G 2 /M phase, with its effectiveness varying in relation to the dose. This outcome suggested that Esc-Furoxan-DEAC ternary hybrids triggers cell apoptosis via the mitochondrial pathway and that Esc has a crucial role in the Esc-Furoxan-DEAC ternary hybrid-driven enhancement of CypD levels ( 14 ).…”