title: Synthesis and biological evaluation of heterocyclic ring-fused betulinic acid derivatives as novel inhibitors of osteoclast differentiation and bone resorption.
abstract: A series of betulinic acid (BA) derivatives were designed and 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. To our delight, most of these compounds exhibited a dramatic increase in inhibitory potency, compared with BA. The most potent compound, 20, showed 66.9% inhibition even at the low concentration of 0.1 μM, which was about 200-fold more potent than the lead compound BA. What's more, the cytotoxicity assay on RAW264.7 suggested that the inhibition of 20 on osteoclast differentiation did 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. More importantly, 20 could attenuate bone loss of ovariectomy mouse in vivo. Therefore, these BA derivatives could be used as potential leads for the development of a new type of antiosteoporosis agent.
authors.affiliation: Shanghai Engineering Research Center for Molecular Therapeutics and New Drug Development, East China Normal University, Shanghai 200062, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.forename: Zhenxi
authors.initials: Z
authors.lastname: Li
authors.forename: Jian
authors.initials: J
authors.lastname: Luo
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.forename: Wen-Wei
authors.initials: WW
authors.lastname: Qiu
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
mesh_terms: D000135:Acid Phosphatase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D050071:Bone Density Conservation Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001862:Bone Resorption / Q000188:drug therapy / Q000473:pathology; D056657:Cathepsin K / Q000037:antagonists & inhibitors / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D005260:Female; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D010052:Ovariectomy; D053978:Pentacyclic Triterpenes; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D053245:RANK Ligand / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D000071681:Tartrate-Resistant Acid Phosphatase; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014315:Triterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000094062:Betulinic Acid
chemical_list: D050071:Bone Density Conservation Agents; D007527:Isoenzymes; D007555:Isoxazoles; D053978:Pentacyclic Triterpenes; D011719:Pyrazines; D011720:Pyrazoles; D011743:Pyrimidines; D053245:RANK Ligand; D013844:Thiazoles; D014315:Triterpenes; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase; D056657:Cathepsin K; D000094062:Betulinic Acid