Synthesis of Curcumin Analogs Targeting Androgen Receptor for the Selective Inhibition of Castration-Resistant Prostate Cancer Cells.

In the present study, a series of curcumin analogs (A1-P3) were designed and synthesized for the inhibition of prostate cancer cells by targeting androgen receptor (AR). All synthesized compounds were structurally characterized by 1H NMR, 13C NMR, and high-resolution mass spectrometry (HRMS). In vitro cytotoxicity assays demonstrated that multiple compounds exhibited comparable or improved cytotoxicity against AR-positive 22Rv1 cells as compared to dimethylcurcumin (DMC, ASC-J9). Among these compounds, compounds A2, A3, B1-B3, D1, F1, F3, G1, G3, H1, and P3 possessed higher selectivity toward prostate cancer cells as compared to DMC. Compounds O1-O3, A1-A3, B1-B3, F1, F3, G1, I1, and P3 exhibited lower cytotoxicity against AR-negative PC-3 cells than those against 22Rv1 cells. Based on the cytotoxicity results, the structure-activity relationships were analyzed. In the AR protein suppression assay, compounds O1-O3, A1-A3, and I1 exhibited similar inhibitory effects on both full-length AR (AR-FL) and AR splice variant 7 (AR-V7) as compared to DMC, while compound P3 exhibited significantly enhanced AR-FL suppression effect as compared to DMC. In comparison, compounds B2, B3, F1, and F3 exhibited reduced AR-FL and AR-V7 suppression effects as compared to DMC; B1 and G1 exhibited no significant suppression effect on AR-FL and AR-V7, suggesting that these compounds might inhibit prostate cancer cells by multiple mechanisms. Molecular docking simulations further confirmed that compounds O1-O3, A1-A3, I1, and P3 displayed high targeting ability to AR. The probable binding modes of these compounds to AR were also revealed. By modifying the molecular structure of curcumin, this study identified several compounds (A2, A3, P3) with high inhibitory activity and selectivity against castration-resistant prostate cancer cells by targeting AR-FL and AR-V7. These three compounds are promising new candidates for castration-resistant prostate cancer drug discovery.