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Prostate cancer is the second leading cause of death in USA and has developed serious resistance to current drugs. Thus, development of new drugs for the treatment of castration‐resistant prostate cancer (CRPC) is urgently needed. In this study, 25 novel derivatives of tanshinone IIA as potential androgen receptor (AR) suppression reagents for the treatment of CRPC have been synthesized. The inhibition on DHT‐mediated AR transactivation and cell viability assay were performed to test the synthesized compounds. The results showed that among 25 new compounds, seven methoxy‐substituted tanshinone IIA derivatives showed significant inhibition effect on DHT‐mediated AR transactivation. In particular, TAN‐24 that contains three methoxy groups showed the strongest inhibition effect on DHT‐mediated AR transactivation. In addition, TAN‐24 also suppressed DHT‐AR transactivation more effectively than those of tanshinoneIIA and enzalutamide. In cytotoxicity against human prostate cancer cell lines assay, TAN‐24 exhibited the most potent in vitro cytotoxicity against LNCaP and CWR22Rv1 cells, with IC50 values 20‐ and 19‐times lower than those of tanshinone IIA and comparable to enzalutamide. TAN‐24 reported in the present work represents a novel and effective AR suppression drug, showing great potential for the treatment of CRPC.

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