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  • Title: Design and synthesis of novel steroidal imidazoles as dual inhibitors of AR/CYP17 for the treatment of prostate cancer.
    Author: Hou Q, He C, Lao K, Luo G, You Q, Xiang H.
    Journal: Steroids; 2019 Oct; 150():108384. PubMed ID: 30885648.
    Abstract:
    Both AR and CYP17 are important targets for blocking androgen signaling, and it has been accepted that multifunctional drugs have a low risk of drug resistance in the treatment of cancer. Thus, herein a series of steroidal imidazoles were designed, synthesized and evaluated as dual AR/CYP17 ligands. Several compounds displayed good biological profiles in both enzymatic and cellular assays. SAR studies showed that introducing oximino at the C-3 position of steroidal scaffold is beneficial to the enhancement of AR antagonistic activity. Among these compounds, the most potent compound 13a exhibited the best AR inhibition (IC50 = 0.5 μM) that was 27-fold increase compared with the hit compound 5 as well as comparable CYP17 inhibition (IC50 = 11 μM). Additionally, 13a displayed promising anti-proliferative effects on LNCap cell lines with the IC50 value of 23 μM which was superior to positive control Flutamide (IC50 = 28 μM). Furthermore, the docking results of 13a revealed that the oxygen atom at the position of C-3 connected to the heme of CYP17, which may be helpful for its satisfactory dual-target inhibition. In summary, this study provides an efficient strategy for multi-targeting drug discovery in the treatment of prostate cancer.
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