Novel naftopidil-related derivatives and their biological effects as alpha1-adrenoceptors antagonists and antiproliferative agents

Abstract Eleven novel naftopidil-related compounds that contain amide and indole groups were designed and synthesized. The biological effects of these compounds on three α 1 -adrenoceptor subtypes and cancerous human prostate cell lines (PC-3, DU-145, and LNCaP) were determined. Compounds 2 , 3 , 5 , 11 , and 12 exhibited an α 1 -adrenoceptor antagonistic activity, whereas compounds 9 , 10 , and 12 displayed moderate antiproliferative activities. Compound 3 exhibited a significant α 1D/1A blocking activity in isolated rat tissues (97.7- and 64.6-fold selective for α 1D and α 1A compared with α 1B ) but not a relevant cytotoxic activity. Compound 12 demonstrated a potent and selective α 1D/1A antagonistic activity (47.9- and 19.1-fold for α 1D and α 1A compared with α 1B ) and a potent antiproliferative activity in PC-3 cells (IC 50  = 15.70 μM). Further testing confirmed that compound 12 inhibited the growth of PC-3 cells by inducing apoptosis and G0/G1 cell cycle arrest, which was mediated by α 1 -adrenoceptor. Therefore, compound 12 is a potential multipotent agent that can act as an effective α 1 -adrenoceptor subtype antagonist for treating benign prostatic hyperplasia and a preventive medication against human prostate cancer.