Discovery of 3-indolylbenzoquinone derivatives with therapeutic potential for breast cancer.

Breast cancer is one of the most prevalent malignant tumors in women, but the side effects and drug resistance limit the long-term effectiveness of existing drugs. To address these issues, we designed and synthesized a series of novel mono- and bis-indole-substituted 3-indolylbenzoquinone derivatives and evaluated their inhibitory activity against breast cancer. Among them, compound 1b demonstrated the most potent inhibitory activity against the MDA-MB-231 breast cancer cell line (IC50 = 3.2 µM) as well as the drug-resistant variant, MCF-7/ADR (IC50 = 8.36 µM). It demonstrated minimal toxicity and superior tumor suppression in a Balb/c mouse model of 4 T1 breast cancer. Mechanistically, compound 1b induced apoptosis and cell cycle arrest at the G2/M phase. Through computational study and CESTA assay, we implicated phosphoinositide 3-kinase α (PI3Kα) as a potential target. Thus, we present compound 1b as a lead candidate for the development of novel, safe, and effective small-molecule therapies against breast cancer.