title: 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 α1-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 α1-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 α1B) and a potent antiproliferative activity in PC-3 cells (IC50 = 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 α1-adrenoceptor. Therefore, compound 12 is a potential multipotent agent that can act as an effective α1-adrenoceptor subtype antagonist for treating benign prostatic hyperplasia and a preventive medication against human prostate cancer.
authors: Pharmaceutical Research Center, Department of Pharmacology, Guangzhou Medical University, Guangzhou 510182, PR China.
authors: Junjun
authors: J
authors: Huang
authors: Guangdong Province Key Laboratory of Microbial Signals and Disease Control, Department of Plant Pathology, South China Agricultural University, Guangzhou 510642, PR China.
authors: Fei
authors: F
authors: He
authors: Pharmaceutical Research Center, Department of Pharmacology, Guangzhou Medical University, Guangzhou 510182, PR China.
authors: Minyi
authors: M
authors: Huang
authors: Pharmaceutical Research Center, Department of Pharmacology, Guangzhou Medical University, Guangzhou 510182, PR China.
authors: Xiawen
authors: X
authors: Liu
authors: Guangzhou Research Institute of Snake Venom, Department of Pharmacology, Guangzhou Medical University, Guangzhou 510182, PR China.
authors: Yan
authors: Y
authors: Xiong
authors: Pharmaceutical Research Center, Department of Pharmacology, Guangzhou Medical University, Guangzhou 510182, PR China.
authors: Yajian
authors: Y
authors: Huang
authors: Pharmaceutical Research Center, Department of Pharmacology, Guangzhou Medical University, Guangzhou 510182, PR China.
authors: Liu
authors: L
authors: Zhu
authors: Department of Pharmacology, Guangzhou Medical University, Guangzhou 510182, PR China.
authors: Ya
authors: Y
authors: Yang
authors: Pharmaceutical Research Center, Department of Pharmacology, Guangzhou Medical University, Guangzhou 510182, PR China.
authors: Xingjie
authors: X
authors: Xu
authors: Pharmaceutical Research Center, Department of Pharmacology, Guangzhou Medical University, Guangzhou 510182, PR China. Electronic address: mryuanmu838@sina.com.
authors: Mu
authors: M
authors: Yuan
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000970:Antineoplastic Agents; D009281:Naphthalenes; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; C064357:naftopidil
keywords: Benign prostatic hyperplasia; Naftopidil; Prostate cancer; α(1)-adrenoceptor subtype