Synthesis and biological evaluation of arylpiperazine derivatives as potential anti-prostate cancer agents

• Published in: Bioorganic & medicinal chemistry 2019-01, Vol.27 (1), p.133-143
• Main Authors: Chen, Hong, Yu, Yu-Zhong, Tian, Xiu-Mei, Wang, Cai-Lu, Qian, Yu-Na, Deng, Zai-An, Zhang, Jing-Xiao, Lv, Dao-Jun, Zhang, Hai-Bo, Shen, Jian-Liang, Yuan, Mu, Zhao, Shan-Chao
• Format: Article
• Language: English
• Subjects: Antagonistic activity; Arylpiperazine derivatives; Binding affinities; Docking study; Prostate cancer; Synthesis
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2018.11.029

[Display omitted] •A novel of arylpiperazine derivatives were synthesized.•Antagonistic potency of derivatives were investigated against AR.•The anti-prostate cancer activities of derivatives was also investigated.•Some derivatives exhibited strong activities against AR and cancer cells.•Molecular docking and SAR of derivatives were also studied. A novel scaffold of arylpiperazine derivatives was discovered as potent androgen receptor (AR) antagonist through rational drug designation based on our pre-work, leading to the discovery of a series of new antiproliferative compounds. Compounds 10, 16, 27, 29 and 31 exhibited relatively strong antagonistic potency against AR and exhibited potent AR binding affinities, while compounds 5, 6, 10, 14, 16, 19, 21, 27 and 31 exhibited strong cytotoxic activities against LNCaP cells (AR-rich) as well as also displayed the higher activities than finasteride toward PC-3 (AR-deficient) and DU145 (AR-deficient). Docking study suggested that the most potent antagonist 16 mainly bind to AR ligand binding pocket (LBP) site through hydrogen bonding interactions. The structure-activity relationship (SAR) of these designed arylpiperazine derivatives was rationally explored and discussed. These results indicated that the novel scaffold compounds demonstrated a step towards the development of novel and improved AR antagonists, and promising candidates for future development were identified.