title: Design, synthesis and SARs of novel salicylanilides as potent inhibitors of RANKL-induced osteoclastogenesis and bone resorption.
abstract: Inhibiting osteoclastogenesis is a promising therapeutic target for treating osteoclast-related diseases. Herein, we synthesized a series of modified salicylanilides and their corresponding 3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-dione and 10-phenyldibenzo[b,f][1,4]oxazepin-11(10H)-one derivatives, and investigated the effects of such compounds on RANKL-induced osteoclast formation. Among them, a salicylanilide derivative (A04) and its 3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-dione derivative (B04) markedly suppressed RANKL-induced osteoclast differentiation and showed no significant cytotoxic effects at doses higher than that required to inhibit osteoclast formation. Both compounds reduced osteoclast formation and bone resorptive activity of osteoclasts in a dose-dependent manner. Further, the anti-osteoclastogenic effects of A04 and B04 may operate through reducing the RANKL-induced nuclear translocation of NFATc1. Accordingly, we present the potent anti-osteoclastogenic compounds A04 and B04 as promising candidates for further optimization as anti-resorptive agents.
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan, ROC; School of Pharmacy, National Defense Medical Center, Taipei 114, Taiwan, ROC.
authors.forename: Chun-Liang
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan, ROC; School of Pharmacy, National Defense Medical Center, Taipei 114, Taiwan, ROC.
authors.forename: Chia-Chung
authors.initials: CC
authors.lastname: Lee
authors.affiliation: Rheumatology/Immunology/Allergy, Taipei Veterans General Hospital, Taipei 112, Taiwan, ROC.
authors.forename: Fei-Lan
authors.initials: FL
authors.lastname: Liu
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan, ROC; School of Pharmacy, National Defense Medical Center, Taipei 114, Taiwan, ROC.
authors.forename: Tsung-Chih
authors.initials: TC
authors.lastname: Chen
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan, ROC; Taiwan International Graduate Program, Molecular and Cell Biology Program, Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan, ROC.
authors.forename: Ahmed Atef
authors.initials: AA
authors.lastname: Ahmed Ali
authors.affiliation: Rheumatology/Immunology/Allergy, Taipei Veterans General Hospital, Taipei 112, Taiwan, ROC; Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan, ROC. Electronic address: ming0503@ms3.hinet.net.
authors.forename: Deh-Ming
authors.initials: DM
authors.lastname: Chang
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan, ROC; School of Pharmacy, National Defense Medical Center, Taipei 114, Taiwan, ROC; Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan, ROC. Electronic address: huanghs99@tmu.edu.tw.
authors.forename: Hsu-Shan
authors.initials: HS
authors.lastname: Huang
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy / Q000517:prevention & control*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D053245:RANK Ligand / Q000187:drug effects / Q000494:pharmacology; D012458:Salicylanilides / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D050778:NFATC Transcription Factors; D053245:RANK Ligand; D012458:Salicylanilides; C505689:Tnfsf11 protein, mouse
keywords: 3-Phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-dione; NFATc1; Osteoclast; Salicylanilide