title: 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.
abstract: A series of novel 6-(2,4-difluorophenyl)-3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-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.
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan, ROC; Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, 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.
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.
authors.forename: Tsung-Chih
authors.initials: TC
authors.lastname: Chen
authors.affiliation: Rheumatology/Immunology/Allergy, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan, ROC.
authors.forename: Feng-Cheng
authors.initials: FC
authors.lastname: Liu
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: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan, ROC; Rheumatology/Immunology/Allergy, Taipei Veterans General Hospital, Taipei 112, 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; Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan, ROC; School of Pharmacy, 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; D002455:Cell Division / Q000502:physiology*; D002460:Cell Line; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology*; D010078:Oxazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D053245:RANK Ligand / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D016328:NF-kappa B; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D010078:Oxazines; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse
keywords: NDMC101; Osteoclastogenesis; Pit formation assay; RANKL; TRAP-staining assay