Novel inhibitors of RANKL-induced osteoclastogenesis: Design, synthesis, and biological evaluation of 6-(2, 4-difluorophenyl)-3-phenyl-2H-benzo[e][1, 3]oxazine-2, 4(3H)-diones. Issue 15 (1st August 2015)

• Record Type: Journal Article
• Authors: Lee, Chia-Chung; Liu, Fei-Lan; Chen, Chun-Liang; Chen, Tsung-Chih; Liu, Feng-Cheng; Ahmed Ali, Ahmed Atef; Chang, Deh-Ming; Huang, Hsu-Shan
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 15(2015)
• Page Start: 4522
• Page End: 4532
• Publication Date: 2015-08-01
• Subjects: NDMC101 -- Osteoclastogenesis -- RANKL -- TRAP-staining assay -- Pit formation assay; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.06.007
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: A series of novel 6-(2, 4-difluorophenyl)-3-phenyl-2 H -benzo[ e ][1, 3]oxazine-2, 4(3 H )-dione derivatives were synthesized and evaluated for their inhibitory effects on osteoclast activities by using TRAP-staining assay. Among the tested compounds, 3d and 3h exhibited more potent osteoclast-inhibitory activities than the lead compound NDMC503 (a ring-fused structure of NDMC101), as reported in our previous study. Both 3d and 3h exhibited two-fold increase in activity compared to NDMC503. In addition, our biological results indicated that 3d and 3h could suppress RANKL-induced osteoclastogenesis-related marker genes, such as NFATc1, c-fos, TRAP, and cathepsin K . Notably, 3d could significantly attenuate the bone-resorbing activity of osteoclasts in the pit formation assay. Thus, this study might provide a new class of lead structures that warrant further development as potential anti-resorptive agents.