Synthesis of 5α-cholestan-6-one derivatives and their inhibitory activities of NO production in activated microglia: discovery of a novel neuroinflammation inhibitor

Ya-Xi Yang; Long-Tai Zheng; Jing-Jing Shi; Bo Gao; Yan-Ke Chen; Hui-Chi Yang; Hong-Li Chen; Yuan-Chao Li; Xue-Chu Zhen

doi:10.1016/j.bmcl.2013.12.055

Synthesis of 5α-cholestan-6-one derivatives and their inhibitory activities of NO production in activated microglia: discovery of a novel neuroinflammation inhibitor

Bioorg Med Chem Lett. 2014 Feb 15;24(4):1222-7. doi: 10.1016/j.bmcl.2013.12.055. Epub 2013 Dec 19.

Authors

Ya-Xi Yang¹, Long-Tai Zheng², Jing-Jing Shi¹, Bo Gao², Yan-Ke Chen², Hui-Chi Yang², Hong-Li Chen³, Yuan-Chao Li⁴, Xue-Chu Zhen⁵

Affiliations

¹ Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Road Zu Chong Zhi, Zhangjiang Hi-Tech Park, Shanghai 201203, PR China.
² Jiansu Key Laboratory for Translational Research for Neuro-Psycho-diseases, Department of Pharmacology, Soochow University College of Pharmaceutical Sciences, Suzhou 215123, PR China.
³ Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Road Ling Ling, Shanghai 200032, PR China. Electronic address: hewachen@163.com.
⁴ 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.
⁵ 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.

PMID: 24456901
DOI: 10.1016/j.bmcl.2013.12.055

Abstract

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.

Keywords: 5α-Cholestan-6-one; Focal cerebral ischemia; Microglia; Neuroinflammation; Nitric oxide.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line
Cell Survival / drug effects
Cholestanones / chemical synthesis
Cholestanones / chemistry
Cholestanones / pharmacology*
Crystallography, X-Ray
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Discovery*
Inflammation / drug therapy*
Inflammation / metabolism
Lipopolysaccharides / pharmacology
Mice
Microglia / drug effects*
Microglia / metabolism
Models, Molecular
Molecular Structure
Nitric Oxide / antagonists & inhibitors*
Nitric Oxide / biosynthesis
Structure-Activity Relationship

Substances

Cholestanones
Lipopolysaccharides
Nitric Oxide