title: Synthesis of heterocyclic ring-fused tricyclic diterpene analogs as novel inhibitors of RANKL-induced osteoclastogenesis and bone resorption.
abstract: A series of heterocyclic ring-fused tricyclic diterpene analogs were synthesized and their inhibitory effects of RANKL-induced osteoclastogenesis were evaluated on bone marrow-derived monocytes (BMMs) by a cell based tartrate-resistant acid phosphatase (TRAP) activity assay. Among them, the most potent compound, 37 (QG368), showed 72.3% inhibition even at a low concentration of 0.1 μM, which was about 188-fold more potent than the lead compound. Cytotoxicity test on BMMs indicated that the inhibition on osteoclast differentiation of 37 did not result from its cytotoxicity. Moreover, 37 also showed no obvious effect on osteoblast differentiation. Mechanistic studies disclosed that 37 can inhibit the expression of osteoclastogenesis-related marker genes, including Nfatc1, TRAP, cathepsin K, C-src and CTR. In particular, 37 could decrease the ovariectomy-induced osteoclast activity and relieve the osteoporosis obviously in vivo. Therefore, these tricyclic diterpene analogs could be served as promising leads for the development of a new class of antiresorptive agents.
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200241, China.
authors.forename: Gao
authors.initials: G
authors.lastname: Wei
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
authors.forename: Yalan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200241, China.
authors.forename: Xiao-Long
authors.initials: XL
authors.lastname: He
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200241, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China. Electronic address: jluo@bio.ecnu.edu.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Luo
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200241, China. Electronic address: wwqiu@chem.ecnu.edu.cn.
authors.forename: Wen-Wei
authors.initials: WW
authors.lastname: Qiu
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects; D001862:Bone Resorption / Q000188:drug therapy* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D004224:Diterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D010012:Osteogenesis / Q000187:drug effects*; D053245:RANK Ligand / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004224:Diterpenes; D006571:Heterocyclic Compounds; D053245:RANK Ligand; C505688:TNFSF11 protein, human
keywords: Diterpenoids; Osteoclast; Osteoporosis; Tricyclic diterpene