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

Chia-Chung Lee; Fei-Lan Liu; Chun-Liang Chen; Tsung-Chih Chen; Feng-Cheng Liu; Ahmed Atef Ahmed Ali; Deh-Ming Chang; Hsu-Shan Huang

doi:10.1016/j.bmc.2015.06.007

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

Bioorg Med Chem. 2015 Aug 1;23(15):4522-4532. doi: 10.1016/j.bmc.2015.06.007. Epub 2015 Jun 10.

Authors

Chia-Chung Lee¹, Fei-Lan Liu², Chun-Liang Chen³, Tsung-Chih Chen³, Feng-Cheng Liu⁴, Ahmed Atef Ahmed Ali⁵, Deh-Ming Chang⁶, Hsu-Shan Huang⁷

Affiliations

¹ 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.
² Rheumatology/Immunology/Allergy, Taipei Veterans General Hospital, Taipei 112, Taiwan, ROC.
³ Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan, ROC.
⁴ Rheumatology/Immunology/Allergy, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan, ROC.
⁵ 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.
⁶ 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.
⁷ 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.

PMID: 26081760
DOI: 10.1016/j.bmc.2015.06.007

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.

Keywords: NDMC101; Osteoclastogenesis; Pit formation assay; RANKL; TRAP-staining assay.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Division / physiology*
Cell Line
Drug Design
Drug Evaluation, Preclinical
Mice
NF-kappa B / metabolism
NFATC Transcription Factors / metabolism
Osteoclasts / cytology*
Oxazines / chemical synthesis
Oxazines / chemistry
Oxazines / pharmacology*
RANK Ligand / antagonists & inhibitors*
RANK Ligand / physiology

Substances

NF-kappa B
NFATC Transcription Factors
Nfatc1 protein, mouse
Oxazines
RANK Ligand
Tnfsf11 protein, mouse