Synthesis of heterocyclic ring-fused tricyclic diterpene analogs as novel inhibitors of RANKL-induced osteoclastogenesis and bone resorption.

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.