Design, synthesis and biological evaluation of magnolol-sulforaphane hybrid analogues as potential therapeutics of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype that primarily relies on chemotherapy. Natural products like magnolol and sulforaphane, especially their synthetic hybrid, have shown promising antitumor activity. To develop more potent agents, we designed and synthesized 15 novel magnolol-sulforaphane hybrid analogues and evaluated their anticancer efficacy. Among them, compound 17a demonstrated the highest potency, exhibiting an average 7.4-fold increase in antiproliferative activity with IC50 values ranging from 0.85 ± 0.04 μM to 1.34 ± 0.02 μM in TNBC cell lines compared to the parent hybrid CT1-3. In vitro, 17a significantly suppressed TNBC cell proliferation, colony formation, migration, and invasion while inducing apoptosis. In vivo, administration of 17a effectively inhibited tumor growth without apparent toxicity in an MDA-MB-231 xenograft model, as evidenced by normal organ morphology. Mechanistically, RNA sequencing revealed that 17a downregulated the nucleotide excision repair (NER) and NF-κB pathways, suppressing expression of NER-related genes (ERCC2, POLE2, LIG1, GTF2H3, and DDB2) at mRNA and protein levels and inhibiting phosphorylation of IKKα and p65. These findings position 17a as a potent therapeutic candidate for TNBC treatment, warranting further clinical investigation.