title: Design, synthesis and biological evaluation of tricyclic diterpene derivatives as novel neuroprotective agents against ischemic brain injury.
abstract: Lead compound 7 has neuroprotective effects, and it was discovered by screening a small synthetic natural product-like (NPL) library. Based on the lead, a series of tricyclic diterpene derivatives was designed and synthesized, and their neuroprotective effects were further evaluated against glutamate-, oxygen and glucose deprivation (OGD)- and nutrient deprivation-induced neuronal injury using cell-based assays. To our delight, most of these synthetic compounds exhibited increased neuroprotective effects and blood-brain barrier (BBB) permeability without cellular toxicity. The most potent compound, compound 30, showed significantly improved neuroprotection against neuronal injury in primary neurons. Furthermore, compound 30 exhibited remarkable neuroprotection in transient middle cerebral artery occlusion (tMCAO) rats by reducing their infarct sizes and neurological deficit scores. A mechanistic exploration using in vitro and in vivo experiments showed that the neuroprotection of these compounds was at least partly mediated by improving the levels of glutathione (GSH), superoxide dismutase (SOD) and heme oxygenase-1 (HO-1) protein. Therefore, these tricyclic diterpene derivatives could be used as promising leads for the development of a new type of neuroprotective agents against ischemic brain injury.
authors.affiliation: Department of Chemistry, School of Chemistry and Molecular Engineering, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Yuan-Xue
authors.initials: YX
authors.lastname: Gao
authors.affiliation: Department of Chemistry, School of Chemistry and Molecular Engineering, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Ya-Zhou
authors.initials: YZ
authors.lastname: Xu
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Yun-Jie
authors.initials: YJ
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Sai
authors.initials: S
authors.lastname: Chang
authors.affiliation: Department of Chemistry, School of Chemistry and Molecular Engineering, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
authors.forename: Li-Gang
authors.initials: LG
authors.lastname: Yu
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Lu-Yong
authors.initials: LY
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liao
authors.affiliation: Department of Chemistry, School of Chemistry and Molecular Engineering, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
authors.forename: Lian-Fang
authors.initials: LF
authors.lastname: Yang
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: tpang@cpu.edu.cn.
authors.forename: Tao
authors.initials: T
authors.lastname: Pang
authors.affiliation: Department of Chemistry, School of Chemistry and Molecular Engineering, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China. Electronic address: wwqiu@chem.ecnu.edu.cn.
authors.forename: Wen-Wei
authors.initials: WW
authors.lastname: Qiu
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000139:chemically induced / Q000188:drug therapy*; D002470:Cell Survival / Q000187:drug effects; D004224:Diterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D018698:Glutamic Acid / Q000378:metabolism; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D004224:Diterpenes; D018696:Neuroprotective Agents; D018698:Glutamic Acid
keywords: Diterpenoids; Glutamate; Ischemic stroke; Neuroprotection; Nutrient deprivation; Oxygen–glucose deprivation