Synthesis, biological evaluation and SAR of naftopidil-based arylpiperazine derivatives
- Bioorg Med Chem Lett. 2018 May 15;28(9):1534-1539. doi: 10.1016/j.bmcl.2018.03.070.
- 1. College of Food and Drug, Luoyang Normal University, Luoyang, Henan 471934, China.
- 2. School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 511436, China. Electronic address: [email protected].
- 3. Pharmaceutical Research Center, Guangzhou Medical University, Guangzhou, Guangdong 511436, China. Electronic address: [email protected].
For the development of potential anti-prostate Cancer agents, 24 kinds of novel naftopidil-based arylpiperazine derivatives have been synthesized and characterized by spectroscopic methods. Their antitumor activities were evaluated against several classical prostate Cancer cell lines including PC-3, LNCaP, and DU145. Among all the compounds, 9, 13, 17, 21 and 27 showed strong cytotoxic activities against DU145 cells (IC50 < 1 μM). Further testing confirmed that compound 17 inhibited the growth of DU145 cells by inducing cell cycle arrest at G0/G1 phase. Besides, antagonistic activities of compounds (9, 13, 17, 21 and 27) towards a1-ARs (α1A, α1B, and α1D) were further evaluated using dual-luciferase reporter assays, and the compounds 13 and 17 exhibited better a1-ARs subtype selectivity. The structure-activity relationship (SAR) of these developed arylpiperazine derivatives was rationally discussed. Taken together, these results suggested that further development of such compounds may be of great interest.