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

作者：Chen, Hongli^*; Han, Chaojun; Wu, Jing; Liu, Xiaoyu; Zhan, Yuexiong; Chen, Jiakang; Chen, Yanke; Gu, Ruinan; Zhang, Li; Chen, Shuangshuang; Jia, Jia; Zhen, Xuechu; Zheng, Long Tai^*; Jiang, Biao^*

来源：ACS Chemical Neuroscience, 2016, 7(3): 305-315.

DOI：10.1021/acschemneuro.5b00256

• Ugi four-component condensation
• microglia
• neuroinflammation
• neuroprotection
• focal ischemic mouse model

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-y1)-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-1 beta, tumor necrosis factor-alpha, and cyclooxygenase-2 in lipopolysaccharide-stimulated microglial cells. Further studies showed that compound 18b significantly suppressed the transcriptional activity of AP-1 and NF-kappa B 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.

• 出版日期2016-3
• 单位苏州大学; 上海科技大学