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

Bioorg Med Chem. 2019 Jan 1;27(1):133-143. doi: 10.1016/j.bmc.2018.11.029.

Hong Chen ¹, Yu-Zhong Yu ², Xiu-Mei Tian ³, Cai-Lu Wang ⁴, Yu-Na Qian ⁵, Zai-An Deng ⁶, Jing-Xiao Zhang ⁴, Dao-Jun Lv ², Hai-Bo Zhang ², Jian-Liang Shen ⁷, Mu Yuan ³, Shan-Chao Zhao ⁸

Affiliations

1 Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, PR China; College of Food and Drug, Luoyang Normal University, Luoyang, Henan 471934, PR China.
2 Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, PR China.
3 School of Basic Medical Sciences, Pharmaceutical Research Center, Guangzhou Medical University, Guangzhou 511436, PR China.
4 College of Food and Drug, Luoyang Normal University, Luoyang, Henan 471934, PR China.
5 Wenzhou Institute of Biomaterials and Engineering, Chinese Academy of Science, Wenzhou 325001, PR China.
6 School of Ophthalmology & Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou 325035, PR China.
7 School of Ophthalmology & Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou 325035, PR China; Wenzhou Institute of Biomaterials and Engineering, Chinese Academy of Science, Wenzhou 325001, PR China. Electronic address: shenjl@wibe.ac.cn.
8 Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, PR China. Electronic address: zhaoshanchao@263.net.

PMID: 30482547 DOI: 10.1016/j.bmc.2018.11.029

Abstract

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.

Keywords

Antagonistic activity; Arylpiperazine derivatives; Binding affinities; Docking study; Prostate cancer; Synthesis.

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