title: Design, synthesis and biological evaluation of nonsecosteroidal vitamin D3receptor ligands as anti-tumor agents.
abstract: 1α,25-dihydroxyvitamin D3(1,25-(OH)2D3, also known as calcitriol), the active form of vitamin D3, is being increasingly recognized for cancer therapy. Our previous work showed that phenyl-pyrrolyl pentane analogs, which mimicked anti-proliferative activities against several cancer cell lines of the natural secosteroidal ligand 1,25-(OH)2D3. Here, in order to optimize the structural features and discover more potent derivative, a series of nonsecosteroidal vitamin D3receptor (VDR) ligands bearing acetylene bond linker was designed, synthesized and evaluated. Most of them showed moderate to good binding affinities and agonistic activities. Especially, compound 19f displayed the most anti-proliferative activities against MCF-7 and PC-3 cells with the IC50values of 1.80 and 5.35μM, respectively, which was comparable to positive control 1,25-(OH)2D3. Moreover, compound 19f exhibited reduced toxicity against human normal liver cell line (L02) compared with the parental compound 7. Besides, the preliminary structure-activity relationships (SARs) were also analyzed.
authors.affiliation: State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of New Drug Discovery, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of New Drug Discovery, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Meixi
authors.initials: M
authors.lastname: Hao
authors.affiliation: State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of New Drug Discovery, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China. Electronic address: zhangcan@cpu.edu.cn.
authors.forename: Can
authors.initials: C
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008958:Models, Molecular; D018167:Receptors, Calcitriol / Q000378:metabolism*; D013256:Steroids / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D018167:Receptors, Calcitriol; D013256:Steroids
keywords: Agonistic activity; Anti-proliferative activity; Binding affinity; Nonsecosteroidal; Phenyl-pyrrolyl pentane skeleton; VDR ligand; Vitamin D(3)