Discovery of 8,9-seco-ent-Kaurane Diterpenoids as Potential Leads for the Treatment of Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is a lethal malignancy without safe and effective therapeutic drugs. In this study, the anti-TNBC bioassay-guided isolation of the medicinal plant Croton kongensis followed by the structural modification led to the construction of a small ent-kaurane diterpenoid library (1-25). With subsequent biological screening, 20 highly potent compounds (IC(50)s < 3 mu M) were identified. Among them, 8,9-seco-ent-kaurane 6 displayed comparable activity (IC(50)s similar to 80 nM) to doxorubicin but with better selectivity. The analysis of structure-activity relationships suggested that the cleavage of the C8-C9 bond and the presence of alpha,beta-unsaturated ketone moiety were essential for the activity. The mechanistic study revealed that 6 induced apoptosis, autophagy, and metastasis suppression in TNBC cells via inhibition of Akt. In vivo, 6 significantly suppressed the TNBC tumor growth without causing side effects. All these results suggested that 6 may serve as a promising lead for the development of novel anti-TNBC agents in the future.

Automated summary

In this study, a series of highly potent anti-TNBC small molecule compounds were isolated through bioassay-guided isolation, with 8,9-seco-ent-kaurane 6 showing promising activity and selectivity. The compounds may induce apoptosis, autophagy, and metastasis suppression in TNBC cells by inhibiting Akt, and demonstrate significant tumor growth suppression effects in vivo. These results suggest that these compounds hold potential for future development as novel anti-TNBC agents.