2. Academic Validation
  3. Design, synthesis and SARs of novel salicylanilides as potent inhibitors of RANKL-induced osteoclastogenesis and bone resorption

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.
Chun-Liang Chen 1,  Chia-Chung Lee 1,  Fei-Lan Liu 2,  Tsung-Chih Chen 1,  Ahmed Atef Ahmed Ali 3,  Deh-Ming Chang 4,  Hsu-Shan Huang 5
Affiliations

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: [email protected].
  • 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: [email protected].
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.

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