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Synthesis and Biological Evaluation of Heterocyclic Ring Fused Betulinic Acid Derivatives as Novel Inhibitors of Osteoclast Differentiation and Bone Resorption
Xu Jun 1,Li Zhenxi 2,Luo Jian 2,Yang Fan 3,Liu Ting 4,liu Mingyao 2,Qiu Wen-Wei 5 * #,Tang Jie 4
1.Shanghai Engineering Research Center of Molecular Theraputics and New Drug Development, East China Normal University, ShangHai 200062
2.Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200062
3. Shanghai Engineering Research Center of Molecular Theraputics and New Drug Development, East China Normal University, Shanghai 200062
4.Shanghai Engineering Research Center of Molecular Theraputics and New Drug Development, East China Normal University, Shanghai 200062
5.Department of Chemistry, East China Normal University, Shanghai 200062
*Correspondence author
#Submitted by
Subject:
Funding: National Natural Science Foundation of China (No.NO. 20802020), Ph.D. Program Foundation of Ministry of Education of China (No.No. 20080269103)
Opened online:13 February 2012
Accepted by: none
Citation: Xu Jun,Li Zhenxi,Luo Jian.Synthesis and Biological Evaluation of Heterocyclic Ring Fused Betulinic Acid Derivatives as Novel Inhibitors of Osteoclast Differentiation and Bone Resorption[OL]. [13 February 2012] http://en.paper.edu.cn/en_releasepaper/content/4463179
 
 
A series of betulinic acid (BA) derivatives were synthesized by introducing various fused heterocyclic rings at C-2 and C-3 positions. Their inhibitory effects of RANKL-induced osteoclastogenesis were evaluated by using a cell-based tartrate-resistant acid phosphatase (TRAP) activity assay. Compared with BA, most of these compounds exhibited a dramatic increase in inhibitory potency. Especially compound 20, which showed 66.9% inhibition even at low concentration of 0.1 M, was about 200-fold more potent than lead compound BA. The cytotoxicity assay on RAW264.7 suggested that the action of 20 on osteoclast differentiation was not result from its cytotoxicity. The primary mechanistic study indicated that 20 could inhibit osteoclastogenesis-related marker gene expression levels of cathepsin K and TRAP. Importantly, this compound attenuated bone loss of ovariectomy mouse in vivo. These BA derivatives could be used as potential leads for the development of a new type of antiosteoporosis agents.
Keywords:betulinic acid derivatives; osteoclast; inhibition
 
 
 

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