Synthesis and Biological Evaluation of Salicylanilide Derivatives as RANKL-Induced Osteoclastogenesis Inhibitors

• Main Authors: Chun-Liang Chen, 陳俊良
• Other Authors: Hsu-Shan Huang
• Format: Others
• Language: en_US
• Published: 2013
• Online Access: http://ndltd.ncl.edu.tw/handle/00818442085569545451

博士 === 國防醫學院 === 生命科學研究所 === 102 === Inhibition of osteoclast formation is a potential strategy to prevent inflammatory bone resorption and treat bone disease. The development of potential antiosteoclastogenic agent is the focus of the present study. Herein, we designed and synthesized the modified salicylanilides and 3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-dione analogues as osteoclastogenesis inhibitors. To investigate the biological activities of these synthetic compounds, we initially evaluated their effects on RANKL-induced osteoclastogenesis from osteoclast precursor cells RAW264.7 by TRAP stain as well as cell cytotoxicity by MTT assay. The most potent compounds 1d and 5d exhibited the strongest antiosteoclastogenic effects, which were selected as candidates for further antiosteoclastogenic evaluation. Both compounds 1d and 5d suppressed RANKL-induced osteoclast differentiation and TRAP activity in a dose-dependent manner. The mechanism study indicated that 1d and 5d could reduce the level of transcription factors NF-κB and NFATc1 in nucleus, and suppress the gene expression levels of osteoclastogenesis-related marker genes during osteoclastogenesis. In addition, 1d and 5d prevented osteoclastic bone resorption dose-dependently, but did not impair osteoblast differentiation in MC3T3-E1. The preliminary structure-activity relationships (SARs) of our novel synthetic compounds described the optimization and modification to a new more potent antiosteoclastogenic inhibitor. Also, salicylanilide and 3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-dione, especially 1d and 5d, could be the novel lead structures for the development of antiresorptive agents.