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

Eleven novel naftopidil-related compounds that contain amide and indole groups were designed and synthesized. The biological effects of these compounds on three alpha(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 alpha(1)-adrenoceptor antagonistic activity, whereas compounds 9, 10, and 12 displayed moderate antiproliferative activities. Compound 3 exhibited a significant alpha(1D/1A) blocking activity in isolated rat tissues (97.7- and 64.6-fold selective for alpha(1D) and alpha(1A) compared with alpha(1B)) but not a relevant cytotoxic activity. Compound 12 demonstrated a potent and selective alpha(1D/1A) antagonistic activity (47.9- and 19.1-fold for alpha(1D) and alpha(1A), compared with alpha(1B)) and a potent antiproliferative activity in PC-3 cells (IC50 = 15.70 mu M). Further testing confirmed that compound 12 inhibited the growth of PC-3 cells by inducing apoptosis and GO/G1 cell cycle arrest, which was mediated by alpha(1)-adrenoceptor. Therefore, compound 12 is a potential multipotent agent that can act as an effective alpha(1)-adrenoceptor subtype antagonist for treating benign prostatic hyperplasia and a preventive medication against human prostate cancer. (C) 2015 Elsevier Masson SAS. All rights reserved.