title: Modified salicylanilide and 3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-dione derivatives as novel inhibitors of osteoclast differentiation and bone resorption.
abstract: Inhibition of osteoclast formation is a potential strategy to prevent inflammatory bone resorption and to treat bone diseases. In the present work, the purpose was to discover modified salicylanilides and 3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-dione derivatives as potential antiosteoclastogenic agents. Their inhibitory effects on RANKL-induced osteoclastogenesis from RAW264.7 cells were evaluated by TRAP stain assay. The most potent compounds, 1d and 5d, suppressed RANKL-induced osteoclast formation and TRAP activity dose-dependently. The cytotoxicity assay on RAW264.7 cells suggested that the inhibition of osteoclastic bone resorption by these compounds did not result from their cytotoxicity. Moreover, both compounds downregulated RANKL-induced NF-κB and NFATc1 in the nucleus, suppressed the expression of osteoclastogenesis-related marker genes during osteoclastogenesis, and prevented osteoclastic bone resorption but did not impair osteoblast differentiation in MC3T3-E1. Therefore, these modified salicylanilides and 3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-diones could be potential lead compounds for the development of a new class of antiresorptive agents.
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University , Taipei 110, Taiwan ROC.
authors.forename: Chun-Liang
authors.initials: CL
authors.lastname: Chen
authors.forename: Fei-Lan
authors.initials: FL
authors.lastname: Liu
authors.forename: Chia-Chung
authors.initials: CC
authors.lastname: Lee
authors.forename: Tsung-Chih
authors.initials: TC
authors.lastname: Chen
authors.forename: Ahmed Atef
authors.initials: AA
authors.lastname: Ahmed Ali
authors.forename: Huey-Kang
authors.initials: HK
authors.lastname: Sytwu
authors.forename: Deh-Ming
authors.initials: DM
authors.lastname: Chang
authors.forename: Hsu-Shan
authors.initials: HS
authors.lastname: Huang
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000517:prevention & control*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D051379:Mice; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D010078:Oxazines / Q000138:chemical synthesis* / Q000494:pharmacology; D053245:RANK Ligand / Q000037:antagonists & inhibitors; D012458:Salicylanilides / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D010078:Oxazines; D053245:RANK Ligand; D012458:Salicylanilides