Institute of Basic and Translational Medicine, Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University , Xi'an , PR China.
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University , Nanjing , PR China.
J Enzyme Inhib Med Chem. 2019 Dec;34(1):1597-1606. doi: 10.1080/14756366.2019.1654469.
Prostate cancer (PCa) is the second leading cause of death in men. Apart from androgen receptor, 5α-reductase has also been recognized as a potential target. In this study, a series of androst-17β-amide compounds have been designed and synthesized targeting both AR and 5α-reductase. Their anti-proliferation activities were evaluated in AR + cell line 22RV1 and AR - cell line PC-3. The results indicated that most of the synthesized compounds inhibited the testosterone-stimulated cell proliferation with good selectivity and safety. Among all the compounds, androst[3,2-c]pyrazole derivatives displayed the best inhibition activity comparable with flutamide. Moreover, most of the synthesized compounds displayed good 5α-reductase inhibitory activities with IC lower than 1 μM. The docking result of -AR indicated that AR was forced to expands its binding cavity and maintain an antagonistic conformation since the steric hindrance of impeded H12 transposition. Overall, compound can be identified as a potential dual 5α-reductase inhibitor and AR antagonist, which might be of therapeutic importance for PCa treatment.
前列腺癌（PCa）是男性死亡的第二大主要原因。除了雄激素受体，5α-还原酶也被认为是一个潜在的靶点。在这项研究中，设计并合成了一系列针对 AR 和 5α-还原酶的雄甾-17β-酰胺化合物。在 AR+细胞系 22RV1 和 AR-细胞系 PC-3 中评估了它们的抗增殖活性。结果表明，大多数合成的化合物对睾酮刺激的细胞增殖具有良好的选择性和安全性。在所有合成的化合物中，雄甾[3,2-c]吡唑衍生物表现出与氟他胺相当的最佳抑制活性。此外，大多数合成的化合物对 5α-还原酶表现出良好的抑制活性，IC 低于 1μM。-AR 的对接结果表明，由于 的空间位阻阻止了 H12 易位，AR 被迫扩大其结合腔并保持拮抗构象。总的来说，化合物 可以被鉴定为一种潜在的双重 5α-还原酶抑制剂和 AR 拮抗剂，这可能对治疗前列腺癌具有重要意义。
