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Modified Quinoxaline‐Fused Oleanolic Acid Derivatives as Inhibitors of Osteoclastogenesis and Potential Agent in Anti‐Osteoporosis
Author(s) -
Zhang YuChao,
Shen Qi,
Zhu MingWu,
Wang Jie,
Du Yun,
Wu Jing,
Li JianXin
Publication year - 2020
Publication title -
chemistryselect
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.437
H-Index - 34
ISSN - 2365-6549
DOI - 10.1002/slct.201904521
Subject(s) - osteoclast , oleanolic acid , rankl , cytotoxicity , osteoporosis , chemistry , acid phosphatase , pharmacology , tartrate resistant acid phosphatase , activator (genetics) , cancer research , endocrinology , medicine , biochemistry , receptor , in vitro , pathology , enzyme , alternative medicine
Osteoporosis is one of the most common diseases for aged people, posing a heavy burden to our aging society. Inhibition of osteoclastogenesis is a main strategy to prevent bone loss or bone micro architecture deterioration caused by postmenopausal osteoporosis. In current study, a series of quinoxaline‐fused oleanolic acid (QOA) derivatives were designed and synthesized. Their inhibitory activity on receptor activator of nuclear factor‐κB ligand (RANKL)‐induced osteoclastogenesis was evaluated using a cell‐based tartrate‐resistant acid phosphatase (TRAP) assay. The most potent compound, QOA derivative 5 l , showed an IC 50 at 62.4 nM, and cytotoxicity assay of bone marrow‐derived monocyte/macrophage (BMDMs) suggested that the inhibition of 5 l on osteoclast differentiation was not due to its cytotoxicity. More importantly, 5 l attenuated bone loss in the bilateral ovariectomy (OVX) mice model, and preliminary mechanism study indicated that 5 l affected the early stage of osteoclastogenesis. Our data demonstrated that these QOA derivatives might serve as potential leads for the development of new anti‐osteoporosis agents.