title: Accessible Method for the Development of Novel Sterol Analogues with Dipeptide-like Side Chains That Act as Neuroinflammation Inhibitors.
abstract: 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.
authors.affiliation: Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University , Shanghai 201210, China.
authors.forename: Hongli
authors.initials: H
authors.lastname: Chen
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University , Suzhou, Jiangsu 215021, China.
authors.forename: Chaojun
authors.initials: C
authors.lastname: Han
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University , Suzhou, Jiangsu 215021, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University , Shanghai 201210, China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University , Shanghai 201210, China.
authors.forename: Yuexiong
authors.initials: Y
authors.lastname: Zhan
authors.affiliation: Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University , Shanghai 201210, China.
authors.forename: Jiakang
authors.initials: J
authors.lastname: Chen
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University , Suzhou, Jiangsu 215021, China.
authors.forename: Yanke
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University , Suzhou, Jiangsu 215021, China.
authors.forename: Ruinan
authors.initials: R
authors.lastname: Gu
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University , Suzhou, Jiangsu 215021, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University , Suzhou, Jiangsu 215021, China.
authors.forename: Shuangshuang
authors.initials: S
authors.lastname: Chen
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University , Suzhou, Jiangsu 215021, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Jia
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University , Suzhou, Jiangsu 215021, China.
authors.forename: Xuechu
authors.initials: X
authors.lastname: Zhen
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University , Suzhou, Jiangsu 215021, China.
authors.forename: Long Tai
authors.initials: LT
authors.lastname: Zheng
authors.affiliation: Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University , Shanghai 201210, China.
authors.forename: Biao
authors.initials: B
authors.lastname: Jiang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D018920:Coculture Techniques; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D002546:Ischemic Attack, Transient / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D013261:Sterols
chemical_list: D000893:Anti-Inflammatory Agents; D018696:Neuroprotective Agents; D013261:Sterols
keywords: Ugi four-component condensation; focal ischemic mouse model; microglia; neuroinflammation; neuroprotection