Synthesis and biological evaluation of rhein amides as inhibitors of osteoclast differentiation and bone resorption.

Abstract

Approaches of targeting excessive activation and differentiation of osteoclasts were considered as an effective treatment option for osteoporosis or osteopenia. In the present work, a series of rhein derivatives were synthesized and employed for their cytotoxicity screening against bone marrow-derived macrophages cells (BMMs) and their inhibition effects on osteoclasts activation and differentiation in vitro using an MTT assay and a TRAP activity assay respectively. Two rhein derivatives d6 and d11 inhibited BMMs activation and differentiation with 98% and 85% inhibitory activity respectively, without showing any cytotoxicity on BMMs. Subsequently, the most potent compound d6 was further validated for its inhibitory effects on the formation of TRAP-positive multinucleated cells and bone resorption as evaluated by TRAP staining and bone resorption assay. The regulation by d6 of osteoclast marker genes assay revealed that treatment of BMMs with M-CSF and RANKL resulted in the stimulation of mRNA expressions of NFATc1, c-fos, TRAP, MMP-9 and cathepsin K which were highly related with osteoclast activation and differentiation, while d6 decreased mRNA expressions of these genes. It was indicated that d6 might regulate osteoclasts activity through RANKL/RANK/NFATc1 pathway. Thus our current work is expected to provide a highly promising approach for the development of a new type of anti-osteoporosis agent.

• Authors: Xing Xu, Xueyu Qi, Yufei Yan, Jin Qi, Niandong Qian, Lei Guo, Changwei Li, Fei Wang, Ping Huang, Hanbing Zhou, Min Jiang, Chunhao Yang, Lianfu Deng
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 123 Pg. 769-776 (Nov 10 2016) ISSN: 1768-3254 [Electronic] France
• PMID: 27541260 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Chemical References

• Amides
• Anthraquinones
• Biomarkers
• NFATC Transcription Factors
• RANK Ligand
• rhein

Topics

• 3T3-L1 Cells
• Amides (chemistry)
• Animals
• Anthraquinones (chemistry, pharmacology, therapeutic use)
• Biomarkers (metabolism)
• Bone Marrow Cells (cytology)
• Bone Resorption (drug therapy, metabolism, pathology)
• Cell Differentiation (drug effects)
• Chemistry Techniques, Synthetic
• Macrophages (cytology, drug effects, metabolism)
• Male
• Mice
• NFATC Transcription Factors (metabolism)
• Osteoclasts (cytology, drug effects)
• RANK Ligand (pharmacology)