Design, synthesis and SARs of novel salicylanilides as potent inhibitors of RANKL-induced osteoclastogenesis and bone resorption

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

doi:10.1016/j.ejmech.2016.04.007

Design, synthesis and SARs of novel salicylanilides as potent inhibitors of RANKL-induced osteoclastogenesis and bone resorption

Eur J Med Chem. 2016 Jul 19:117:70-84. doi: 10.1016/j.ejmech.2016.04.007. Epub 2016 Apr 6.

Authors

Chun-Liang Chen¹, Chia-Chung Lee¹, Fei-Lan Liu², Tsung-Chih Chen¹, Ahmed Atef Ahmed Ali³, Deh-Ming Chang⁴, Hsu-Shan Huang⁵

Affiliations

¹ Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, 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 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.
⁴ Rheumatology/Immunology/Allergy, Taipei Veterans General Hospital, Taipei 112, Taiwan, ROC; Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan, ROC. Electronic address: ming0503@ms3.hinet.net.
⁵ Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan, ROC; School of Pharmacy, National Defense Medical Center, Taipei 114, Taiwan, ROC; Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan, ROC. Electronic address: huanghs99@tmu.edu.tw.

PMID: 27089213
DOI: 10.1016/j.ejmech.2016.04.007

Abstract

Inhibiting osteoclastogenesis is a promising therapeutic target for treating osteoclast-related diseases. Herein, we synthesized a series of modified salicylanilides and their corresponding 3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-dione and 10-phenyldibenzo[b,f][1,4]oxazepin-11(10H)-one derivatives, and investigated the effects of such compounds on RANKL-induced osteoclast formation. Among them, a salicylanilide derivative (A04) and its 3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-dione derivative (B04) markedly suppressed RANKL-induced osteoclast differentiation and showed no significant cytotoxic effects at doses higher than that required to inhibit osteoclast formation. Both compounds reduced osteoclast formation and bone resorptive activity of osteoclasts in a dose-dependent manner. Further, the anti-osteoclastogenic effects of A04 and B04 may operate through reducing the RANKL-induced nuclear translocation of NFATc1. Accordingly, we present the potent anti-osteoclastogenic compounds A04 and B04 as promising candidates for further optimization as anti-resorptive agents.

Keywords: 3-Phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-dione; NFATc1; Osteoclast; Salicylanilide.

MeSH terms

Animals
Bone Resorption / drug therapy
Bone Resorption / prevention & control*
Cell Differentiation / drug effects
Cells, Cultured
Dose-Response Relationship, Drug
Drug Design
Mice
NFATC Transcription Factors / metabolism
Osteoclasts / cytology
Osteoclasts / drug effects*
RANK Ligand / drug effects
RANK Ligand / pharmacology
Salicylanilides / chemical synthesis*
Salicylanilides / pharmacology
Structure-Activity Relationship

Substances

NFATC Transcription Factors
RANK Ligand
Salicylanilides
Tnfsf11 protein, mouse