Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Road Zu Chong Zhi, Zhangjiang Hi-Tech Park, Shanghai 201203, PR China.
Jiansu Key Laboratory for Translational Research for Neuro-Psycho-diseases, Department of Pharmacology, Soochow University College of Pharmaceutical Sciences, Suzhou 215123, PR China.
Bioorg Med Chem Lett. 2014 Feb 15;24(4):1222-7. doi: 10.1016/j.bmcl.2013.12.055. Epub 2013 Dec 19.
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 5α-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-α, interleukin (IL)-1β, 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.
神经胶质细胞激活介导的神经炎症在多种神经炎症性疾病的发生发展过程中发挥着关键作用，这些疾病包括中风、阿尔茨海默病、帕金森病、多发性硬化症和缺血性疾病。抑制小胶质细胞的激活可能会减轻炎症状态下的神经元退行性变。在本研究中，我们制备了一系列 5α-胆甾烷-6-酮衍生物，并评估了这些化合物在 LPS 刺激的 BV-2 小胶质细胞中的抗炎作用。这些衍生物是由易得的猪去氧胆酸（1）合成的。在所测试的化合物中，有几个类似物（16-18、25、35、38）对一氧化氮的产生具有很强的抑制活性，且没有或仅有较弱的细胞毒性。化合物 16 还能显著抑制 LPS 刺激的 BV-2 小胶质细胞中 TNF-α、白细胞介素（IL）-1β、环氧化酶（COX-2）和诱导型一氧化氮合酶（iNOS）的表达。此外，化合物 16 还能显著减少局灶性缺血小鼠模型中的梗死体积。
