Spirocyclohexane-Chroman-4-one Derivatives as Selectively Cytotoxic Agents in Breast Cancer Models.

The design of novel small molecules with high selectivity for anticancer action remains a priority in the development of chemotherapy. A combination of the "privileged scaffold" of the chroman-4-one with rigid spirocyclic structures offers a strategy for modulating the specificity of action. A collection of 28 spirocyclohexane-chroman-4-one derivatives was screened using fluorescence cell coculture test, and compound 1 was selective in the breast cancer model. Structure-activity relationship analysis was performed within three rounds of optimization with rational synthesis of derivatives. Reduction of the carbonyl group to hydroxyl and incorporation of a dioxolane group into the spirocyclohexane ring reduced toxicity toward noncancerous VA13 and MCF10A cells. The lead compound 42 with this elaborated structure exhibited cytotoxicity against MCF7 cells (IC50 ≈ 3.8 μM) and remained significantly less cytotoxic to both noncancerous cells. It highlights the potential of spirocyclic-fused chroman-4-ones as selective cytotoxic agents through rigidifying the molecular scaffold and precisely tuning the functional group positioning.