Synthesis of 5α-cholestan-6-one derivatives and their inhibitory activities of NO production in activated microglia: Discovery of a novel neuroinflammation inhibitor
Synthesis of 5α-cholestan-6-one derivatives and their inhibitory activities of NO production in activated microglia: Discovery of a novel neuroinflammation inhibitor
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5α-胆甾坦-6-酮衍生物的合成及其对活化小胶质细胞NO产生的抑制活性：新型神经炎症抑制剂的发现
DOI：
10.1016/j.bmcl.2013.12.055
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发表时间：
2014-02-15
影响因子：
2.7
通讯作者：
Zhen, Xue-Chu
中科院分区：
文献类型：
--
作者：
Yang, Ya-Xi;Zheng, Long-Tai;Zhen, Xue-Chu
胶质细胞活化介导的神经炎症在包括中风、阿尔茨海默病、帕金森病、多发性硬化和缺血在内的多种神经炎症性疾病的过程中起关键作用。抑制小胶质细胞活化可以改善炎症条件下的神经元变性。在本研究中，制备了许多5 α-胆甾烷-6-酮衍生物，并在LPS刺激的BV-2小胶质细胞中评价了这些化合物的抗炎作用。这些衍生物是由容易获得的猪去氧胆酸（1）合成的。在测试的化合物中，几种类似物（16-18、25、35、38）对一氧化氮产生表现出有效的抑制活性，而没有或具有弱的细胞毒性。化合物16还显著抑制LPS刺激的BV-2小胶质细胞中TNF-α、白细胞介素（IL）-1 β、环氧合酶（考克斯-2）以及诱导型一氧化氮合酶（iNOS）的表达。此外，化合物16显著减少局灶性缺血小鼠模型中的梗塞体积。(C)2013爱思唯尔有限公司保留所有权利。
Glial activation-mediated neuroinflammation plays a pivotal role in the process of several neuroinflammatory diseases including stroke, Alzheimer's diseases, Parkinson's diseases, multiple sclerosis and ischemia. Inhibition of microglial activation may ameliorate neuronal degeneration under the inflammatory conditions. In the present study, a number of 5 alpha-cholestan-6-one derivatives were prepared and the anti-inflammatory effects of these compounds were evaluated in LPS-stimulated BV-2 microglia cells. Those derivatives were synthesized from readily available hyodeoxycholic acid (1). Among the tested compounds, several analogs (16-18, 25, 35, 38) exhibited potent inhibitory activities on nitric oxide production with no or weak cell toxicity. Compound 16 also significantly suppressed the expression of TNF-alpha, interleukin (IL)-1 beta, cyclooxygenase (COX-2) as well as inducible nitric oxide synthase (iNOS) in LPS-stimulated BV-2 microglia cells. In addition, compound 16 markedly reduced infarction volume in a focal ischemic mice model. (C) 2013 Elsevier Ltd. All rights reserved.