Synthesis of 5α-cholestan-6-one derivatives and their inhibitory activities of NO production in activated microglia: discovery of a novel neuroinflammation inhibitor.
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.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Road Zu Chong Zhi, Zhangjiang Hi-Tech Park, Shanghai 201203, PR China.
Ya-Xi
YX
Yang
Jiansu Key Laboratory for Translational Research for Neuro-Psycho-diseases, Department of Pharmacology, Soochow University College of Pharmaceutical Sciences, Suzhou 215123, PR China.
Long-Tai
LT
Zheng
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Road Zu Chong Zhi, Zhangjiang Hi-Tech Park, Shanghai 201203, PR China.
Jing-Jing
JJ
Shi
Jiansu Key Laboratory for Translational Research for Neuro-Psycho-diseases, Department of Pharmacology, Soochow University College of Pharmaceutical Sciences, Suzhou 215123, PR China.
Bo
B
Gao
Jiansu Key Laboratory for Translational Research for Neuro-Psycho-diseases, Department of Pharmacology, Soochow University College of Pharmaceutical Sciences, Suzhou 215123, PR China.
Yan-Ke
YK
Chen
Jiansu Key Laboratory for Translational Research for Neuro-Psycho-diseases, Department of Pharmacology, Soochow University College of Pharmaceutical Sciences, Suzhou 215123, PR China.
Hui-Chi
HC
Yang
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Road Ling Ling, Shanghai 200032, PR China. Electronic address: hewachen@163.com.
Hong-Li
HL
Chen
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Road Zu Chong Zhi, Zhangjiang Hi-Tech Park, Shanghai 201203, PR China. Electronic address: ycli@mail.shcnc.ac.cn.
Yuan-Chao
YC
Li
Jiansu Key Laboratory for Translational Research for Neuro-Psycho-diseases, Department of Pharmacology, Soochow University College of Pharmaceutical Sciences, Suzhou 215123, PR China. Electronic address: zhenxuechu@suda.edu.cn.
Xue-Chu
XC
Zhen
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002778:Cholestanones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D013329:Structure-Activity Relationship
D002778:Cholestanones; D008070:Lipopolysaccharides; D009569:Nitric Oxide
5α-Cholestan-6-one; Focal cerebral ischemia; Microglia; Neuroinflammation; Nitric oxide