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

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

Research output: Contribution to journal › Article › peer-review

11 Citations (Scopus)

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.

Original language	English
Pages (from-to)	4522-4532
Number of pages	11
Journal	Bioorganic and Medicinal Chemistry
Volume	23
Issue number	15
DOIs	https://doi.org/10.1016/j.bmc.2015.06.007
Publication status	Published - Jul 23 2015

Keywords

NDMC101
Osteoclastogenesis
Pit formation assay
RANKL
TRAP-staining assay

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmc.2015.06.007

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CCDC 1417633: Experimental Crystal Structure Determination
Lee, C. (Contributor), Liu, F. (Contributor), Chen, C. (Contributor), Chen, T. (Contributor), Liu, F. (Contributor), Ali, A. A. A. (Contributor), Chang, D. (Contributor) & Huang, H. (Contributor), Unknown Publisher, Jul 23 2015
DOI: 10.5517/cc1jl53d, http://www.ccdc.cam.ac.uk/services/structure_request?id=doi:10.5517/cc1jl53d&sid=DataCite
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Lee, C. C., Liu, F. L., Chen, C. L., Chen, T. C., Liu, F. C., Ahmed Ali, A. A., Chang, D. M., & Huang, H. S. (2015). 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. Bioorganic and Medicinal Chemistry, 23(15), 4522-4532. https://doi.org/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. / 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.

In: Bioorganic and Medicinal Chemistry, Vol. 23, No. 15, 23.07.2015, p. 4522-4532.

Research output: Contribution to journal › Article › peer-review

Lee, CC, Liu, FL, Chen, CL, Chen, TC, Liu, FC, Ahmed Ali, AA, Chang, DM & Huang, HS 2015, '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', Bioorganic and Medicinal Chemistry, vol. 23, no. 15, pp. 4522-4532. https://doi.org/10.1016/j.bmc.2015.06.007

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. / 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. In: Bioorganic and Medicinal Chemistry. 2015 ; Vol. 23, No. 15. pp. 4522-4532.

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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.",

keywords = "NDMC101, Osteoclastogenesis, Pit formation assay, RANKL, TRAP-staining assay",

author = "Lee, {Chia Chung} and Liu, {Fei Lan} and Chen, {Chun Liang} and Chen, {Tsung Chih} and Liu, {Feng Cheng} and {Ahmed Ali}, {Ahmed Atef} and Chang, {Deh Ming} and Huang, {Hsu Shan}",

note = "Funding Information: The present study was supported by the National Science Council Grant ( NSC 101-2113-M-016-001 ), Ministry of Science and Technology ( MOST 102-2314-B-075-083-MY3 ), and Taipei Medical University ( TMU 102-AE1-B32 ). We also thank Ting-Shen Kuo for kindly providing the information of crystallography. ",

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T2 - Design, synthesis, and biological evaluation of 6-(2,4-difluorophenyl)-3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-diones

AU - Lee, Chia Chung

AU - Liu, Fei Lan

AU - Chen, Chun Liang

AU - Chen, Tsung Chih

AU - Liu, Feng Cheng

AU - Ahmed Ali, Ahmed Atef

AU - Chang, Deh Ming

AU - Huang, Hsu Shan

N1 - Funding Information: The present study was supported by the National Science Council Grant ( NSC 101-2113-M-016-001 ), Ministry of Science and Technology ( MOST 102-2314-B-075-083-MY3 ), and Taipei Medical University ( TMU 102-AE1-B32 ). We also thank Ting-Shen Kuo for kindly providing the information of crystallography.

PY - 2015/7/23

Y1 - 2015/7/23

N2 - 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.

AB - 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.

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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

Keywords

ASJC Scopus subject areas

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CCDC 1417633: Experimental Crystal Structure Determination

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