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Updated: May 1, 2026
Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
Design, synthesis, and biological evaluation of selective cytotoxicity-derived Miliusol derivatives inducing profound
Xiaoling Cheng1, Weiji Chen1, Wenli Hao2
1College of Applied Sciences, Shenzhen University, Shenzhen 518060, China.; Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen 518060, China.
Abstract:
Triple-negative breast cancer (TNBC) remains a challenging malignancy due to its aggressive nature and lack of targeted therapies. Miliusol, a natural product isolated from Miliusa tenuistipitata, exhibits potent anti-proliferative activity against TNBC but suffers from non-selective cytotoxicity. In this study, we employed a selective cytotoxicity-guided strategy to design and synthesize two novel series of Miliusol derivatives. MM-13 displayed enhanced tumor-selective cytotoxicity and demonstrated superior anti-proliferative and anti-migratory effects in TNBC cell lines compared to Miliusol, while showing minimal toxicity toward non-tumorigenic MCF-10A cells. Mechanistic studies revealed that MM-13 could inhibit glycolysis and induce DNA damage and apoptosis via the AKT/mTOR pathway. Importantly, MM-13 significantly suppressed tumor growth and metastasis in a 4T1 murine model without observable systemic toxicity. Our findings have enhanced the structure-activity relationship of Miliusol-type compounds and identify MM-13 as a promising candidate for TNBC-targeted therapy, offering a rational approach for improving natural product-derived anticancer agents.
Insights
Researchers developed MM-13, a novel Miliusol derivative, to combat triple-negative breast cancer (TNBC). This compound shows enhanced tumor-selective cytotoxicity and anti-cancer effects with minimal toxicity, offering a promising new TNBC therapy.
Area of Science:
- Natural Product Chemistry
- Oncology
- Medicinal Chemistry
Background:
- Triple-negative breast cancer (TNBC) presents a significant therapeutic challenge due to its aggressive nature and limited targeted treatment options.
- Miliusol, a natural product, demonstrates anti-proliferative effects against TNBC but lacks selectivity, causing non-specific cytotoxicity.
- Developing selective and effective therapies for TNBC is crucial to improve patient outcomes.
Purpose of the Study:
- To design and synthesize novel Miliusol derivatives with enhanced tumor-selective cytotoxicity for TNBC treatment.
- To evaluate the anti-proliferative, anti-migratory, and toxicological profiles of these derivatives in TNBC models.
- To elucidate the underlying molecular mechanisms of action for the most promising derivative.
Main Methods:
- A selective cytotoxicity-guided strategy was used to synthesize two series of Miliusol derivatives.
- In vitro assays assessed anti-proliferative and anti-migratory effects on TNBC cell lines and normal cells.
- In vivo studies in a 4T1 murine model evaluated tumor growth suppression and metastasis inhibition.
- Mechanistic studies investigated the impact on glycolysis, DNA damage, apoptosis, and the AKT/mTOR pathway.
Main Results:
- MM-13, a novel derivative, exhibited superior anti-proliferative and anti-migratory activity against TNBC cell lines compared to Miliusol.
- MM-13 demonstrated enhanced tumor-selective cytotoxicity, with minimal toxicity observed in non-tumorigenic MCF-10A cells.
- In vivo studies showed significant suppression of tumor growth and metastasis in the 4T1 murine model without systemic toxicity.
- Mechanistic investigations revealed MM-13 inhibits glycolysis and induces DNA damage and apoptosis via the AKT/mTOR pathway.
Conclusions:
- MM-13 represents a promising candidate for targeted triple-negative breast cancer therapy, offering improved efficacy and selectivity over the parent compound.
- The study enhances the structure-activity relationship understanding of Miliusol-type compounds for anticancer drug development.
- This work provides a rational approach for optimizing natural product-derived agents for cancer treatment.
