Accessible Method for the Development of Novel Sterol Analogues with Dipeptide-like Side Chains That Act as Neuroinflammation Inhibitors

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• 作者：Hongli Chen ; Chaojun Han ; Jing Wu ; Xiaoyu Liu ; Yuexiong Zhan ; Jiakang Chen ; Yanke Chen ; Ruinan Gu ; Li Zhang ; Shuangshuang Chen ; Jia Jia ; Xuechu Zhen ; Long Tai Zheng ; Biao Jiang
• 刊名：ACS Chemical Neuroscience
• 出版年：2016
• 出版时间：March 16, 2016
• 年：2016
• 卷：7
• 期：3
• 页码：305-315
• 全文大小：639K
• ISSN：1948-7193

文摘

A number of novel sterol derivatives with dipeptide-like side chains were synthesized using an Ugi four-component condensation method and assayed to test their anti-inflammatory effects in activated microglial cells. Compound 18b ((3S,10R,13S)-N-((R)-1-(tert-butylamino)-1-oxo-3-phenylpropan-2-yl)-3-hydroxy-N,10,13-trimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide) was identified as the most potent anti-inflammatory agent in the series of compounds analyzed. Compound 18b markedly inhibited the expression of proinflammatory factors, including inducible nitric oxide synthase, interleukin (IL)-6, IL-1β, tumor necrosis factor-α, and cyclooxygenase-2 in lipopolysaccharide-stimulated microglial cells. Further studies showed that compound 18b significantly suppressed the transcriptional activity of AP-1 and NF-κB in activated microglial cells, which was likely mediated by the inhibition of the p38 MAPK and JNK signal transduction pathways. In addition, compound 18b displayed neuroprotective effects in a microglial-conditioned medium/neuron coculture and an experimental focal ischemic mouse model.