Design, synthesis, and biological evaluation of selective cytotoxicity-derived Miliusol derivatives inducing profound TNBC regression in vivo.

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.