Design and Synthesis of Cryptotanshinone Derivatives with Enhanced Anti-Triple-Negative Breast Cancer Activity via Ferroptosis Induction

Breast cancer remains the most prevalent malignancy worldwide, with triple-negative breast cancer (TNBC) representing an aggressive subtype lacking effective targeted therapies. Cryptotanshinone (CTS), a bioactive diterpenoid quinone, has demonstrated anti-TNBC activity potentially associated with ferroptosis induction; however, its poor solubility and metabolic instability limit further development. In this study, a series of CTS derivatives was designed by introducing hydroxy acid ester and amino acid ester moieties at the A ring to improve druggability and biological activity. Their antiproliferative activities against TNBC cell lines (4T1 and MDA-MB-231) were evaluated using the CCK-8 assay, and IC50 values were determined for selected compounds. Among 22 synthesized derivatives, 1-(tert-butyl) 2-((1R)-1,6,6-trimethyl-10,11-dioxo-1,2,6,7,8,9,10,11-octahydrophenanthro[1,2-b]furan-9-yl) (2S)-pyrrolidine-1,2-dicarboxylate (AA3-2) exhibited significantly enhanced activity compared with CTS. Mechanistic studies indicated that AA3-2 induced ferroptosis-related cell death, as evidenced by its sensitivity to Ferrostatin-1 and Erastin, along with increased intracellular reactive oxygen species and iron accumulation. These findings suggest that structural modification of CTS can effectively enhance its anti-TNBC activity and support ferroptosis as a potential mechanism, providing a promising lead for further optimization.