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

Abstract

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.