Luoyang Key Laboratory of Organic Functional Molecules, College of Food and Drug, Luoyang Normal University, Luoyang 471934, China.
State Key Laboratory of Ophthalmology, Optometry and Vision Science, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou 325035, China; Wenzhou Institute of Biomaterials and Engineering, Chinese Academy of Science, Wenzhou 325001, China.
Bioorg Med Chem. 2019 Oct 15;27(20):115081. doi: 10.1016/j.bmc.2019.115081. Epub 2019 Aug 28.
Prostate cancer (PCa) is a major cause of cancer-related male death in worldwide. To develop of potential anti-prostate cancer agents, 22 kinds of 4-Amino-2H-benzo[h]chromen-2-one analogs were designed and synthesized as potent androgen receptor (AR) antagonist through rational drug modification leading to the discovery of a series of novel antiproliferative compounds. Analogs (3, 4, 5, 7, 8, 10, 11, 12, 16, 18, 21, 23, and 24) exhibited potent antagonistic potency against AR (inhibition >50%), and exhibited potent AR binding affinities as well as displayed the higher activities than finasteride toward LNCaP cells (AR-rich) versus PC-3 cells (AR-deficient). Moreover, the docking study suggested that the most potent antagonist 23 mainly bind to AR ligand binding pocket (LBP) site through Van der Waals' force interactions. The structure-activity relationship (SAR) of these designed 4-Amino-2H-benzo[h]chromen-2-one analogs was rationally explored and discussed. Collectively, this work provides a potential lead compound for anticancer agent development related to prostate cancer therapy, and took a step forward towards the development of novel and improved AR antagonists.
前列腺癌（PCa）是全球男性癌症相关死亡的主要原因。为了开发潜在的抗前列腺癌药物，我们通过合理的药物修饰设计并合成了 22 种 4-氨基-2H-苯并[h]色烯-2-酮类似物，作为有效的雄激素受体（AR）拮抗剂，从而发现了一系列新的抗增殖化合物。类似物（3、4、5、7、8、10、11、12、16、18、21、23 和 24）对 AR 表现出很强的拮抗活性（抑制率>50%），并且具有很强的 AR 结合亲和力，对 LNCaP 细胞（富含 AR）的活性高于非那雄胺对 PC-3 细胞（缺乏 AR）的活性。此外，对接研究表明，最有效的拮抗剂 23 主要通过范德华力相互作用与 AR 配体结合口袋（LBP）结合。对这些设计的 4-氨基-2H-苯并[h]色烯-2-酮类似物进行了合理的构效关系（SAR）研究和讨论。总的来说，这项工作为与前列腺癌治疗相关的抗癌药物开发提供了一个潜在的先导化合物，并朝着开发新型和改进的 AR 拮抗剂迈出了一步。
