Modified quinoxaline-fused oleanolic acid derivatives as inhibitors of osteoclastogenesis and potential agent in anti-osteoporosis
Modified quinoxaline-fused oleanolic acid derivatives as inhibitors of osteoclastogenesis and potential agent in anti-osteoporosis
复制标题
修饰的喹喔啉融合齐墩果酸衍生物作为破骨细胞生成抑制剂和抗骨质疏松症的潜在药物
DOI：
10.1002/slct.201904521
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发表时间：
2020
期刊：
影响因子：
2.1
通讯作者：
Li Jian-Xin
中科院分区：
文献类型：
--
作者：
Zhang Yu-Chao;Shen Qi;Zhu Ming-Wu;Wang Jie;Du Yun;Wu Jing;Li Jian-Xin
骨质疏松症是老年人最常见的疾病之一，给我们的老龄化社会带来了沉重的负担。抑制破骨细胞生成是预防绝经后骨质疏松引起的骨丢失或骨微结构恶化的主要策略。本研究设计并合成了一系列喹喔啉稠合的油酸衍生物。使用基于细胞的抗酒石酸酸性磷酸酶（TRAP）试验评价其对核因子-κB配体受体激活剂（RANKL）诱导的破骨细胞生成的抑制活性。最有效的化合物QOA derivative 5l显示出62.4 nM的IC 50，骨髓来源的单核细胞/巨噬细胞（BMDM）的细胞毒性试验表明，5l破骨细胞分化的抑制不是由于其细胞毒性。 更重要的是，51减轻了双侧卵巢切除（OVX）小鼠模型的骨丢失，初步的机制研究表明，51影响破骨细胞的早期生成。我们的数据表明，这些QOA衍生物可能作为开发新的抗骨质疏松剂的潜在线索。
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 derivative5l, showed an IC50at 62.4 nM, and cytotoxicity assay of bone marrow‐derived monocyte/macrophage (BMDMs) suggested that the inhibition of5lon osteoclast differentiation was not due to its cytotoxicity. More importantly,5lattenuated bone loss in the bilateral ovariectomy (OVX) mice model, and preliminary mechanism study indicated that5laffected 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.