Combination of indoline with alepterolic acid produces potent anti-breast cancer agents

Alepterolic acid, a labdane diterpenoid derived from Aleuritopteris argentea (S. G. Gmél.) Fée, has demonstrated promising biological properties that make it potentially useful for anticancer therapies. This research designed and synthesized a series of twenty-one novel derivatives of alepterolic acid featuring dihydroindole scaffolds, and assessed their anticancer potential in vitro. Among these compounds, the derivative incorporating a 1-(6-iodoindolin-1-yl) substituent (compound 9k) exhibited superior inhibitory activity against the triple-negative breast cancer (TNBC) cell line MDA-MB-231, showing an IC₅₀ value of 94.30 ± 3.26 nM. Subsequent mechanistic analyses revealed that compound 9k significantly suppressed colony formation, inhibited cellular migration, decreased mitochondrial membrane potential (MMP), and promoted apoptosis via reactive oxygen species (ROS) generation. Moreover, in vivo experiments indicated that this derivative effectively restrained tumor growth without noticeable toxic side effects. Finally, utilizing network pharmacology and molecular docking approaches, we elucidated the potential mechanism by which compound 9k induced apoptosis in TNBC cells and identified ten key core genes involved in this process. These results collectively highlight the potential of alepterolic acid derivatives as promising therapeutic candidates for TNBC.